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Electrical activity in the hippocampal formation of the rat : role of ascending monoamine-containing… Assaf, Souhile Y. 1978

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ELECTRICAL ACTIVITY IN THE HIPPOCAMPAL FORMATION OF THE RAT:  ROLE OF ASCENDING MONOAMINE-CONTAINING  SYSTEMS.  by  SOUHILE Y. ASSAF B.Sc,  U n i v e r s i t y o f Western O n t a r i o , 1974  M.Sc,  U n i v e r s i t y of Western O n t a r i o , 1975  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF • DOCTOR OF PHILOSOPHY  in THE  FACULTY OF GRADUATE STUDIES  (Department o f P h y s i o l o g y )  We accept  t h i s t h e s i s as conforming  to the r e q u i r e d s t a n d a r d  THE UNIVERSITY OF BRITISH COLUMBIA September, 1978  (c)  S o u h i l e Y. A s s a f , 1978  In p r e s e n t i n g t h i s  thesis  in p a r t i a l  f u l f i l m e n t o f the requirements f o r  an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, the L i b r a r y s h a l l I  f u r t h e r agree  make it  freely available  that permission  for  I agree  r e f e r e n c e and  f o r e x t e n s i v e copying o f  this  that  study. thesis  f o r s c h o l a r l y purposes may be granted by the Head of my Department or by h i s of  this  representatives. thesis  It  is understood that copying or p u b l i c a t i o n  f o r f i n a n c i a l gain s h a l l  written permission.  Department of The U n i v e r s i t y o f B r i t i s h 2075 Wesbrook P l a c e V a n c o u v e r , Canada V6T 1W5  Date  Columbia  not be allowed without my  ABSTRACT The  effects of e l e c t r i c a l  stimulation  c o n t a i n i n g n u c l e i , t h e median r a p h e ( L C ) , on e x t r a c e l l u l a r l y r e c o r d e d were  studied  observations systems  in  urethane  suggested  originating  in  r h y t h m i c a l slow a c t i v i t y and/or  the  population  of t h e p e r f o r a n t  path  and  LC,  (RSA) r e c o r d e d  The f o l l o w i n g  and  noradrenergic  in  the  supporting  hippocampal a c t i v i t y  modulate  dentate  gyrus  cells to stimulation  (PP) i n p u t , i n the  t o the bursting discharge  thereby  activty  rats.  dentate  the  gyrus  pattern of medial  neurones. E l e c t r o l y t i c o r k a i n a t e l e s i o n s o f RSA  coeruleus  respectively,  response of granule  1. RSA (3-7 Hz,) r e c o r d e d related  monoamine-  hippocampal e l e c t r i c a l  serotonergic  MR  the  (MR) a n d t h e l o c u s  anaesthetized  that  of  the  conclusion  was i n i t i a t e d  (DG)  was  septal  (MS)  MS  abolished  that  rhythmical  by MS n e u r o n e s . ,  2. S t i m u l a t i o n o f MR r e s u l t e d i n d i s r u p t i o n o f t h e b u r s t i n g discharge of  o f MS n e u r o n e s and d e s y n c h r o n i z a t i o n  forebrain  serotonin  chlorophenylalanine guipazine of  MR  following  (p-CPA)  o f RSA.  pretreatment  eliminated  these  with  These  data  confirmed  that  the  MS and d e s y n c h r o n i z a t i o n 3.  LC  effects  o f hippocampal e l e c t r i c a l  discharge activity.  s t i m u l a t i o n e v o k e d RSA. I n t r a c e r e b r a l i n j e c t i o n s o f  6-hydroxydopamine noradrenaline  while  a serotonin-  c o n t a i n i n g system mediates t h e d i s r u p t i o n of b u r s t i n g in  para-  responses  (1 mg/kg), a s e r o t o n i n a g o n i s t , m i m i c k e d  stimulation.  Depletion  (6-OHDA)  which  depleted  hippocampal  (NA) d i d n o t e l i m i n a t e t h i s r e s p o n s e . I n a d d i t i o n ,  i i i  electrolytic suggested  l e s i o n s of t h e LC that  formation  are  not  d i d not  eliminate  NA-containing  afferents  essential for  the  to  RSA. the  generation  These  data  hippocampal  of  rhythmical  activity, 4. the  Stimulation  d e n d r i t i c l a y e r o f DG  granule c e l l increased PP  of the  synaptic blocked  a m p l i t u d e of t h e  p o t e n t i a l . The p-CPA and  r e s p o n s i v e n e s s of The  and  LC,  synaptic to the  potential  indicated  that  discharge  On  or  e v o k e d by  and  LC  of  stimulation  specifically  LC  a test  amplitude or r a t e of r i s e  nuclei  the were  that  these  influenced  the  cells,  that changes i n the  via  occur i n  the  absence  were c o n f i r m e d u s i n g the  commissural  extrinsic  of a p o p u l a t i o n  amplitude  of  the  afferents of  granule  of  changes  in  the  an a d d i t i o n a l a f f e r e n t  projection. to  DG  may  cells  These  data  potentiate  without  the  enhancing  potentials. the  basis  pharmacologically and  spike  ME  the  s u c h as t h o s e o b s e r v e d f o l l o w i n g s t i m u l a t i o n  could  dentate  synaptic  population  dentate granule  spike,  recorded i n  6-0HDA, r e s p e c t i v e l y , s u g g e s t i n g  observations  population  spikes  potentials i n  s t i m u l a t i o n of  e f f e c t s o f MR  monoamine-containing  o f MR  population  without a l t e r i n g the  by  5.  and  body l a y e r . C o n d i t i o n i n g  the  pulse  PP r e s u l t e d i n s y n a p t i c  LC  formation.  of  the  distinct  modulate  above  data,  n e u r o n a l systems  electrical  activity  i t was  concluded  originating in  the  in  that MR  hippocampal  TABLE 01 -CONTENTS C e r t i f i c a t e Of E x a m i n a t i o n  ........................  i  A b s t r a c t .......................................... Table  i  i  of contents................................,.  iv  A c k n o w l e d g e m e n t s .............................. ...  x i i  Table List  Of E g u i v a l e n t s And A b b r e v i a t i o n s ............. x i v Of T a b l e s  ..............................,  xvi  L i s t Of F i g u r e s ...................................  xvii  1 0_Introduction A  1.1.  ..................................  R e v i e w Of The L i t e r a t u r e  ...................... .  1.1.1 The H i p p o c a m p a l F o r m a t i o n  5  ................... 5  M a j o r A f f e r e n t s ............................... a. T h e P e r f o r a n t P a t h  1  ......................  b. C o m m i s s u r a l / A s s o c i a t i o n a l  System  8 8  ........ 11  c.  Septal-Hippocampal P r o j e c t i o n  ........... 12  d.  Monoamine P a t h w a y s ...................... 18  M a j o r H i p p o c a m p a l E f f e r e n t s ................... a. F i m b r i a - F o r n i x S y s t e m Plasticity  Of  Synaptic  26  Transmission  Hippocampal Formation  24  In  The  ......................  27  1.1.2 T h e S e p t a l A r e a ............................  30  M a j o r A f f e r e n t s ............................... 32 a. H i p p o c a m p a l I n p u t s b.  . .... .................  Hypothalamic Inputs  c. A m y g d a l o i d I n p u t s  32  ..................... 34  .. .................. ... 35  d. Monoamine P a t h w a y s ....................... 35 1.1.3  Rhythmical  Activity  In  The  Septal-  H i p p o c a m p a l A x i s ...............................  40  Spontaneous  P a t t e r n s Of H i p p o c a m p a l  Activity  Electrical  .................. ................. 41  S o u r c e s Of BSA ................................ 42 Role  Of A s c e n d i n g S y s t e m s I n The G e n e r a t i o n  Of  HS A ........................................ Role  Of  The  S e p t a l A r e a I n The G e n e r a t i o n  44  Of  R SA ........... ....«.•.........*...........* . 47 Role  Of P h a r m a c o l o g i c a l l y  Distinct  Systems  The C o n t r o l Of S e p t a l - H i p p o c a m p a l A c t i v i t y a. A c e t y c h o l i n e b.  In . 49  ....................,........  Noradrenaline  49  ........................... 52  c . Dopamine  53  d. . S e r o t o n i n  54  e. O t h e r T r a n s m i t t e r s Relationship  ...................... 55  Of S e p t a l And H i p p o c a m p a l  Activity  To B e h a v i o u r ............................... 56 1.2 The P r e s e n t  S t u d y ............................ 61  0 Gen e r a l Met ho ds .....,. ......*.....•..•..•.• • • .. . 6 3 2.1 S u r g i c a l P r e p a r a t i o n :  ........................ 63  2.2 S t i m u l a t i n g And R e c o r d i n g Single Unit A c t i v i t y Electrical  P r o c e d u r e s ......... 64  And E v o k e d P o t e n t i a l s .,..,65  Activity  Of  The  Hippocampal  F o r m a t i o n .................................. 2.3 D a t a A n a l y s i s : Single Unit  Activity  Evoked F i e l d s Rhythmical  67 69  .......................... 69  • • • • . « . . . . . * . . . . . . . . . . . . . . . . . , . • . 71  Electrical Activity  74  2. 4 L e s i o n i n g T e c h n i q u e s ......................... 75  vi  Electrolytic  Lesions  A c u t e And C h r o n i c  ..........................  ................ 7 6  Transections  Neurochemical Lesions  76  .........................  78  2.5  N e u r o c h e m i c a l A s s a y s ......................... 8 0  2.6  H i s t o l o g i c a l A n a l y s i s ........................ 8 1  Chapter Of  3:„ B o l e , O f The Septal^Area^In... The  Generatjog  ....,...........  H i p p o c a m p a l Electr^.gaj.^;A-cti,vity  82  3. 1 Introduction 3.2  Experimental  3.3  Results  82 83  Procedures  84  Spontaneous  Electrical  Activity  Of  The  H i p p o c a m p u s And The D e n t a t e G y r u s .......... 8 4 Septal  Unit  Activity  Hippocampal  Response  Electrolytic Septal  Area  Septal  Neurones  Chapter  4_JL  Of T h e  In  The  . . . . . . , , * . . . . . . . . . . . , , . . . . . . . . . . . . . 11 5  Neurones  C o r r e l a t i o n s With Morphological  3*5 SuHInicizry  After  ......................... 1 0 9  D i s c h a r g e P a t t e r n Of S e p t a l  Regulation  90  ................................101  Forebrain  Discussion  3.4  Patterns  And K a i n i c a c i d L e s i o n s  D i s c h a r g e P a t t e r n Of Isolated  .....,-....................  . . . . . . . . . . 1 1 5  Studies  Of H i p p o c a m p a l A c t i v i t y  ....... 1 1 6  ..,...,..,..117  •••*••#*•••»•*•••#»•#•»••*•••*•••»*••# ^19 Role__Qf_A_Ra£he-sero  C o n t r o l .Of S e p t a l 4.1  Introduction  4.2  Experimental  4.3  Besults  Hippocampal A c t i v i t y - . . . . . . . . . . . 1 2 3 •**,,*123  Procedures  124  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 6  vii  R e s p o n s e Of I - N e u r o n e s To Raphe S t i m u l a t i o n  ...126  R e s p o n s e Of B - n e u r o n e s  ...132  Effect  Of  Raphe  Electrical Effects  To Raphe S t i m u l a t i o n  Stimulation  Hippocampal  Activity  Of  135  p - c h l o r o p h e n y l a n i n e On  Hippocampal A c t i v i t y Effects  On  Of  Septal-  ....................... 140  Quipazine  On  Septal-Hippocampa1  Activity., Effects  Of  142 5 - h y d r o x y t r y p t o p h a n On  Electrical 4.4 D i s c u s s i o n  Activity  Hippocampal  ........................ 145  .................. ................. 148  E f f e c t Of MR S t i m u l a t i o n 0 B I - n e u r o n e s . E f f e c t O f MR S t i m u l a t i o n Regulation  On B - n e u r o n e s  Of H i p p o c a m p a l  P o s s i b l e R o l e Of S e r o t o n i n  Activity  .......148 ........149  ............ 150  .................... 151  4.5 Sum mary .......,.............................. 154 Chapter  5: — T h e •. - D o r s a l  Noradrenergic  Hippocampal E l e c t r i c a l A c t i v i t y 5.1 I n t r o d u c t i o n  .................. 157  ......................158  ........... ........................... 159  Spontaneous  And  Sensory  Electrical Activity. Effect  And  ................................... 157  5.2 E x p e r i m e n t a l P r o c e d u r e s 5.3 R e s u l t s  System  Of  LC  Evoked  Patterns  Of  ......................,159  Stimulation  On  Hippocampal  Activity. Effects  Of  164 6-OHDA  Stimulation  On  RSA  Initiated  By  LC  .................... ........,..,169  E f f e c t s Of Amphetamine  ,.....,,..,.,,..,,,..,,,172  5. 5 D i s c u s s i o n ...................................177 Does The D o r s a l NA B u n d l e U n d e r l y R SA ? .......177 A c t i o n Of Amphetamine ......................... 179 P o s s i b l e C o n t r i b u t i o n O f U r e t h a n e A n a e s t h e s i a .180 5.5 Summary Chapter  .....181  6: C h a r a c t e r i z a t i o n Of  dentate Projection  The  Perforant  Path-  ............................... 182  6.1 I n t r o d u c t i o n 6.2  182  E x p e r i m e n t a l P r o c e d u r e s ......................187  6. 3 R e s u l t s  .188  I d e n t i f i c a t i o n Of Dentate Responses.  .......... 193  a. M o l e c u l a r L a y e r .......* b. C e l l  Layer  ......193  ..............................201  c. S i n g l e O n i t D i s c h a r g e ...................220 P o t e n t i a t i o n Of D e n t a t e E x t r a c e l l u l a r  Responses  ........................ 230 a. P o p u l a t i o n EPSP .........................230 b. P o p u l a t i o n  Spike  c. S i n g l e U n i t  236  D i s c h a r g e ................... 241  6.4 D i s c u s s i o n Field The  ... 244  Analysis  O f The P e r f o r a n t P a t h I n p u t To  D e n t a t e G y r u s ..........................244  R e s p o n s e Of S p o n t a n e o u s l y F i r i n g  G-cells.  .....248  P o t e n t i a t i o n Of T h e E x t r a c e l l u l a r EPSP ........ 251 P o t e n t i a t i o n Of The P o p u l a t i o n QhSLR%SS.JI±^.  Neurona 1  ,Transmission  G y r u s : R o l e Of The C o m m i s s u r a l 7.1 I n t r o d u c t i o n  :  S p i k e ..........252 I n The - D e n t a t e ;  I n p u t ............. 256  •*.... ............... , . - . . . * . , . . 256  ix  7.2 Experimental Procedures. ..................... 257 7. 3 Results  258  I d e n t i f i c a t i o n Of The Dentate Responses .......261 a. Molecular Layer ......................... 2 6 1 B. G - c e l l Layer ............................ 273 c. S i n g l e Unit  Discharge ...................277  O r i g i n Of The Commissural Pathway. ............ 286 E f f e c t s Of Commissural S t i m u l a t i o n On PP-evoked Responses .................................. 287 7.U  Discussion Field  .............................,.....298  A n a l y s i s Of The Commissural Input To The  Dentate  ....................................298  E f f e c t Of Commissural S t i m u l a t i o n On PP Responses  Evoked  ............303  7. 5 Summary .. .... Chap.ter  305  8 _i_ _ T he , Rap he- s er o ton i n S y stem •• An d - N eurona .1 ai  Transmission I n The Dentate Gyrus ......,,......••306 8.1 I n t r o d u c t i o n .................................306 8.2 Experimental Procedures  .....307  8.3 Results ...................................... 308 E f f e c t s Of MR S t i m u l a t i o n Effects  Of  MB  On G - c e l l s ........,.308  Stimulation  On  PP-evoked  Responses .................................. 313 Relationship  Between E f f e c t s Of MR  Stimulation  On P o p u l a t i o n Spike And I n h i b i t i o n Of S i n g l e Onits. Effects  .....................................320 Of  p-CPA  S t i m u l a t i o n Of MR  On  Respones  Evoked  By 323  X  8. 1 D i s c u s s i o n Effects  *..325  Of  MB  Stimulation  On  Spontaneous  D i s c h a r g e Of G - c e l l s Effects  Of  MB  327  Stimulation  On  PP-evoked  Responses Relationship  32 8  Between  Inhibition  P o t e n t i a t i o n Of The P o p u l a t i o n  Of  G - c e l l s And  Spike  Role For Serotonin:  ..........329  ...............329  8.5 Summary .......................... ............ 331 Chapter  9:.  The_  L.ocus„_ -Coeruleus ,  And , , N e u r o n a l  i  T r a n s m i s s i o n . I n , The D e n t a t e G y r u s 9.1 I n t r o d u c t i o n  ................332  ................................. 332  9.2 E x p e r i m e n t a l P r o c e d u r e s  ...33 3  9.3 R e s u l t s  ....333  E f f e c t s Of LC S t i m u l a t i o n On D e n t a t e C e l l s Effect  Of  LC  Stimulation  Responses. Effects  Of  Effects  Field  .................................338 6-OHDA  Lesions  N o r a d r e n e r g i c Pathway 9.4 D i s c u s s i o n  On P P - e v o k e d  ...,333  Of  The  Dorsal  ...................... 345  .................••................346  Of LC S t i m u l a t i o n  On G - c e l l D i s c h a r g e .346  E f f e c t Of LC S t i m u l a t i o n On P P - e v o k e d  Responses  ....................................34 8 9.5 Summary  ................................ .....,349  C h a p t e r 10; G e n e r a l 10,1  Discussion-......................350  Patterns  Activity  Of  Hippocampal  Electrical  .................. .. ..... • . .. ....... .351  10.2 The S i g n i f i c a n c e Of H i p p o c a m p a l  Population  xi  Responses 10.3  Rhythmical  ...... .. Activity  .......354 And  Neuronal  Transmission In the Dentate Gyrus References  358  .......... • . 363  V i t a ................................................400  xii  ACKNOWLEDGEMENTS The a u t h o r following during  appreciates preparation  the assistance of this thesis;  provided  by t h e  Dr.  J . J . M i l l e r f o r t h e s u p e r v i s i o n , c r i t i c i s i m s and a s s i s t a n c e t h a t he p r o v i d e d t h r o u g h o u t t h e r e s e a r c h .  Mrs.  H e l e n B r a n d e j s who p r o v i d e d e x c e l l e n t t e c h n i c a l a s s i s t a n c e at a l l s t a g e s o f t h e e x p e r i m e n t s and i n p a r t i c u l a r t h e spectrofluorometric assays.  Mr.  Tom R i c h a r d s o n f o r t h e f i l e s and computer a n a l y s i s p o s s i b l e .  Mrs. Ms.  Margaret Stuerzl noradrenaline.  which  Smith f o r t h e radioenzymatic  L i z . Barbour f o r a s s i s t a n c e i n t h e experiments C h a p t e r 5.  Messrs Dr.  devices  made t h e assays f o r  reported  in  Kurt Henze a n d R a l p h A s s i n a for reproduction of the i l l u s t r a t i o n s and t h e i r generous t e c h n i c a l a s s i s t a n c e .  S t e p h e n Mason f o r p r o v i d i n g some o f t h e l e s i o n e d i n C h a p t e r 9 and f o r r e a d i n g t h e t h e s i s .  rats  used  Drs.  F. L i o y , H. McLennan And P, Vaughan f o r m e d my a d v i s o r y c o m m i t t e e and r e a d t h e t h e s i s ,  Drs.  H,C. F i b i g e r , J.A, P e a r s o n And A.G. P h i l l i p s f o r answering a l o t o f g u e s t i o n s and p r o v i d i n g s u p p l i e s a n d f a c i l i t i e s whenever r e g u i r e d .  Mr.  H a r r y Kohne a n d D e p a r t m e n t o f P h y s i o l o g y f o r b u i l d i n g c r u c i a l hardware.  Messrs  P h i l H i c k s , Don R u t h e r f o r d , Ron S k e l t o n , J o h n W i l c o x a n d Dr. Neil McNaughton f o r reading early drafts of the t h e s i s and p r o v i d i n g v a l u a b l e d i s c u s s i o n s .  Mrs. . Hary F o r s y t h And Mr. James secretarial assistance. The  technical staff  Loo  R e s e a r c h Was F u n d e d By MRC Of Canada.  f o r typographical  and  DECLARATION The Sept.  data  presented  were  obtained  between Sept,  1975 a n d  1978 when t h e a u t h o r was i n t r a i n i n g i n t h e D e p a r t m e n t  Physiology,  University  o f B r i t i s h Columbia.  Becords  which  i l l u s t r a t e c e r t a i n o b s e r v a t i o n s were s e l e c t e d . P o l y g r a p h but  not o s c i l l o s c o p e  reproduced  photographs  or  computer  plots  of  best  records were  by t h e I n s t r u c t i o n a l M e d i a C e n t r e a t U.B.C. And were  r e t o u c h e d a t t h e i r d i s c r e t i o n where n e c e s s a r y . The  t e x t o f t h e t h e s i s was composed u s i n g FMT  s o f t w a r e a v a i l a b l e on t h e U.B.C. c o m p u t i n g  system.  documentation  xiv  l i l k E OF EQUIVALENTS AND  ABBREVIATIONS  Eg.ivalents h i p p o c a m p u s = amnions h o r n = h i p p o c a m p a l f i e l d s dentate  gyrus = f a s c i a dentata =  dentate  hippocampal f o r m a t i o n = hippocampus + dentate potentiation  = f a c i l i t a t i o n = enhancement  Ef§Suently Osed AP B-neurone  gyrus  of test  responses  Abbreviations  anterior-posterior  stereotaxic  co-ordinate  s e p t a l neurone which d i s c h a r g e s  CNS  c e n t r a l nervous system  COMM  hippocampal commissural  DA  dopamine  DO  dentate  EC  entorhinal  cortex  EPSP  excitatory  postsynaptic potential  G-cell  dentate  HRP  horseradish  I-neurone  CA1-4  i n bursts  pathway  gyrus  granule  cell  peroxidase  s e p t a l neurone d i s p l a y i n g  L  medial-lateral  LC  locus  MF  mossy f i b r e  MS  medial  MR  median r a p h e  NA  noradrenaline  PP  perforant  RSA  r h y t h m i c a l slow  stereotaxic  irregular  co-ordinate  coeruleus pathway  septal  nucleus nucleus (norepinephrine)  path activity  discharge  XV  p-CPA  p-chlorophenylalanine  5- .HT  5-hydroxytryptan.ine  6- OHDA  6-hydroxydopamine  (serotonin)  xvi  L I S T OP TABLES  T a b l e I : Comparison Of S e p t a l Neurones I n f l u e n c e d Stimulation  By MR  I n C o n t r o l And p - C P A - T r e a t e d  Rats.,,,....................................... 139  T a b l e I I : E f f e c t s Of C o n d i t i o n i n g Commissural Pathway  S t i m u l a t i o n Of The  On P P - e v o k e d  Population  S p i k e s . . ........ .........................,,, 290  T a b l e I I I : E f f e c t s Of p-CPA On H i p p o c a m p a l 5-HT And R e s p o n s e s To S t i m u l a t i o n Of The M e d i a n Raphe.  326  xvii  Fig.  1- 1: Drawing Of The I n t r i n s i c  Synaptic  O r g a n i z a t i o n Of The Hippocampal Formation..... 8  Fig.  2- 1: Schematic I l l u s t r a t i o n Of E x t r a c e l l u l a r Recording Technique.  Fig.  2- 2: Measurements  ................69  Of Amplitudes And Sate Of Rise  Of Evoked F i e l d P o t e n t i a l s . . . . . . . . . . . . . . . . . . . . 73  Fig.  3 - 1 : Patterns Of E l e c t r i c a l A c t i v i t y  Recorded  From The Dentate Gyrus Of A Urethans A n a e s t h e t i z e d Rat.  Fig,  ................86  3- 2: L o c a t i o n Of Recording E l e c t r o d e I n The Dentate Gyrus,••«..••..»«.<•••...........,,,.. 89  Fig.  3- 3: D i f f e r e n c e s In The Discharge P a t t e r n s Of S e p t a l Neurones Recorded During Rhythmical Or Desynchronized Hippocampal A c t i v i t y . . . . . . . . 92  Fig.  3- 4: L o c a l i z a t i o n Of B-neurones In The S e p t a l A r e a . . . . . . . a , . . . ' , , , . . . * . . . . . . . » * . * , , ' « . , # * , , , ,.94  xviii  Fig.  3-  5:  C h a r a c t e r i s t i c s Of  Fig,  3-  6:  Bursting Discharge Pattern Neurones F o l l o w i n g  Fig,  3-  7:  E f f e c t s Of Of The  A S e p t a l B-neurone.........  Of  Septal  H i p p o c a m p a l S t i m u l a t i o n . . . . 100  Electrolytic  S e p t a l A r e a On  And  Kainate  Lesions  Hippocampal  Electrical Activity,  Fig.  3-  8:  Extent  Of  Lesions  Fig,  3-  9:  3-11:  3-12:  Kainic-induced 106  Neuronal Degeneration Following  Discharge Patterns I n The  Fig.  And  S e p t a l Area.  I n j e c t i o n s I n t o The  Fig.  ...103  Electrolytic  I n The  Deafferented  Of  Septal  ....108  Neuronas  Forebrain.................  R e l a t i o n s h i p B e t w e e n The The  Kainic  S e p t a l Area.  S c h e m a t i c I l l u s t r a t i o n Of The  A r e a And  97  114  Proposed  Brainstem,  Septal  H i p p o c a m p a l F o r m a t i o n . . . . . . . . . . . . 121  xix  Fig.  4 - 1 : Response  O f S e p t a l I - n e u r o n e s To Raphe  Stimulation.  Fig.  .128  4- 2: L o c a l i z a t i o n Of S t i m u l a t i n g E l e c t r o d e s I n The  R e g i o n O f T h e Raphe And The  C o r r e s p o n d i n g Response  Fig.  4- 3: C h a r a c t e r i s t i c s Of A B-neurone Single Pulse  Fig.  During  S t i m u l a t i o n Of M R . . . . . . . . . . . 134  4- 4: E f f e c t s O f R e p e t i t i v e MB S t i m u l a t i o n Bursting Control  Fig.  Of I - n e u r o n e s . . . . . . . . . . 131  On The  D i s c h a r g e P a t t e r n Of B - n e u r o n e s I n And p-CPA T r e a t e d R a t s . . . . . . . . . . . . . . . .  137  4- 5: E f f e c t s O f R e p e t i t i v e MR S t i m u l a t i o n On Hippocampal E l e c t r i c a l A c t i v i t y I n C o n t r o l And p-CPA T r e a t e d r a t s . . . . . . . . . . . . . . . . . . . . . . . 141  Fig.  4 - 6 : E f f e c t s O f Q u i p a z i n e On H i p p o c a m p a l Electrical  Fig.  Activity,.............,.....,.....,144  4- 7: E f f e c t s O f 5-HT On H i p p o c a m p a l  Electrical  Activity......................................  Fig.  4 - 8 : A Schematic I l l u s t r a t i o n Synaptic  Arrangements  147  Of The P r o p o s e d  Between The MR,  Septum, And H i p p o c a m p a l  Formation.............156  XX  Fig.  5- 1: R h y t h m i c a l E l e c t r i c a l  a c t i v i t y Recorded I n  The D e n t a t e G y r u s Of C o n t r o l And T r e a t e d R a t s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161  Fig.  5 - 2 : F r e g u e n c y Of S p o n t a n e o u s l y O c c u r r i n g A n d Elicited  Fig.,  RSA  163  5- 3: E f f e c t s Of S t i m u l a t i o n I n The R e g i o n Of The L o c u s C o e r u l e u s On E l e c t r i c a l A c t i v i t y Of The D e n t a t e G y r u s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167  Fig.  5- 4: L o c a t i o n Of S t i m u l a t i n g E l e c t r o d e s I n The R e g i o n Of LC And I n t e n s i t y T h r e s h o l d F o r The G e n e r a t i o n Of RSA........................ 171  Fig.... 5- 5: E l e c t r i c a l A c t i v i t y  R e c o r d e d I n The D e n t a t e  G y r u s Of A 6-OHDA T r e a t e d R a t . . . . . . . . . . . . . . . . 174  Fig.  5 - 6 : F r e g u e n c y Of RSA As A F u n c t i o n Of LC S t i m u l u s I n t e n s i t y I n C o n t r o l And 6-OHDA Lesioned Rats.  Fig,,  176  5 - 7 : E f f e c t s O f Amphetamine On E l e c t r i c a l Activity  Of The D e n t a t e G y r u s .  184  xxi  Fig.  6-  1: L a m i n a r O r g a n i z a t i o n Of A f f e r e n t s To  The  Dentate.  Fig.  6-2:  184  D e p t h P r o f i l e s Of The E v o k e d I n The  Field  Potentials  D e n t a t e G y r u s By A Weak  Perforant Path Volley  Fig.  6-3:  Field  Potentials  190  E v o k e d I n The  D e n t a t e By  PP S t i m u l a t i o n A t V a r i o u s I n t e n s i t i e s  Fig..  6- 4: I d e n t i f i c a t i o n Of The F i e l d Recorded  F i g . , 6-  5: R e l a t i o n s h i p  Fig.  6- 6: I d e n t i f i c a t i o n Of The At G - c e l l  6- 7: D e v e l o p m e n t Spike.  19 5  Between PP S t i m u l u s I n t e n s i t y  D e n d r i t i c R e g i o n Of The  Recorded  Potentials  I n The D e n t a t e M o l e c u l a r L a y e r . .  And A m p l i t u d e Of R e s p o n s e s  Fig.  19 2  Of The  Recorded  In  Dentate,  Evoked  The 197  Potential  Body L a y e r .  200  Dentate Population 20 3  xxii  Fig.  6-  8: E f f e c t s Of S t i m u l u s I n t e n s i t y And  Fig.  6-  9: The  L a t e n c y Of The  6-10:  Amplitude  G - c e l l Layer response  C e l l L a y e r Response Recorded  D e p t h s I n The  Fig.  On  At  Various  Dentate.  P r e s y n a p t i c And  20 5  20 8  P o s t s y n a p t i c Responses  F o l l o w i n g S t i m u l a t i o n Of The P e r f o r a n t Path.  Fig,  6-11:  210  A n t i d r o m i c And  Orthodromic  Activation  Of  Dentate Granule C e l l s .  Fig.  6-12:  213  Identification  Of The  Component (N3)  Recorded  Following  Late  Negative  I n The  Dentate  S t i m u l a t i o n Of The P e r f o r a n t  Path.  Fig.  6-13:  D i s c h a r g e P a t t e r n Of  Fig.  6-14:  The  216  Dentate Granule  R e s p o n s e Of An I d e n t i f i e d  G r a n u l e C e l l To S t i m u l a t i o n Of  6-15:  I d e n t i f i c a t i o n Of D e n t a t e  219  Dentate The  Perforant Path.  Fig,  Cells.  222  Neurones.,  224  xxiia  L e a f x x i i i does not  exist.  xxiv  Fig.  6-16:  Response  Of H i l a r  Stimulation  Neurones  Followinq  Of The P e r f o r a n t  P a t h And  The  Mossy F i b r e s .  Fig.  6-17:  Paired  227  Pulse Potentiation  Extracellular  Fig.  6-18:  Statistical  Fig.  6-19:  Paired-pulse  6-20:  6-21:  6-22:  7-  Of The  EPSP  Potentiation  238  Interpretation  Of The  Perforant  Responses  Perforant  Path.  243  Recorded I n 248  Potentials  D e n t a t e By S t i m u l a t i o n  P a t h And  240  Paired  PP S t i m u l a t i o n .  1: L a m i n a r P r o f i l e s Of The F i e l d I n The  Spike.  D i s c h a r g e By  Of The  Dentate Following  Evoked  Paired-  Of The P o p u l a t i o n  Of G - c e l l  232  And  S p i k e Response.,  E f f e c t s Of S t i m u l u s I n t e n s i t y On  The  Fig.  Of EPSP P o t e n t i a t i o n .  Potentiation  Pulse Stimulation  Fig.  229  Analysis  pulse Potentiation  Fig.  The  EPSP.  The P o p u l a t i o n Fig.  Of  Of  C o m m i s s u r a l Pathway.  The 260  XXV  Fig.,  7- 2: L a m i n a r P r o f i l e s Field  Stimulation  7- 4: F i e l d  Of The  7- 5; R e s p o n s e Neurones Perforant  7- 6:  Following  Responses  Evoked  S t i m u l a t i o n On  By A T e s t 289  Dentate  Granule C e l l s . ,  Fig.  8- 2: I n h i b i t i o n Of S p o n t a n e o u s l y F i r i n g Cells  By MR  Stimulation.  279  On  Path V o l l e y .  1: E f f e c t s Of MB  273  The  Input.  E f f e c t s Of C o m m i s s u r a l S t i m u l a t i o n  Perforant  The  Dentate  S t i m u l a t i o n Of  P a t h And C o m m i s s u r a l  266  Granule  P a t h And C o m m i s s u r a l P a t h w a y s .  Dentate F i e l d  8-  Following  S t i m u l a t i o n Of  Of S p o n t a n e o u s l y F i r i n g  264  Field  Dentate  P o t e n t i a l s R e c o r d e d I n The  Perforant  Fig.  Pathway.  C o m m i s s u r a l Pathway.  C e l l Layer Following  Fig,,  Of The COM  R e c o r d e d I n The  Stimulation  Fig.  Dentate  7- 3: C h a r a c t e r i s t i c s Of E a r l y And L a t e Responses  Fig.  Secondary  P o t e n t i a l s R e c o r d e d I n The  Following  Fig.  Of P r i m a r y And  310  Dentate 312  xxvi  Fig,,  8- 3: R e l a t i o n s h i p B e t w e e n I n h i b i t i o n Of C e l l s And P o s i t i o n Of The Electrode  Fig,  8-4:  Dentate  Stimulating  In The R e g i o n Of MR.  E f f e c t s Of MR  315  S t i m u l a t i o n On PP  Evoked  A c t i v a t i o n Of D e n t a t e C e l l s .  Fig,  8- 5: E f f e c t s Of MR C o n d i t i o n i n g F i e l d Responses  Evoked  317  Pulses  By The  On  The  Perforant  Path.  Fig.  319  8- 6: F a c i l i t a t i o n Response  Of The  Following  Population PP  And MR  Spike Conditioning  Pulses.  Fig.  8- 7: R e l a t i o n s h i p B e t w e e n I n h i b i t i o n Of And  Fig,  322  A m p l i t u d e Of The  Population  9- 1: E f f e c t s Of LC S t i m u l a t i o n On  G-cells  Spike.  Dentate  Neurones.  Fig.  9-  335  2: E f f e c t s Of LC S t i m u l a t i o n On Dentate Population  Fig.  9- 3: R e l a t i o n s h i p Pulses Spike.  325  PP-evoked  Responses.  340  Between The Number Of  And A m p l i t u d e Of The  LC  Population 342  xx v i i  Fig.  9-4:  Histological Localization  Of  Stimulation  E l e c t r o d e I n LC.  Fig.  9- 5; E f f e c t s Of  6-OHDA On  342. 1  The  Response To  LC  Stimulation.  Fig,  10-  1: P r o p o s e d  345  E x t r i n s i c I n f l u e n c e s On  T r a n s m i s s i o n I n The  Neuronal  Dentate Gyrus.  360  1  JL 0 IlJIROrjJLJGTIQN The foundations of contemporary based  on  composed  the of  electrical  assumption individual  activity  that  cells  that  generate  by chemical processes, i s  t r a n s m i t t e d t o adjacent neurones a t s p e c i a l i z e d called  'synapses'  Cajal,  1911;  Katz and K u f f l e r , now  firmly  extended  between view  of  the  of  and  somata  Eccles,  concepts  modes  chemical  dendrites,  1936;  these  new  regions  Sherrington,1906; Vogt,  1941) . /Although  including  this  1905;  Peldberg and  established,  organization junctions  (Langley,  Dale,  organization  are  synaptic electrical  and  nervous  axons have  system,  The  mechanisms by which i n f o r m a t i o n i s t r a n s m i t t e d from r e g i o n of the CNS  are  the nervous system i s  nerve  which,  neuroscience  one  t o another and the i n t r i n s i c s y n a p t i c  of the v a r i o u s n u c l e i are the concerns of  systems neurophysiology. The  methodology  parallelled  these  combination  of  anatomical  for  recording  intracellular  activity  has  developments  of  the  resulting  has in  a  pharmacological  waves  provided  role  and  single  cells  generated  by  extracellular combined populations  i n f o r m a t i o n about  o r g a n i z a t i o n of major neuronal understand  neurosciences  technigues. The use of m i c r o e l e c t r o d e s  a n a l y s i s of slow neurones  the  electrophysiological,  and  electrical  of  of  systems.  with of  the s y n a p t i c In  order  these systems i n the  to  overall  2  pattern must  of  be  brain  related  function  electrophysiological  to  a n a t o m i c a l and  both  data  biochemical  data. This  i n t e g r a t i v e approach i s p o s s i b l e i n t h e study  of t h e hippocampal f o r m a t i o n simple  and  well  defined  afferents terminate i n allowing  correlation  characteristic (Adey  which synaptic  discrete  a  organization. I t s  layers  or  features  of  i t s electrical  activity  Eccles  and  Loyning,  Lomo, 1 9 7 1 a ) . The  spontaneous  hippocampal activity  in the  (RSA;  theta  wave  patterns  particularly  hippocampus 1938;  and  Green  Gogolak,  spontaneous  patterns  characteristic  the  septal  of single area  potentiated to  transmission  units  (Jung  and  Spencer,  and  1962)., I n of  1961;  Petsche,  addition  to the  hippocampal  extracellular  field  activity,  potentials  Lomo, 1 9 7 1 a ) . T h e s e f i e l d  cortex  processes  associated  and s t o r a g e o f i n f o r m a t i o n  are (Gloor  responses are  by r e p e a t e d s t i m u l a t i o n and h a v e t h u s study  most  and A r d u i n i , 1 9 5 4 ; v o n E u l e r  e v o k e d by s t i m u l a t i o n o f t h e e n t o r h i n a l a l , 1964;  the slow  r h y t h m ) , have been s t u d i e d  and  G r e e n , 1960; K a n d e l  of  rhythmical  and r e l a t e d t o t h e a c t i v i t y  Kornmuller,  Stumpf  slow  formation,  extensively  used  subfields  a n d M e y e r , 1952; G r e e n and A r d u i n i , 1 9 5 4 ; G l o o r ,  1964;  et  relatively  of neuroanatomical data with the  V e r a a n d S p e r t i , 1964; A n d e r s e n ,  and  has  with (Lomo,  been  neuronal 197 1b;  3  Bliss  and  Loio,  1973;  Douglas  and  S t e w a r d , W h i t e , Cotman and L y n c h , Early  studies  electrical  have  activity  Goddard,  1975;  1976).  proposed  that  i s controlled  hippocampal  by n e u r o n a l s y s t e m s  o r i g i n a t i n g i n d i f f u s e regions of the brainstem and  Arduini,  1954). While the p r e c i s e n e u r o a n a t o m i c a l  and n e u r o c h e m i c a l o r i g i n s known,  the  technigues systems  (Green  recent for  has  of  these  systems  development  mapping  revealed  of  are  histochemical  pharmacologically that  receives direct serotonin-  distinct  the hippocampal  and  not  formation  noradrenaline-containing  p r o j e c t i o n s f r o m t h e m e d i a n r a p h e n u c l e u s and t h e l o c u s coeruleus, respectively T o r p , 1962; F u x e , Since  these  brainstem  regions  involved  1  1954;  The  present  1975). diffuse  cortical  and  ( M o r u z z i and Magoun, 1949;  Green  Lindsley,  1960) ,  they  may  be  monoamine  electrical  activity  recorded  in the  mechanisms  activity.  study  ascending  the  modulate  and  i n d e t e r m i n i n g t h e c h a r a c t e r i s t i c f e a t u r e s of  hippocampal e l e c t r i c a l  aim o f  Thieme  systems are w i t h i n the  which  'arousal  Arduini,  Hillarp,  1965; U n g e r s t e d t , 1971; H o o r e ,  monoamine  hippocampal and  (Falck,  examines  systems and  in  evoked  the the  role  of  the  c o n t r o l of slow  field  potentials  t h e h i p p o c a m p a l f o r m a t i o n o f t h e r a t . The experiments by  spontaneous  which  has  been  to  these extrinsic  patterns  of  delineate inputs  rhythmical  the  influence  hippocampal  4  activity  and  neuronal  transmission  e n t o r h i n a l c o r t e x and the d e n t a t e qyrus.  between  the  5  Ixli.-  THE  LITE8ATURE  H i £ £ C c a m p a l F o r m a t i on  Ji1..1 The The cortical  OF  hippocampal  formation  is  a  This  region  is  subdivided  hippocampus p r o p e r , t h e d e n t a t e gyrus the  s u b i c u l a r c o m p l e x . The  be f u r t h e r CA4)  subdivided into  i n which  (Lorente  de  No, 1934;  a curved  <CA1,  Both  the  granule c e l l s Fig.  1-1,  either  and  form  these  layers  bodies  dendrites  of  granule  cells  be  intrinsic  Golgi  type  formation. to II  the  addition  to  The  basket  CA4  cell  which cells. and  As  almost  dentate  shown  in  exclusively  Pyraraidale),  cell  is  the  O r i e n s , Radiatum bodies  or  the  (Stratum M o l e c u l a r e ) . In  p y r a m i d a l and  latter  hippocampal  (basket) c e l l s  n u m e r o u s p y r a m i d a l and  The  granule  t y p e s h a v i n g s h o r t axons can  hippocampal  cell  gyrus  {Stratum  granule  a d d i t i o n t o the l o n g axoned many c e l l  pyramidal  1956).  {Stratum  of pyramidal c e l l s  Lacunosum), dentate  and  layers.  contain  can  CA3  pyramidal c e l l s  well defined  pyramidal c e l l  dendrites  of dentate  hippocampal  Dentata)  CA2,  type i s the  Blackstad,  sheet  the  hippocampus proper  4 fields  the major c e l l  lateral  into  (Fascia  layer enters the h i l u s of the dentate f o r m e d by  shaped  area l y i n g adjacent t o the w a l l of the  ventricles.  and  horn  found  neurones,  cells  in  which  formation,  which  granule c e l l s  be  granule  the may  include  appear t o c o n t a c t (Cajal,  1968).  c e l l s there are several layers  In of  6  polymorphic pyramidal  cells cells  (Strata in  Polymorphe)  or  the dentate h i l u s  modified  ( L o r e n t e de No,  1934) . As shown i n F i g . 1 - 1 , t h e a x o n s form  the  mossy  fibre  d e n d r i t e s o f CA3 c e l l s and  Himer,  the f i m b r i a reach  the  cells  system  (Cajal,  granule  which  1968;  cells  contacts  Barber,  the  Vaughan  1 9 7 4 ) . The a x o n s o f CA3 c e l l s p r o j e c t i n t o giving basal  off  Schaeffer  dendrites  whose a x o n s ,  in  of  turn,  dentate  granule  a f f e c t CA3 and CA1 c e l l s  collaterals  CA1 and CA2  form  synaptic o r g a n i z a t i o n suggests influence  of  pyramidal  alveus.  This  t h a t any a f f e r e n t s  which  cells  along t h i s  the  which  would  tri-synaptic  The  precise laminar organization of this  will  become more a p p a r e n t  following  seguentially  an  loop.  neuronal  loop  examination  of  the a f f e r e n t s t o the hippocampal f o r m a t i o n .  H§-3°£ A f f e r e n t s  A A 1'iie Pg£f 2£ant P a t h The  major  afferent  f o r m a t i o n i s from perforant The  path  t h e e n t o r h i n a l c o r t e x b y way  (PP) f i b r e  anatomical  p r o j e c t i o n t o the hippocampal  studies  system of  of  PP  fibres  portion of the dentate  which  Hjorth-Simonsen  terminate  molecular  the  ( L o r e n t e de No, 193 4) .  demonstrate that t h e l a t e r a l e n t o r h i n a l r e g i o n source  of  in  (1973) i s the  the outer  l a y e r while the medial  7  1-  I i  of  Drawing  Organization  Of The  The  HipEOcamjaal  Aj, t r a n s v e r s e s e c t i o n l a y e r s CA1-CA4 and gyrus  (DG).  fibres  (MF)  from  CA3  and  showing  pyramidal  granule c e l l s i n the  which  project to  Schaeffer  CA3.  and  collaterals  cell  dentate mossy  Projections  various  surface  pyramidal  of  blade of the (HF)  CA1  dentate is  (Sch)  area onto  CA1.  Bjj, d e t a i l o f t h e  (1911).  Formatio|n  Axons o f g r a n u l e c e l l s f o r m  d e n d r i t e s o f CA2  figure  Sy.nap.tiS  are v i a the f i m b r i a to t h e s e p t a l  by  fissure  Intrinsic  the  layers  gyrus.  cell The  demarcation  i s m o d i f i e d from Green  from  dorsal  to the  lower  hippocampal zone.  (1964) and  This Cajal  B.  Alveus  I  ^  S  v s  Oriens Pyramidale  s.  As  Radiatum Lacunosum  HF  1/  Q MF  s  Moleculare  ~ " S."Granufosum S. Polymorphe  OO  9  entorhinal  region  gives  rise  to  PP  fibres  that  terminate i n the middle molecular l a y e r o f the dentate., Electron  microscopic  investigations  mode  termination  is  of  dendritic  spines  of  suggest that t h e  primarily  dentate  en  £§ssaae  granule c e l l s  onto  (Nafstad,  1967). These  anatomical  electrophysiological  data  have  analysis  been of  confirmed  field  by  potentials  r e c o r d e d i n t h e d e n t a t e f o l l o w i n g s t i m u l a t i o n o f t h e PP or  the  entorhinal  cortex  itself  (Gloor,  Sperti,  1964; Lomo, 1971a; S t e w a r d , H h i t e ,  Lynch,  1976).  extracellular of  single  excitatory cells.  The  potentials  unit PP  relationships  between  indicated  onto  The p o t e n c y o f t h i s  the input  a  and  C o t m a n , and  and i n t r a c e l l u l a r  activity input  Vera  these  recordings  monosynaptic  dendrites  of granule  i s reflected  by  the  synchronous a c t i v a t i o n o f a population  of g r a n u l e  cells  by  (Andersen,  Bliss  single pulse stimulation  and S k r e d e ,  1971).  Furthermore, the input is  o f t h e PP  organized  in parallel  f r o m t h e PP t o t h e s t r i p s or lamellae  stimulation  of a d i s c r e t e  cells  i n a t h i n band o f t i s s u e r o u g h l y  to  only the  longitudinal  (Lomo,1971a). it  part of  From  axis  recordings  appears that an a f f e r e n t  of g r a n u l e e e l s  within  a  PP  of  such  excites  the  that  granule transverse  hippocampus  of single unit  volley excites a lamella  dentate  (Andersen  activity population et a l .  10  1971;).  Andersen,  1975)., Following  the s i n g l e spike  a c t i v a t i o n of granule c e l l s produced by PP a long This and  period of i n h i b i t i o n i s recorded  stimulation,  (Lomo,  i n h i b i t i o n i s s i m i l a r to that reported Kandel  are  (1961) i n CA1  inhibited  previously described  in  a  by  later  postulated  to  result  mechanism  (Gloor,  1963;  of  whether  the  a  lesser  terminate i n  section, from  this  a  Hjorth-Simonsen,  1973)  Powell, 1965)  However,  the  lesions  of  degeneration  of  and  inhibition  is  inhibitory  PP  and  degeneration  fibres  Jeune,  the  the  in  1972;  (Baisman,  hippocampus., CA1  following  cortex  may  be  route  to  CA 3  en  to  f i b r e s are known to  p o s s i b l y i n CA1  entorhinal  of  be  projection  s u b f i e l d s of  sparse the  will  recurrent  (Hjort h-Simonsen  Cowan and  As  were  Andersen et a l , 1964).  number  CA3  Spencer  they  stimulus.  In a d d i t i o n to the massive PP dentate  by  c e l l s i n that n e a r l y a l l c e l l s  independent  activated  1971a).  due  to  (Hjorth-  Simonsen, 1973). E l e c t r o p h y s i o l o g i c a l evidence tends to support  these  anatomical  p o t e n t i a l s are recorded the  PP  recorded  (Gloor i n CA1  and  longer  or  CA3  et  i n CA3  since  f o l l o w i n g s t i m u l a t i o n of  have s u b s t a n t i a l l y  smaller  l a t e n c i e s than those recorded  and  may  Winson and  monosynaptic  a l , 1964), In c o n t r a s t , the  therefore  trisynaptic circuitry 1975;  data  be  described  Abzug, 1978).,  amplitudes  i n the  mediated previously  fields  dentate  through  th  (Andersen,  11  5A. ••Commissural/Associational System The  commissural  (COMM)  connections  hippocampus have been  mapped  (Blackstad,  autoradiographic  Cowan,  1956},  1973)  (Andersen  et  and  out using  of the  degeneration (Gottlieb  electrophysiological  and  technigues  a l , 1961; Deadwyler, White, Cotman and  Lynch, 1975). Whereas a l l f i e l d s o f the hippocampus and dentate gyrus r e c e i v e fibres  COMM i n p u t s ,  i s restricted  the o r i g i n  t o CA3-CA4 o f the  hippocampus ( G o t t l i e b and Cowan, 1973; and  Laurberg, 1978).  leave the proximal  of COMM  contralateral  Hjorth-Simonsen  The l a r g e myelinated COMM f i b r e s  contralateral  hippocampus  t o the i n f e r i o r  blade  v i a the a l v e u s  of the dentate and  p r o j e c t through the v e n t r a l p s a l t e r i u m , r e - e n t e r i n g the hippocampus near CA3. In the dentate, the the  inner  molecular  COMM input  layer  below  i s r e s t r i c t e d to the PP  Remarkably, there i s no o v e r l a p between the and  COMM  system.  i n n e r v a t e d by the termination  overlap  associational ipsilateral are  COMM  o f the  i p s i l a t e r a l CA3c the  However,  t h e same  input  zone  i s also  associationa1  synapses, entorhinal that  the zone o f  system o r i g i n a t i n g i n  (Simmer, 1970)., The s i g n i f i c a n c e  between fibres  the termination arising  CA3, r e s p e c t i v e l y ,  from  contralateral  i s not  systems and those a v a i l a b l e  of  of COMM and and  yet c l e a r . There  few d e t a i l e d e l e c t r o p h y s i o l o g i c a l s t u d i e s o f  projection  is  these  are d i s c u s s e d i n  12  more d e t a i l i n Chapter 7, The  COMM  input  to CA1 terminates  basal d e n d r i t e s o f pyramidal  cells  Gottlieb  The input  and Cowan,  1973).  (Andersen, 1960;  d e n d r i t e s i s more massive as i n d i c a t e d degeneration 1958) of  following  COfiM  and a l a r g e r negative  the COHM  pathway  similarities  between  stimulation  of  stimulation terminate 1960;  (Cragg  apical  the dense (Blackstad, stimulation  and Hamlyn, 1957). The wave  evoked  collaterals  that on  by  wave evoked by  Schaeffer  primarily  onto  transections  the s y n a p t i c  suggests  on a p i c a l and  both  apical  of  and  these  dendrites  by COMM  inputs  (Andersen,  see F i g . 4 i n Andersen, 1975)  Qx. Sepjtal-Hi£rjocam£al P r o j e c t i o n Although the p r o j e c t i o n s from the s e p t a l the  hippocampus  species  using  organization  of  have  various  studied technigues,  of  a  i n the r a t , concluded  the hippocampus over the alveus hippocampus.  experimental aspect  precise  Haisman  preparation  found  the f o r n i x  (1966) that  of t h e medial s e p t a l nucleus  band send f i b r e s through the v e n t r a l  midline reaching  throughout  using only  Powell  degeneration  t h a t f i b r e s from  t o terminate  to  number of  the  Nauta-Gygax  s e p t a l regions enter the body of  the  in a  t h i s system i s f a r from c l e a r ,  (1963), on the b a s i s study  been  area  t h e same the  caudal  and the d i a g o n a l portion  of the  13  fimbria except  which CA1.  disagreed lesions  w i t h Raisman of  the  i s  topographical case  hippocampal and  septal  no  simple  the  interpretations  area  result  following  tentative in light  septal  ascending  fibres  for  the  the  studies.  pattern  lesions  of p o s s i b i l i t i e s t h a t  in  including  i n the above of  (1971)  reported that  explanation  found  regions  Tassoni  i n the d o r s a l hippocampus  differences  degeneration  disrupt  a l l  (1966) s i n c e t h e y  medial  only  There  I n any  in  More r e c e n t l y , S i e g e l  degeneration CA1.  terminate  have  to  lesions  c o u r s i n g through  the  of be also  septal  area. Another  technigue  septal-hippocampal  t h a t has  been used  projections  t r a n s p o r t of t r i t i a t e d  is  amino a c i d s t o  the  The  with proper  p r e c a u t i o n s , i t m i n i m i z e s the  f i b r e s of passage  Price, reveals  1972).  orthograde hippocampal  contribution  areas  autoradiography which  cannot  technigues  observed  easily  (Swanson  F o l l o w i n g .3H-proline i n j e c t i o n s i n t o  in  several  of the dentate gyrus. In c o n t r a s t to  histochemical  localization  and  hippocampus  those  the  hippocampus  hilar  experiments  the  the  CA3,  degeneration  of  of  and  labelling  i n c l u d i n g CA2, region  CA4  regions  and  often  be  m e d i a l s e p t a l - d i a g o n a l band a r e a , s u b s t a n t i a l is  the  (Cowan, G o t t l i e b , H e n d r i c k s o n  using degeneration  Cowan, 1977).  map  t h i s technigue i s that,  Furthermore,  terminal  demonstrated  of  the  formation.  of  advantage  to  and  based  the the on  of acetylcholinesterase  14  ( r e v i e w e d below) Swanson and Cowan (1974) to  find  evidence for a s i g n i f i c a n t  were  unable  p r o j e c t i o n from  the  m e d i a l - s e p t a l d i a g o n a l band c o m p l e x t o CA 1 o r t h e i n n e r molecular layer of the dentate Bose,  Hattori  and  Fibiger  (1976)  f i n d i n g s s i n c e they reported leucine  into  the  medial  substantial labelling hippocampus layer  of  substantial  and  dentate.  into  molecular  that septal  CA3  the  CA4  However,  trans-synaptic layer  Schubert,  as  supported  nucleus  and  medial  recently,  injections  but only sparse l a b e l l i n g the  adenosine  of  g y r u s . , More  of  3H-  results in  zones  of  the  i n the molecular  infections  septal  these  of  3H-  nucleus r e s u l t i n  labelling  of  w e l l as i n the h i l a r  the  inner  region  (Rose  1977).,  In a d d i t i o n t o the anatomical t e c h n i g u e s d e s c r i b e d above, h i s t o c h e m i c a l s t a i n i n g f o r (AchE)  has  been u s e d  septal afferents.  t o map  out the t e r m i n a t i o n of the  T h i s enzyme i s  layers  i n t h e h i p p o c a m p u s and  Lewis,  1967;  Mellgren  and  Fonnum, Srebo,  1970;  acetylcholinesterase  located  dentate gyrus  heaviest  innermost  staining  1 9 7 3 ) . The  al,  1973;  consists  p o r t i o n of the m o l e c u l a r  the granule c e l l  Following  (Shute  electrolytic  and 1970;  dentate r e g i o n s t a i n s  of  a  proper band  layer  in  adjacent  b o d i e s and t h e d e n t a t e h i l u s  Lynch and Cotman,  discrete  Storm-Mathisen,  more h e a v i l y f o r AchE t h a n t h e h i p p o c a m p u s the  in  and the to  (Mosko e t  1975). lesions  of  the  medial  15  s e p t a l - d i a g o n a l band area the staining  is  abolished  Mellgren,  1974)  and the o v e r a l l a c t i v i t y (CAT)  (McGeer, Hada, Tergo and  or  pattern  of  AchE  (Lewis et a l , 19 67; Srebro and  cholineacetyltransferase  1970,  above  Jung,  is  of  AchE  greatly  1969;  reduced  Storm-Mathisen,  1972). In c o n t r a s t , l e s i o n s of the l a t e r a l  lateral  hypothalamus d i d not i n f l u e n c e  AchE (McGeer e t a l , 1969; Mellgren suggesting  and  and  septum  hippocampal  Srebro,  1973)  t h a t a c h o l i n e r g i c input t o the hippocampal  formation o r i g i n a t e s i n or passes  through  the  medial  s e p t a l area. Under  normal  r e g i o n of the  conditions  dentate  which  the  middle  contains  molecular  associational,  commissural and e n t o r h i n a l t e r m i n a l s does not s t a i n f o r AchE,  but  marked  destruction  of  these systems r e s u l t s i n a  intensification  of  AchE  deafferented  zones  Cotman, 1972;  Lynch and  lesion  in  the  (Lynch,  in  1975).  A  subsequent  s e p t a l area a b o l i s h e s t h i s  p a t t e r n o f AchE s t a i n i n g as w e l l as the normal pattern  of  AchE  in  the  hilus  may  positions in degenerating  new  layered  (Lynch, 1972). On the  b a s i s of these data, i t has been suggested that afferents  the  Mathews, Mosko, Parks and  Cotman,  medial  staining  septal  undergo c o l l a t e r a l s p r o u t i n g and take up the  outer  entorhinal  molecular afferents  layer (See  vacated Lynch  by and  Cotman, 1975 f o r review). S t u d i e s o f the uptake of t h e p r e c u r s o r c h o l i n e and  16  the subsequent  release  of  acetylcholine  (Ach)  also  s u p p o r t t h e s u g g e s t i o n t h a t Ach i s p r o b a b l y r e l e a s e d i n the hippocampal f o r m a t i o n from t e r m i n a l s o r i g i n a t i n g i n the  septal  area.  Hippocampal synaptasomes  affinity  uptake system f o r  choline  reduced  following  septal  medial  and A g h a j a n i a n , 1972; only  Kuhar,  i n t h e hippocampus  uptake  of  choline  may  have a  which lesions  1975).  greatly  (Kuhar, Both decrease  is  and c o r t e x s u g g e s t i n g t h a t  the  be  a  This  is  reasonably  specific  i n d i c a t o r o f A c h t u r n o v e r (Yamamura and S n y d e r , Studies hippocampus, cup is  which  measure  utilizing  high  Ach  release  a m o d i f i c a t i o n of  1972).  from  the  the  cortical  t e c h n i g u e , s u g g e s t t h a t t h e r e s t i n g r e l e a s e o f Ach markedly i n c r e a s e d  septum  (Smith,  1972,  by  stimulation  of  medial  1977).  These  e f f e c t s are s p e c i f i c to medial septal stimulation  since  stimulation  of  hippocampus  does  hippocampus  1974; Tmdar, 1975,  the  lateral not  (Smith,  septum  influence 1972,  or Ach  1974;  contralateral release  i n the  Dudar,  1975).  A d m i n i s t r a t i o n o f h e m i c h o l i n i u m - 3 (which b l o c k s uptake)  causes  Ach f o l l o w i n g and K u h a r ,  a g r a d u a l , dose-dependent  medial septal s t i m u l a t i o n  choline  depletion  of  (Rommelspacker  1974). ,  The a c t i o n o f Ach on h i p p o c a m p a l n e u r o n e s h a s b e e n studied  using  micro-iontophoretic  technigues  S t r a u g h a n , 1975  f o r r e v i e w ) . Many h i p p o c a m p a l  are  by  excited  Ach  (Herz  and  (See  neurones  Nacimiento,  1965;  17  Salmoiraghi 1966).  and S t e f a n i s , 1965; B i s c o e  The  receptors  may be m u s c a r i n i c but  not that  atropine  of these cholinoceptive  produced  (Biscoe  by  glutamate,  both  cholinoceptive.  few o f t h e s e c h o l i n o c e p t i v e  and  cells  but i t a p p e a r s  granule  cells  are  More r e c e n t l y , Wheal and M i l l e r  (1977)  t h a t e l e c t r i c a l s t i m u l a t i o n of t h e medial  s e p t a l a r e a a n d t h e PP a c t i v a t e t h e same g r a n u l e but  only  atropine.  the This  cholinergic region  septal  further supports the suggestion  system  originating  selectively  excites septal cells  conclusions  be  sure  conclusion,  pharmacological  support  the  isstill  However,  i t i s  stimulation  their  axons  but  through t h i s area.  Thus  the neuroanatomical,  existence  p r o j e c t i o n w h i c h may u s e  gyrus  septal  reviewed of  Ach  a as  histochemical  above  strongly  septal-hippocampal a  t r a n s m i t t e r . , The  of s e p t a l t e r m i n a l s  controversial since  i n the dentate  some s t u d i e s  e t a l , 1972; S t o r m - M a t h i s e n , 1974) r e p o r t input terminating  the  be t e n t a t i v e .  studies  precise organization  a  the m e d i a l  that  and  by  that  based on e l e c t r i c a l s t i m u l a t i o n o f  s e p t a l area can o n l y  and  to  f i b r e s o f passage c o u r s i n g  In  in  excites dentate granule c e l l s . difficult  any  cells  evoked a c t i v a t i o n i s blocked  extremely  not  by  and S t r a u g h a n , 196 5; Wheal and M i l l e r ,  pyramidal  have r e p o r t e d  neurones  i s blocked  electrophysiologically identified  that  Straughan,  s i n c e t h e e x c i t a t i o n p r o d u c e d by A c h ,  1977). U n f o r t u n a t e l y , were  and  i n the supragranular  (Lynch  a substantial  zone a s w e l l  as  18  in  the  h i l u s whereas o t h e r s  Rose e t a l , 1976) of  the  only report  hilus.  interpretation staining  Cowan,  substantial  1975;  innervation  These d i f f e r e n c e s a r e r e l e v a n t f o r of  d a t a b a s e d on  in  the  Cotman, 1975)  and  is  onto granule  directly  {Swanson and  intensification  re-innervated  dentate  the  of AchE  (Lynch  and  to determine whether the s e p t a l i n p u t c e l l s and/or neurones i n  the  hilus.  £*., Monoamine P a t h w a y s The  development  histofluorescenee containing c e l l 1962;  of  method  bodies  and  C a r l s o n , F a l c k and  Thieme  and  Thorp,  neuroanatomical  and  hippocampus.,  As  monoamines  noradrenaline  Ungerstedt, dopamine  amounts 1971;  in  the  p l a y an i m p o r t a n t  1962;  combined  CNS  (Falck,  Falck,  Hillarp,  with  existing  technigues  below,  substantial  of  the  monoamine  have  formed  monoamine p r o j e c t i o n s t o  outlined  contains  trace  fibres in  biochemical the  Falck-Hillarp  visualizing  Hillarp,  formation  only  for  1962)  the b a s i s f o r s t u d y i n g  the  (NA)  and  hippocampal  amounts serotonin  dopamine  Moore, 1 9 7 5 ) . The  the  (for low  of  the  (5-HT)  but  reviews  see  concentration  of  h i p p o c a m p u s s u g g e s t s t h a t i t does role i n synaptic transmission  area  a s i d e from being  The  purpose  and  postulated  a  precursor  for  in  role  of  c o n t a i n i n g t e r m i n a l s i n the hippocampal  not this  noradrenaline.  of t h i s s e c t i o n i s to d e s c r i b e the physiological  the  NA  source  and  formation.  5-HT  19  Noradrenaline Fuxe cell  INAll  (1964,  1965)  first  d e s c r i b e d N&  containing  bodies l o c a t e d i n v a r i o u s n u c l e i i n the b r a i n s t e m .  F l u o r e s c e n c e h i s t o c h e m i c a l mapping o f t h e i r  projections  indicated  fine  which  that these n u c l e i give  descend  and  ascend  the in  present the  Ungerstedt,  dorsal  pons,  (Anden  the  LC  to  1966;  locus  relevant  (LC),  most o f w h i c h c o n t a i n Axons from  rostrally.  p r o j e c t i o n i s through  The  most  the d o r s a l  projects into the medial forebrain  terminate  throughout  the f o r e b r a i n ,  Anden e t a l , 1966;  F u x e , Hamberger  including  1968;  Ongerstedt,  1971; l i n d v a l l and  Jones  and  1977;  lesions  in  Moore, the  marked l o s s o f (Anden  et  experiments containing  LC NA  al,  or  dorsal  fluorescence  1966;  provide projection  since destruction  Moore,  to  the  the  (Fuxe,  Hokfelt,  B j o r k l u n d , 1974,  1978).  Electrolytic  NA b u n d l e  result i n a  in  Ongerstedt, additional  and  NA  bundle  s e p t a l r e g i o n , h i p p o c a m p u s and t h e e n t i r e c o r t e x 1965;  to  nucleus  coeruleus  U n g e r s t e d t , 1971). and  Fuxe,  F u x e , H o k f e l t and  1 9 7 1 ) . Most  packed c e l l s  caudaily  rostral  which  the  a l , 1966;  project  prominent bundle  et  axons  Dahlstrom,  t h e s i s i s the i d e n t i f i c a t i o n of a  c o n s i s t i n g of t i g h t l y NA  (Anden,  O l s o n and O n g e r s t e d t ,  U n g e r s t e d t , 1969;  to  f o r long distances reaching  w i d e s p r e a d a r e a s i n t h e CNS Larsson,  rise  the  above  1971).  support  areas  Biochemical for  hippocampal  an  NA  formation  of t h e d o r s a l b u n d l e s e v e r e l y r e d u c e s  NA c o n t e n t o f t h e h i p p o c a m p u s  (Moore,  1973;  Kobayashi,  20  Palkovits,  Kopin  electrical of  and  Jacobowitz,  s t i m u l a t i o n o f t h i s pathway c a u s e s  NA i n t h e h i p p o c a m p u s  and U n g e r s t e d t , The  whereas  a release  ( A r b u t h n o t t , Crow, F u x e ,  Olson  1970).  NA c o n t a i n i n g f i b r e s r e a c h t h e h i p p o c a m p u s v i a  the f o r n i x  o r by l o o p i n g a r o u n d t h e c o r p u s c a l l o s u m and  entering  through  Lindvall  and  using  1974)  an  the  cingulum  Bjorklund,  dopamine-beta-hydroxylase to  fornix-fimbria  find  1971;  1974; M o o r e , 1 975) . However,  immunofluorescence  (1975) f a i l e d  (Ungerstedt,  technigue  (DBH),  to  Swanson  DBH-containing  visualize  a n d Hartman  fibres  i n the  s u g g e s t i n g t h a t t h e c a u d a l r o u t e may be  more i m p o r t a n t . , The  difficulties  terminals make  a  and  densest  in  terminal  adjacent  description  (Jones  distribution  mossy  and  pyramidal  layer cell  between  NA  Moore,  of  their  with  distribution  autoradiographic  1977) ,  a  layered  NA  t h e h i p p o c a m p u s may be described.„The region  to  (Swanson and H a r t m a n , molecular  combined  fibre-CA3  projection  discriminating  b a s e d on NA o r DBH f l u o r e s c e n c e  However,  technigues  dense  fibres  precise  tentative.  in  of  the  i s the  dentate  hilus  zone f o l l o w e d by stratum  the  dentate  moderately  lacunosum  1975; J o n e s and Moore, and  the  and  of  CA1  1977).  The  area  of  b o d i e s were o n l y s p a r s e l y l a b e l l e d .  More  recently, a h i s t o f l u o r e s c e n c e technigue f o r v i s u a l i z i n g a d r e n e r g i c r e c e p t o r s was u s e d t o s t u d y  the distribution  21  of p o s s i b l e Atlas,  NA  1977).  receptor  sites  a  it  density  (i.e. sites  The on  studies described  high  propranolol)  (Melamed,  of  above,  this  beta-adrenergic  and  study  receptor  which b i n d a f l u o r e s c e n t analogue  i n the dentate  granule  of  cell layer.,  e f f e c t s o f m i c r o - i o n t o p h o r e t i c a l l y a p p l i e d NA  neurones i n t h e hippocampal f o r m a t i o n produces  cells  lahav  I n c o n t r a s t t o NA hist©fluorescence and  autoradiographic reports  sites  a  (Herz  Stefanis,  long  and  latency  i n h i b i t i o n of  Nacimiento,  1965;  Biscoe  1965;  and  the  action  that  pyramidal  Salmoiragfai  Straughan,  S t r a u g h a n , 1975 f o r r e v i e w ) . S e g a l attempted t o r e l a t e  indicate  and Bloom  1966;  and See  (1974 a,b)  of iontophoreticallv  a p p l i e d NA and t h e e f f e c t s o f e l e c t r i c a l  stimulation of  LC  These  on  hippocampal  pyramidal  cells,,  r e p o r t e d t h a t LC s t i m u l a t i o n o r d i r e c t NA i n h i b i t blocked  pyramidal  cells.  by b e t a - a d r e n e r g i c  i n 6-hydroxydopamine-treated 1974b). still  Although  no f i r m  containing hippocampal  these  terminals formation.  application  Moreover, these  in  of  e f f e c t s were  a n t a g o n i s t s a n d were a b s e n t rats  (Segal  and  data a r e s u g g e s t i v e ,  physiological  authors  evidence synaptic  Bloom, there i s  implicating function  of  NAthe  22  Serotonin The  15-HTJLI  5-HT  originates nuclei  i n n e r v a t i o n of the hippocampal  from  neurones  within  the  midbrain raphe  ( D a h l s t r o m and F u x e , 1 9 6 5 ; Anden e t  Biochemical indicate  studies  Lorens  that  the  median  and  not  the  superior)  h i p p o c a m p a l 5-HT, Bjorklund Halaris,  by  raphe  al,  1966),  Guldberg  (nucleus  (1974)  centralis  d o r s a l raphe i s the s o u r c e of  Histofluorescence  e t a l , 1973) 1975)  and  formation  (Fuxe e t a l ,  and a u t o r a d i o g r a p h i c  1970;  (Moore  s t u d i e s i n d i c a t e t h a t axons a r i s i n g  from  t h e median  raphe ascend i n t h e m e d i a l f o r e b r a i n  to  the hippocampal f o r m a t i o n v i a the f o r n i x  reach  and  bundle and  the cingulum,  of  H i t h i n the hippocampal formation tha  distribution  5-HT  study  is  almost  impossible  h i s t o c h e m i c a l methods due  t o t h e low  small  size  method  ( L i n d v a l l and B j o r k l u n d ,  the  of  the t e r m i n a l s .  localization  detailed on  a n a l y s i s o f 5-HT  fluorescence  and  Even t h e g l y o x y l i c  acid  1974)  essentially  procedures  Moore  suggest  from  overlaps  and  the the  described i n the previous s e c t i o n 1974;  which  a  band  that  NA  the raphe  innervation  (Conrad, Leonard  Halaris,  a p p r o x i m a t e l y 65 um  based  median  1 9 7 5 ) , The  t e r m i n a t i o n i n the hippocampal formation i s to  improves  s y s t e m s . However, d a t a  d i s t r i b u t i o n o f axons a r i s i n g  Pfaff,  usinq  o f c a t e c h o l a m i n e s does not a i d i n t h e  autoradiographic  nucleus  to  and  densest  restricted  wide, a l o n g the  ventral  23  border of cannot cell  dentate  be  granule  determined  bodies  neurones.  of  is  must be  pattern  does  or  l a y e r (See  subjacent  M o o r e , 1975  k e p t i n mind t h a t not  the  et  not  al  5-HT  innervation  serotonergic.  (1976)  have  amino  to  the  d e s t r u c t i o n o f 5-HT  transport  hippocampal  from  the  formation.  support the conclusion  median  Both  that the  these  containing  t e r m i n a l s i n the hippocampal  applied  to  (Stefanis, (Segal short  not  and  in  innervation  (2-15  sec)  which, u n l i k e the  persist  after  relative  NA to  the was  anaesthetized  depression  1965)  and  of  application  a weak d e p r e s s a n t o f comparable  cats rats  caused  a  neuronal  depressent a c t i o n of  when  5-HT  iontophoretically  Straughan,  drug  5-HT  of  formation.,  B l o o m , 1 9 7 4 a ) . I n most c a s e s 5-HT  latency  the  observations  distribution  been  cells  Biscoe  stopped. In f a c t , firing  has  pyramidal  1964;  and  discharge  (5-HT)  the  reduced to  pattern of  above  acid.  terminals  raphe  described  Serotonin  reflects  of  that  result in  with 5,6-dihydroxytryptamine r e s u l t s i n g r e a t l y axonal  More  shown  a similar  p a t t e r n of t e r m i n a t i o n  of  terminal  MB  "selective"  on  Fig.,*!)..  i n j e c t i o n s of r a d i o l a b e l e d 5-HTP i n t o t h e  Furthermore,  It  hilar  above  necessarily reflect  Halaris  1975).  t o moderate i n n e r v a t i o n  s i n c e some r a p h e n e u r o n e s a r e recently  (Moore,  these t e r m i n a l s are  cells  sparse  the dentate molecular It  whether  granule  There  cells  NA,did  had  been  neuronal ejection  24  c u r r e n t s were u s e d Neither the  { B i s c o e and S t r a u g h a n , mechanism  by  which  1966).  5-HT  depresses  hippocampal neurones nor t h e p h y s i o l o g i c a l  significance  of  reasons  this  action  are  known.  p o s t u l a t e d r o l e f o r 5-HT i n t h e hippocampus have  receptors  o n t o them as  For  o r NA  these  i n synaptic  must be t e n t a t i v e ;  for  substances  any  transmission  many  cells  may  not n o r m a l l y r e l e a s e d  transmitters.  Major Hippocampal Although  Efferents  the  efferent  connections  of  the  h i p p o c a m p a l f o r m a t i o n h a v e been s t u d i e d f o r more t h a n a century,  our  understanding  comparatively  vague.  descriptions  of  the  Only  of  their organization i s  recently  have  hippocampal e f f e r e n t s other than  t h e f o r n i x b e e n a t t e m p t e d . The new  d a t a have p r o m p t e d  r e - e v a l u a t i o n of t h e w i d e l y held view t h a t is  the  major,  i f  not  hippocampal formation Cajal,  1911; N a u t a ,  emphasized efferents (Chronister 1973;  the to and  detailed  the  only,  efferent  ( M a y n e r t , 1872; 1956;  cortical White,  Von  Guillery,  importance  of  and 1975;  the  fornix from t h e  Gudden,  1957)  a  1881;  and  have  caudally-directed  subcortical  regions  H j o r t h - S i m o n s e n , 1971,  Swanson and Cowan, 1 9 7 7 ) . , A n o t h e r new  regions of  the  extrahippocampal  development  has b e e n i n r e g a r d t o what  hippocampal projections.  formation At  give  rise  the simplest  to  level.  25  t h e d e n t a t e gyrus does n o t projections  fibre  Likewise  extrahippocampal associational ipsilateral (Zimmer,  projection the  CA4  and and  Gottlieb  and  extrahippocampal  the  projection  precommissural  do  substantial  as  Saisman  Field  CA3  a s an  septal  area  a l ,  1966).  and p r o j e c t s t h r o u g h t h e  fornix bilaterally  to the l a t e r a l  the  subiculum  the  septal alveus  (Hjorth-Simonsen,  1973;  a n d Cowan, 1977) . The s u b i c u l u m , i n t u r n , g i v e s  r i s e t o t h e massive 1966; Swanson On t h e b a s i s  post commissural  and Cowan,  only  (Baisman e t  the  hippocampus  1977).  of t h e a b o v e  contributes  fornix  data,  t o the precommissural  fornix  whereas t h e s u b i c u l u m i s t h e s o u r c e o f t h e e n t i r e commissural mammillary  projection to nuclei.  In  the  anterior  addition  indirect  formation through  connections  to  thalamic  nuclei  of may  post-  thalamic  and  these  direct  more  detail  extrahippocampal projections described i n below,  the  extrahippocampal  to  proper  to  well  et  (Swanson and Cowan, 1977) and t h r o u g h  al,  to  intrahippocampal  the  most  no  respectively  area  Swanson  rise  Cowan, 1973).  1973;  adjacent  have  give  dentate,  to  CAi  pyramidal  projections  Cowan,  from  entirely  cells  projections  projection  arises  CA3-CA4  extensive  associational/commissural  Perhaps  but  commissural  to  and  to  contralateral  rise  (Gottlieb  extrahippocampal  pyramidal  projection  1970;  gives  any  since i t s outflow c o n s i s t s almost  o f t h e mossy cells.  have  the  hippocampal  influence  the  26  frontal  and  c a l l e d Papez  p a r i e t a l lobes thereby completing the so(1937)  lilferia^Fornix Although arrangement fundamental studies species  circuit.  System  Elliot of  Smith  the  fornix  have  conforms  shown  significant  precommissural  the  same  subseguent  the  between  same  species  and N a u t a ,  projections  1959). I n t h e r a t , contained  i n the  f o r n i x p r o j e c t t o t h e s e p t a l n u c l e i and  t h e p r e o p t i c r e g i o n and to  many  the  1902; S i m p s o n , 1 9 5 2 ; Cowan and  1955; V a l e n s t e i n  the d i r e c t hippocampal  to  that  differences  and i n d i f f e r e n t s t r a i n s o f  Powell,  the  through  mammillary  hypothalamic r e g i o n and  concluded  plan i n a l l vertebrates,  ( E d i n g e r and W a l l e n b e r g ,  fornix  (1897)  the body  columns and  ( C a j a l , 1911; N a u t a ,  Cowan, 1 9 7 1 ) . O n l y  of  the  1956;  the  medial Swanson  a few f o r n i c a l f i b r e s r e a c h t h e  m i d b r a i n i n t h e r a t . I n c o n t r a s t , t h e c a t f o r n i x has massive  projection  to  the  rostral  raid-brain  f i b r e s to t h e medial hypothalamic region In  primates the  pronounced  than  dorsal  fornix  Several topographical  1959).  are  less  t h e y a r e i n r o d e n t s and do n o t a p p e a r  t o t e r m i n a t e c a u d a l t o t h e mammillary and C r e s w e l l ,  and few  (Nauta,  projections  a  bodies  (Paletti  1976). proposals  have  organization  been  made r e g a r d i n g t h e  o f t h e hippocampal  v i a t h e f i m b r i a - f o r n i x . R a i s m a n e t a l (1966)  efferents suggested  27  that  CA1  region  principally  w h i l e CA3 p r o j e c t s t o  contrast that  projects  Siegel  the  by  respectively.  the  the medial  lateral  e t a l (1974) a l s o u s i n g  medial  innervated  to  and  the  lateral  dorsal  regions  ventral  s u b i c u l u m may a l s o be t o p o g r a p h i c a l l y  the  dorsoventral  the  the  In  are  hippocampus,  The p o s t c o m m i s s u r a l f o r n i x o r i g i n a t i n g i n  the  that  septum.  r a t s , suggest  septal  and  septal  a x i s . Swanson and Cowan  d o r s a l subiculum  mammillary  complex  the  (1977)  in  suggest  projects predominantly  and  rostral  organized  the  ventral  hypothalamus  upon  subiculum  projects  to  and t h e b a s a l  forebrain  i n c l u d i n g t h e n u c l e u s accumbens and  the  bed  nucleus of the s t r i a t e r m i n a l i s .  P l a s t j c i t y •• Of S j r n a r r t i c T r a n s m i s s i o n I n The H i p p o c a m p a l Formation Since formation  the  major  afferents  using  both  evaluating  of s y n a p t i c  transmission.  evaluated  afferent  plasticity the  by  resulting  to  Structural  determining following  the  h a s been s t u d i e d  changes  i t i s an i d e a l  s t r u c t u r a l and f u n c t i o n a l  readjustments which occur major  hippocampal  neuroanatomical  e l e c t r o p h y s i o l o g i c a l technigues,  been  the  o c c u p y d i s c r e t e d e n d r i t i c l a y e r s w h i c h c a n be  identified  for  to  in  efficacy  from p r e v i o u s  same  of  system  modifications  plasticity the  region. by  synaptic  has  anatomical  elimination  primarily  and  of  a  Functional determininq transmission  a c t i v a t i o n o f t h e same pathway.  28  Both  of  these  understanding  of  processing and functional present  approaches the  work  and  contribute  mechanisms  storage of  plasticity  may  will  direct  be  an  associated  with  however,  only  information,  has  to  relevance  reviewed  to  below.  the  Several  reviews on t e r m i n a l p r o l i f e r a t i o n and synaptogenesis the hippocampal formation available  (Lynch  and  in  f o l l o w i n g d e a f f e r e n t a t i o n are  Cotman, 1975;  ficSilliams  and  Lynch, 1978)., A feature  of  all  hippocampal formation synaptic The  field  responses and  which  amplitude  are  B l i s s and  pulse  projection  in  of  of  as  an  the t e s t  enhancement  pulse  simplest  extracellular cells  (Lomo, 1971b;  example  of  this  the  perforant  path-dentate  monosynaptic t e s t EPSP  (the synchronous  discharge  of  a  c e l l s ) responses were both p o t e n t i a t e d by a (20-300 mesc) c o n d i t i o n i n g v o l l e y .  was  potentiated  as  much  as  10 0%  The  test  while  p o p u l a t i o n s p i k e could be p o t e n t i a t e d up t o 300%. o b s e r v a t i o n s have been r e c e n t l y confirmed (Steward  in  by Lomo (1971b) using double  r a b b i t . The  population spike  preceding  by  provided  the  the  repetitive stimulation.  r a t e of r i s e of  Lomo, 1973), The was  in  an i n c r e a s e i n the number of  stimulation  number  and  activated  phenomenon  EPSP  during  i n c r e a s e d e f f i c a c y i s seen the  afferents  s t u d i e d so f a r i s the i n c r e a s e i n  transmission  both  and  excitatory  et  al,  1976;  Assaf and  the i n v i t r o hippocampal s l i c e  in  the These  the  M i l l e r , 1978)  rat  and i n  (Dudek et a l , 1975).  29  I f some e x c i t a t o r y formation {usually  are  synapses  stimulated  with  in  the  hippocampal  particular  frequencies  4-15/sec) t h e r e i s a g r a d u a l i n c r e a s e  i n the  a m p l i t u d e o f e v o k e d p o t e n t i a l s u n t i l a maximum is  o b t a i n e d a f t e r 10-30 s t i m u l i  ( B l i s s a n d Lomo, 1973;  Andersen,  1975). With  duration  o f t h e enhanced p o t e n t i a l s i s s h o r t e r ,  way t o a p e r i o d  higher  response  stimulation  more o b v i o u s i n t h e mossy f i b r e - C A 3 path-dentate projection  Tetanic  stimulation  responsiveness of  the  volleys  several  delivered  gives  e t a l , 1977; T y l e r  and  potentiation  is  presynaptic  fibre  adjacent (Lynch  synaptic et  Dunwiddie depression  and  inputs  of  the with  t o an  pathway  1975;  which  is  increased to  single  ( B l i s s a n d Lome, has  Andersen  1978).  and  than  1975).  recently  hippocampal s l i c e  Lynch,  volley  Lynch  rise  dependent  a l , 1977;  simultaneously pathway.  not  (Andersen,  potentiation  and A l g e r ,  Dunwiddie  facilitation"  hours l a t e r  demonstrated i n i n v i t r o  1977;  giving  pathway t h a n i n t h e  stimulated  1973), S i m i l a r p o s t - t e t a n i c been  the  of depression usually l a s t i n g less  5 minutes. This s o - c a l l e d "freguency  perforant  rates,  The  on  changes  i s  not  were  (Lynch et a l ,  observed in  observed  not  the in  tetanized  Andersen e t a l , 1977). I n f a c t , (1978)  recently  reported  a  n o n - t e t a n i z e d pathway which o c c u r s potentiation  of  the  stimulated  30  Mechanisms  which  functional plasticity suggests that  More  (1 978)  not  to  of Chapter  lxl±2 The The located  Septal  Dunwiddie,  that  synaptic  between  the  comprises anterior  extent  and  caudally  (Hines,  callosum;  rat  p o s t e r i o r and 1974).  The  be  ventral  divisions  medial s e p t a l r e g i o n  medial s e p t a l r e g i o n in  dendrites 1974).  group of  Golgi  of  at  nuclei lateral  the  into  dorsallv frontal  of  the  septal  fornix  and  Cowan, medial  diagonal  distinguishing feature  i s the mass of l a r g e long  of  neurones  spine-free  Swanson and  l a r g e b i p o l a r neurones are  of  lateral,  c o n s i s t s of the  Petsche, 1969;  by  cortex  area  medial,  (Swanson  have  the  Stephan, 1965). On  the nucleus of the  preparations  (Tombol and  These  is  These  the  commissure;  subdivided  band of Broca v e n t r a l l y . The  which  a  Andy and  s e p t a l nucleus d o r s a l l y and  the  transmission  r o s t r a l l y by the  Young, 1936;  may  and  i n more d e t a i l  horns  b a s i s of i t s c y t o a r c h i t e c t u r e  the  Madison  potentiation.  by the descending columns  1922;  the  amounts of  i s bounded v e n t r a l l y by  d e c u s s a t i o n s of the a n t e r i o r corpus  (1975)  8.  area  Their  the  cf  Area  septal  ventricles.  the  Andersen  other p o s s i b i l i t i e s are d i s c u s s e d  the end  forms  a changed a b i l i t y of  necessary f o r producing long-term and  above  d e l i v e r increased  recently,  observed  the  known.  reflect  terminal  transmitter. Lynch  are  they may  presynaptic  mediate  Cowan,  interposed  by  31  many s m a l l primarily into  n e u r o n e s . The  lateral  o f medium s i z e d c e l l s  dorsal,  intermediate  of  embedded  the  within  which  and  (Swanson and Cowan, 1 9 7 4 ) . The consists  septal region  ventral  posterior  septo-fimbrial  the  can  within  ventral  the  septal  exception  of  precommissural  which r e c e i v e s Stephan,  subdivisions septal  region  which  fornix  and  tightly  is  poorly  defined  from t h e  is the  packed  with  bed n u c l e u s o f t h e s t r i a  afferents  1965,  grouped  v e n t r a l hippocampal commissure.  region the  be  nucleus  t r i a n g u l a r s e p t a l nucleus which contains cells  consists  The the  terminalis  amygdala  (Andy  1974; T o m b o l and P e t s c h e , 1969;  and  Swanson  and Cowan, 1 9 7 4 ) . , A l t h o u g h t h e above d e s c r i p t i o n  and t e r m i n o l o g y a r e  b a s e d p r i m a r i l y on i n v e s t i g a t i o n s i n t h e r a t , t h e y be  applicable  s e p t a l region  to  other  retains the  mammalian above  features  since  in  evolution.  This  progressive  e n l a r g e m e n t and r e l a t i v e d e v e l o p m e n t  p r i m a t e septum  uniformity  species  1974).  the  primate  i s maintained despite  (Andy and S t e p h a n , 1965,  may  the  of the  32  Major  Afferents The  septal region  receives  from  the  hippocampal  from  the  cortico-medial  terminalis by way  and  of the  from  amygdala  via  h y p o t h a l a m i c and  midbrain  have  septal region. region  forebrain  stria  recently,  o r i g i n a t i n g i n t h e pons and  the b a s i s of these  occupies  system,  the  More  been shown t o e x t e n s i v e l y On  afferents  midbrain regions  medial f o r e b r a i n bundle.  monoamine s y s t e m s  m i d b r a i n and  major  formation v i a the f o r n i x  ascending  septal  its  a  i n n e r v a t e the  connections,  pivotal  position  the  between  areas,  Jbs. Hj£ppcampal Xg.£Uts The  major i n p u t from t h e hippocampal  the precommissural  fornix  terminates  s e p t a l r e g i o n ( P o w e l l e t a l , 1957; Swanson and that  lesions  of  in  the  Swanson and  in  fields  lateral  Cowan  to  CA1  and  the  dorsal  C A3  (1977)  suggested  of the precommissural  fornix  destroyed  by  autoradiographic concluded  that  these  studies,  from  lesions. Swanson  observed  result and  s e p t a l n u c l e u s . More  proper s i n c e f i b r e s o r i g i n a t i n g also  lateral  R a i s m a n e t a l , 1966;  that  p a t t e r n o f d e g e n e r a t i o n does not i n d i c a t e source  the  Cowan, 1977) , R a i s m a n e t a l (1966)  degeneration d i s t r i b u t e d parts  formation via  lateral recently,  the  above  that the  i s the  in  sole  hippocampus  the subiculum On and  the major s o u r c e of these  the Cowan  basis  are of  (1977)  precommissural  33  fibres  may  be  afferents  to  the the  topographically  i p s i l a t e r a l subicular lateral  septal  region.  The  reqion  are  organized such t h a t d o r s a l hippocampal  r e g i o n s p r o j e c t e x c l u s i v e l y t o t h e d o r s a l aspect o f the l a t e r a l s e p t a l nucleus and v e n t r a l project area  to  the v e n t r a l portions  (Raisman et a l , 1966;  Swanson  and  responses following  organization  were  recorded  stimulation  These data, taken described  and  The  s t u d i e s of McLennan and M i l l e r  Tassoni,  1971;  Electrophysiological  short  the  latency  this  field  l a t e r a l s e p t a l area  of the f i m b r i a . together  septal-hippocamapal  with  the  previously  projection  (section  1.1.1), e s t a b l i s h a r e c i p r o c a l l i n k area  septal  (1974b,1976) support  since in  fields  of the l a t e r a l  Siegel  Cowan, 1977).  topographical  hippocampal  between the  septal  and the hippocampal f o r m a t i o n . The precommissural  f o r n i x terminates i n the t h i s , i n turn,  lateral  septal  nucleus  and  p r o j e c t s t o the medial s e p t a l area which  sends e f f e r e n t s t o the hippocampal formation.  34  3U  Y %9%h 3 1 a mi c I npat s The  medial  forebrain  bundle  (MFB)  i s the major  i n p u t from the hypothalamus and the midbrain 1969). Since the MFB both  of  these  c o n s i s t s of f i b r e s o r i g i n a t i n g  regions, i t is d i f f i c u l t  c o n t r i b u t i o n of hypothalamic however,  Guillery of  hypothalamic  areas  r e g i o n . On the originate medial  nuclei  (1957) suggested  s e p t a l group  fine  fibres  and  other  Kuypers,  1958;  large  observations  that  electrical  b u r s t i n g d i s c h a r g e of  and  electrical in  Nauta  functional  and  S u t i n , 1966). supported  by  s t i m u l a t i o n i n the  desynchronization  neurones;  1972;  in  of  contrast,  the o p p o s i t e e f f e c t s  Wilson  et  However, any c o n c l u s i o n s based on the above or  to  a c t i v i t y and d i s r u p t i o n of the septal  Lindsley,  septal  appear  1957;  Wolf and  s t i m u l a t i n g more m e d i a l l y produces (Anchel  lateral  p r o j e c t p r i m a r i l y to the  1961;  l a t e r a l hypothalamus r e s u l t s hippocampal  in  fibres  This anatomical d i f f e r e n t a t i o n i s p a r t l y the  system,  that a hypothalamo-  (Guillery,  Morest,  this  p r o j e c t s to the l a t e r a l  hand,  region  to  in  t o a s s e s s the  originates  i n the midbrain and  septal  (Milhouse,  al,  1S75).  anatomical  data should be r e - e v a l u a t e d i n l i q h t of  the p o s s i b i l i t y t h a t  electrodes  stimulate  monoamine-containing f i b r e s which  ascending  in  these  sites  pass through t h i s area to terminate i n the s e p t a l (see  below).  may  area  35  C._ A i y g d a l o i d The  major  terminalis amygdaloid the s t r i a 1940;  i n p u t from t h e amygdala i s v i a t h e s t r i a  which  originates  1 9 5 5 ; Nauta, 1971).  v e n t r a l amygdalofugal  and  {Fox,  that  amygdalofugal  hypothalamus  nucleus  of  (personal  neurone i n the hypothalamic  input  originates  in  to  the  diagonal  1 9 5 6 ; Leonard both t h e s t r i a  band  and S c o t t , terminalis  pathways a l s o p r o j e c t v e n t r a l l y to  and  b u n d l e . On t h e b a s i s o f Renaud  bed  n u c l e i and p r o j e c t s v i a t h e  1 9 4 0 ; Nauta,  past the s e p t a l region area,  corticomedial  1 9 6 6 ; Cowan e t a l , 1 9 6 5 ;  pathway  I t i s noteworthy  the  the  second  A  b a s o l a t e r a l amygdaloid  1971).  the  t e r m i n a l i s i n the v e n t r a l s e p t a l r e g i o n {Fox,  and S c o t t ,  region  in  n u c l e u s and i n n e r v a t e s  Gloor,  Leonard the  Inputs  terminate  in  into  medial  can  suggests project  preoptic forebrain  electrophysiological  communication) amygdala  the  the  evidence  that to  t h e same  septal  and  sites.  Ms. Monoamine P a t h w a y s  Noradrenaline On  the  histochemical terminals  jNA) ; T  b a s i s o f F a l c k - H i l l a r p and g l y o x y l i c a c i d s t u d i e s , the r e g i o n a l d i s t r i b u t i o n  within  of  NA  t h e s e p t a l a r e a h a s b e e n f o u n d t o be  d e n s e i n l a t e r a l s e p t u m and s p a r s e i n t h e m e d i a l s e p t a l area  (Moore e t a l , 1 9 7 1 ; L i n d v a l l a n d B j o r k l u n d ,  1974).  36  Recently, Moore (1978) has noted of  stria  terminalis  t h a t the  receives  a  bed  very  i n n e r v a t i o n . Moreover, the g l y o x y l i c a c i d reveal  numerous  fine  d e n d r i t e s which may  terminals  make en  nucleus dense  NA  preparations  near c e l l bodies  JBstssage  synapses  and  in  the  s e p t a l area and then continue to more r o s t r a l f o r e b r a i n and  cortical  1971;  areas  (Ongerstedt,  1971;  L i n d v a l l and B j o r k l u n d , 1974; As i n the case o f  septal  area  has  other  been  Segal  Moore,  forebrain  coeruleus  and L a n d i s , 1974;  LC  result  in  only  a  content, suggesting t h a t a septal  NA  originates  (LC)  (Ungerstedt,  Jones and Moore, 1971).  48%  t r a n s e c t i o n s caudal to LC a l s o (47%)  decrease  lesions  i n septal  proportion  other  regions.  result  in  d e p l e t i o n s of of s e p t a l NA,  s e p t a l NA may  that  substantial in  the  NA-containing  However, Moore (1978) has r e c e n t l y shown of  1975) regions,  shown t o r e c e i v e  a f f e r e n t s from the l o c u s 1971;  Moore et a l ,  NA of  Since  substantial  the other sources of  be i n more caudal brainstem  sites.  Dopamine I D f t j i At one the  septal  time, the c a t e c h o l a m i n e r g i c i n n e r v a t i o n area  was  considered  e x c l u s i v e l y of NA nerve t e r m i n a l s More  recently,  aspect  of  consist  (Moore e t a l ,  histofluorescence  demonstrated a high d e n s i t y medial  to  DA  almost 1971).  studies  terminals  of the l a t e r a l s e p t a l region  of  have in  the  (Lindvall,  37  1975; has  Moore, 1975, shown  that  bundle at the  1978). Furthermore, L i n d v a l l transection  of  the medial f o r e b r a i n  l e v e l of the r o s t r a l s u b s t a n t i a n i g r a , or  b i l a t e r a l e l e c t r o l y t i c l e s i o n s of the A10 cell  (1975)  group r e s u l t i n  a  complete  loss  mesencephalic of  septal  DA  terminals. Small  injections  of  area r e s u l t i n e x t e n s i v e ventrolateral  extent  the i n t e r p e d u n c u l a r Moore,  1978).  biochemical  HBP  i n t o the l a t e r a l s e p t a l  l a b e l l i n g of neurones  of  the A10  nucleus (Assaf  Taken  together  in  area a t the l e v e l and  these  Miller,  originates  in  ventromedial  tegmentum  and  s e p t a l area . In c o n t r a s t ,  the  anatomical  A10  region  innervates  there  are  the  of  1977;  s t u d i e s suggest a d i r e c t dopaminergic  system which  the  and fibre  of  the  lateral  relatively  few  f i b r e s to the medial s e p t a l r e g i o n . The not  f u n c t i o n a l r o l e of DA  yet c l e a r . Assaf and  electrical  Miller  i n the s e p t a l r e g i o n i s (1977) have shown  s t i m u l a t i o n i n the r e g i o n  of A10  results in  a short l a t e n c y e x c i t a t i o n of s e p t a l neurones which dependent  on  an  intact  dopamine  d i s t r i b u t i o n of the a c t i v a t e d neurones that  of  the  histochemical  dopamine  innervation  system. is  similar  based  experiments mentioned above.  that  on  is The to the  38  S e r o t o n i n jtS-HT).:. On t h e b a s i s o f a u t o r a d i o g r a p h i c data, serotonin-containing c e l l midbrain  raphe  nuclei  1974;  1974).  Lesions  forebrain  bundle  the s e p t a l area 1972;  the  significantly  and  proximity  tothe  Heller,  of  1967,  and G u l d b e r g ,  raphe  reduce  (Moore a n d H e l l e r ,  n u c l e i make i t d i f f i c u l t of  (Moore  midbrain  Lorens and G u l d b e r g , The  bodies l o c a l i z e d  C o n r a d e t a l , 1974; L o r e n s in  biochemical  h a v e been shown t o e x t e n s i v e l y  innervate the septal region Moore,  and  or  medial  5-HT c o n t e n t o f  1967; Kuhar  et a l ,  1974; J a c o b s e t a l , 1 9 7 4 ) .  the  dorsal  to localize  and the  median raphe exact  s e p t a l 5-HT u s i n g l e s i o n i n g t e c h n i g u e s . H o w e v e r , t h e  results  of  Halaris (J.J.  et  autoradiographic a l , 1S76)  Miller,  and  unpublished  (Conrad HHP  et  tracing  observations)  a l , 1974; technigues  indicate that  t h e m e d i a n r a p h e c o n t r i b u t e s s u b s t a n t i a l l y more to  origin  the septal  fibres  area than does t h e d o r s a l raphe.  Unlike the catecholamines,  5-HT d o e s n o t f l u o r e s c e  well i n Falck-Hillarp  p r e p a r a t i o n s and t h u s mapping i t s  distribution  the  overcome t h i s projections  within  difficulty to  the  s e p t a l area i s d i f f i c u l t . the  septum  distribution was  a u t o r a d i o g r a p h i c t r a c i n g o f amino a c i d s precursor 1976). run  5-HTP  These  (Conrad  studies  et  indicate  of  studied and  To  raphe using  the  5-HT  a l , 1974; H a l a r i s e t a l , that  raphe  forward i n t o the medial f o r e b r a i n bundle  axons and r e a c h  39  the  septal  area v i a the  innervation for  a  t h r o u g h o u t the  dense  fibres  band. T h e r e  medial s e p t a l  et a l  i n the  (1976) c a u t i o n  that  some  medial s e p t a l nucleus are f o r n i x . Some  fibres  the  probably the  r e d u c e HBP raphe  transport  Previous  reported  of  the  results  i n h i b i t i o n of s e p t a l  of  the  fibres  of  these  hippocampus  since  nucleus  significantly  hippocampus to the  median  1978). have  unit  implicated  discharge.  iontophoretic  Segal  (Moore,  of  5-HT  (1976) in  a  neurones.  latency  the  (1964)  a p p l i c a t i o n of  reported long  in  Stefanis  spontaneous d i s c h a r g e of s e p t a l  recently,  stimulation  septal  Miller,  septal  to  from the  studies  that  depresses the More  project medial  ( A s s a f and  control  dense  nucleus except  passage which c o n t i n u e i n t o the  lesions in  is  band i n i t s most l a t e r a l a s p e c t s  1975). H a l a r i s the  diagonal  5-HT  neurones.  that (>25  raphe msec)  40  1I.IJL3 8h£thmiGal  Activity.  In  The  Se£tal-Hi£jBocamjal  Axis The  slow e l e c t r i c a l a c t i v i t y  of the neocortex and  hippocampus have been s t u d i e d i n r e l a t i o n  to the  of  a t t e n t i o n and  'arousal',  the  movement {Moruzzi 1954;  Lindsley,  indicate  that  neocortex  sleep-waking  cycle,  and Magoun, 1949; Green and 1960; Vanderwolf,  low  voltage  fast  and r h y t h m i c a l slow  activity  in  the  a c t i v i t y r e c o r d e d i n the 'activation  The s u b c o r t i c a l mechanisms u n d e r l y i n g these  p a t t e r n s a r e not c l e a r ,  although  ascending  there  evidence  that  determine  the p a t t e r n s of n e o c o r t i c a l  activity.,  Arduini,  1972). These s t u d i e s  hippocampal f o r m a t i o n may be c o n s i d e r e d as patterns'.  level  Furthermore,  inputs  from  not due t o t h e d i r e c t  on  the  hippocampus  extensive  the  brainstem  and  hippocampal  i t has been suggested  rhythm f o r slow e l e c t r i c a l a c t i v i t y is  is  but  of the  hippocampus  a c t i o n of brainstem may  be  t h a t the  generated  afferents by  the  r h y t h m i c a l b u r s t i n g d i s c h a r g e of s e p t a l neurones which, in  turn,  r e l a y i t t o the hippocampus (Petsche, Stumpf  and Gogolak, 1962). The aim of the present to  review  concepts, ,  the  studies  which  have  section  is  l e d t o the above  41  S p o n t a n e o u s P a t t e r n s Of In  Electrical  Hj.£ioGaffl£al  the terminology of  clinical  Activity  electrophysiology  slow e l e c t r i c a l  waves a r e d e s c r i b e d on t h e b a s i s o f  freguency  p a t t e r n of t h e i r o c c u r r e n c e ,  and  and  shape.  The  and Hz. of  rat  of  (up t o  2mV)  s m a l l waves h a v i n g f r e g u e n c i e s r a n g i n g b e t w e e n  2-50  c o n s i s t s of a m i x t u r e o f l a r g e  However, t h e o c c u r r e n c e o f t h e s e  waves i s n o t random and  by  activity  amplitude, the  hippocampus  electrical  the  certain  different  p a t t e r n s which  freguencies  and  are  amplitudes  types  dominated have  been  recorded. The  most c o n s p i c u o u s  i s a r h y t h m i c a l slow  (fiSA) c o n s i s t i n g  of a t r a i n  with a freguency  v a r y i n g b e t w e e n 3-12  observation  RSA  of  was  of r o u g h l y s i n u s o i d a l  made  the  Hz.  .  The  by Jung and  (1938) i n t h e r a b b i t ' s h i p p o c a m p u s with  activity  terminology of c l i n i c a l  and  first  Kornmuller  in  accordance  electrophysiologyi s  designated a * t h e t a rhythm' s i n c e i t s freguency between of  RSA  used  4-7  hz. Although  i n some s p e c i e s t h e  i s beyond t h i s r a n g e , to  denote  independent In  the  and  c o n t r a s t t o RSA,  is  Arduini,  activity  may  *theta*  ranged  freguency i s  hippocampal  still  activity  of i t s freguency. a desynchronized  mixture of l a r g e i r r e g u l a r activity  the term  regular  waves  waves and  a l s o recorded from 1954;  Vanderwolf,  fast  activity low  voltage  the hippocampus 1971).  Both  of a  (Green  types  be r e c o r d e d s p o n t a n e o u s l y , b u t RSA  of  i s more  42  prominently Arduini,  Sources  during  Of  those  in  patterns of e l e c t r i c a l  recorded  and  similar  i n t h e hippocampus have been  observed  and A r d u i n i , as  a  of  the b r a i n , n o t a b l y the thalamus  1954),  the  hippocampus  has  been  source  o f * t h e t a * s i n c e 1) a c l e a r  zone and p h a s e r e v e r s a l s h a v e been d e m o n s t r a t e d  the hippocampus activity  (Green  has  been  n e u r o n e s which  e t a l , 1960) and 2)  related  were o b s e r v e d  w i t h t h e r e g u l a r slow  to fire  of  thought  the pyramidal c e i l  RSA  More  the  (Green,  generator  which  activity, layer  two  generators  If  i t was  recordings  are  the  initially  and of  Stumpf, RSA  taken  layer  1960).  have 1976).  l o c a t e d i n s t r a t u m o r i e n s o f CA1  o t h e r more v e n t r a l i n t h e m o l e c u l a r gyrus.  establish  ( W i n s o n , 1974;1975; B l a n d e t a l , is  1961).  was t h e s o l e g e n e r a t o r  Maxwell,Schindler  recently,  described  electrical  local  i n b u r s t s i n phase  waves ( K a n d e l a n d S p e n c e r ,  source  in  hippocampal  t o the d i s c h a r g e of  B a s e d on t h e above c r i t e r i a  of  (Green  activity  regions  established null  arousal  HSA  other  (Green  of  1954, See s e c t i o n s 1.3.3).  Although to  states  of  been One  and t h e dentate  simulatneously  from  43  these 'independent' degrees  out  of  g e n e r a t o r s , the RSA waves  phase. The p h y s i o l o g i c a l  and the independence have not yet been  of the  two  are  180  significance  different  generators  established.  The events u n d e r l y i n g RSA a r e not known. Von Euler and  Green  (1960) suggested t h a t RSA i s a r e f l e c t i o n of  a s e r i e s o f d e c l i n i n g s p i k e s generated w i t h i n the neurone  and  compared  i t to  'inactivation  d e s c r i b e d by G r a n i t and P h i l l i p s they  suggested  that  phasic  (1956).  processes' i n a p o p u l a t i o n o f neurones On the other hand Kandel and Spencer  including neurones  delayed  process'  Furthermore,  a f f e r e n t i n p u t s from the  s e p t a l area cause synchronously o c c u r r i n g  et a l (1964) have  same  suggested t h a t  'inactivation  and thereby RSA.  (1961) and Andersen  intrinsic  after-polarization  and r e c u r r e n t basket i n h i b i t i o n  of  mechanisms pyramidal  (Gloor, 1963)  favour the development o f ' t h e t a ' i n the presence of  a  steady and s u s t a i n i n g e x c i t a t o r y i n p u t s . Although t h e r e is  still  c o n t r o v e r s y over whether RSA i s an i n t r i n s i c  property of the hippocampus or the r e s u l t afferent  impulses,  of  rhythmic  t h e r e i s g e n e r a l agreement that i t  i s r e l a t e d to the d i s c h a r g e p a t t e r n of s e p t a l  neurones.  44  B o l e Of A s p e n d i n g S y s t e m s I n The G e n e r a t i o n Of RSA The f i r s t s u g g e s t i o n t h a t t h e was  related  to ascending i n f l u e n c e s  was made by G r e e n a n d A r d u i n i peripheral and  stimulation  produced  RSA  and  of  the  indicator  of  proposed that The  *arousal'.  studies  initial  1962;  reticular  formation  desynchronization  and  Hagoun  (1949)  desynchronization  Green  observation  elicits (Torii,  Kawamura,  addition,  and  RSA 1961;  Nakamura  Arduini  classification  has  of  been  Yokata  (1954) pattern*.  and the  Arduini reticular  confirmed  and  an  by  Fujimori,  many 1964;  a n d T o k i z a n e , 196 1; P e t s c h e e t a l , 1972; H a c a d a r e t a l ,  'reticular of  Green  stimulation  A n c h e l and L i n d s l e y ,  However, t h e t e r m  of  had  as  RSA i s t h e ' h i p p o c a m p a l a r o u s a l  (1954) t h a t e l e c t r i c a l formation  In  neocortical  neocortical  that  e l i c i t e d h i p p o c a m p a l RSA  simultaneously. Since Horuzzi used  RSA  from t h e midbrain  desynchronization.  electrical  of  (1954) who o b s e r v e d  sensory s t i m u l a t i o n  neocortical  earlier  production  1974).  formation' i s a functional  collections  of  nuclei  having  a  c a u d a l - r o s t r a l e x t e n t from the medulla t o t h e m i d b r a i n . These n u c l e i c o n t a i n and  ascending  cells  axons  including the forebrain 1955;  Scheibel  which have projecting  and c o r t e x  and S c h e i b e l ,  long to  (Brodal  descending  many and  regions Rossi,  1958; N a u t a a n d K u y p e r s ,  1958;  Magni and W i l l i s , 1963). I n  more  precisely  an  attempt  t h e o r i g i n s of these ascending  to  map  systems  45  which e l i c i t  RSA  Eacadar e t a l {1974) demonstrated  electrical  stimulation  mesencephalic  of  and  pontine  c h a r a c t e r i s t i c hippocampal  tegmentum  oralis,  gigantocellularis elicit  RSA  distinct  regions  p a t t e r n s . They  s i t e s i n r e t i c u l a r i s pontis reticularis  anatomically  whereas  elicited  reported  locus  and  that  that  coeruleus,  the  midbrain  stimulation  of  raphe  n u c l e i and n u c l e u s r e t i c u l a r i s p o n t i s c a u d a l i s produced hippocampal d e s y n c h r o n i z a t i o n . T o r i i proposed  that  some  distinct  (1961) had  ascending  systems  produce hippocampal d e s y n c h r o n i z a t i o n whereas systems  elicit  RSA.,  This  proposal  earlier may  adjacent  was based on the  o b s e r v a t i o n that e l e c t r i c a l s t i m u l a t i o n i n  the  ventral  lateral  hypothalmus  (15-30 Hz)  a c t i v i t y of  midbrain  tegmentum  or  produces an i n c r e a s e i n the f a s t the  rabbit  hippocampus  dorso-lateral  whereas  medic-  stimulation  in  the  tegmentum and medial hypothalamic r e g i o n  e l i c i t s RSA. , Although ascending  inputs  eliciting not  the  from  studies the  demonstrate  brainstem  that  production of RSA.  the  brainstem  Stimulation of  hypothalamus  hippocampal RSA  is  that  are capable of  c h a r a c t e r i s t i c hippocampal p a t t e r n s  prove  posterior  above  they  do  necessary f o r the  sites  such  as  the  are a l s o e f f e c t i v e i n producing and  Fujimori,  1964;  Bland and Vanderwolf, 1972). This may  be due, i n  part,  to  through  (Torii,  stimulation the  1961;  of  hypothalamus.  Yakota  ascending  fibres  coursing  However, a r o s t r a l midbrain  46  transection cerveau  at  the  isole)  meso-diencephalic does  net  block  -junction  RSA  s t i m u l a t i o n o f t h e p o s t e r i o r hypothalamus Domino, 1 9 6 8 ) , which and  have  Furthermore,  a  chronic  Villablanca,  RSA  high  is  t h a n t h e b r a i n s t e m may these  areas  hypothalamic  and V a n d e r w o l f ,  diffuse  and  hypothalamic  (Kawamura  and  in  isole  cats  (Olmstead  not do  1973). systems  neither  that  sites  essential  not  since  abolish  massive  RSA  (Shishaw  Rather, these s t u d i e s which the  produce  RSA  indicate are  b r a i n s t e m nor t h e  very  posterior  regions are a b s o l u t e l y necessary  p r o d u c t i o n o f RSA.  other  p l a y a r o l e i n the g e n e r a t i o n of  are  lesions  that ascending  by  1977).  Although these s t u d i e s suggest  RSA,  generated  "recorded  cerveau  (high  for  the  T h e r e f o r e s m a l l and l a r g e l e s i o n s  of  v a r i o u s r e g i o n s from the medulla t o the d i e n c e p h a l o n  do  not  eliminate  RSA  lesions involving  a l t o g e t h e r . The  only exceptions are  t h e m e d i a l s e p t a l - d i a g o n a l band a r e a .  I n c h r o n i c and a c u t e p r e p a r a t i o n s e l e c t r o l y t i c of  the  medial  septum  abolish  a l l RSA  sensory s t i m u l a t i o n or e l e c t r i c a l  1965  for  review).  and  Furthermore,  large septal l e s i o n s  the  normally  associated  s l e e p i s a b o l i s h e d (Brugge, 1977).  These d a t a suggest  of  Arduini,  Deisenhammer, 1959;  following RSA  p r o d u c e d fay  stimulation  v a r i o u s s i t e s d i s c u s s e d a b o v e ( G r e e n and Brucke, Petsche, P i l l a t  lesions  RSA  1965;  1954;  Stumpf,  does not r e c o v e r  ( B r u g g e , 1 965) with  the  and  walking or Kolb  and  even active  Whishaw,  that the s e p t a l area plays a  47  critical  r o l e i n t h e g e n e r a t i o n of  12.1s. Qf. The  RSA.  S e p t a l A r e a I n The G e n e r a t i o n Of  Following the i n i t i a l above, a r e l a t i o n s h i p  RSA  l e s i o n experiments described the discharge pattern  of  s e p t a l n e u r o n e s and h i p p o c a m p a l e l e c t r i c a l a c t i v i t y  was  described  by  between  Petsche  e t a l ( 1 9 6 2 ) , Many c e l l s  m e d i a l s e p t a l - d i a g o n a l band bursts  which  neurones  fire  hippocampal Stumpf,  are  region  synchronous  with  desynchronization  in  RSA.  i n an i r r e g u l a r o r random  et  of  ( P e t s c h e e t a l , 1965; The the  (1974,1976) is of  projection  from  resulted  lateral  are s t i l l  bursting  fimbria,  the i n an  neurones  septal  control. the  hippocampal  major formation  activation-inhibition  s e p t a l neurones  neurones..On  that  hippocampal  the  discharge  RSA  between  not c l e a r . , M c L e n n a n  demonstrated  under  stimulation  bursting  the  or  W i l s o n e t a l , 1976) .  activity  activity  septum,  a l , 1962;  s e p t a l n e u r o n e s and  bursting discharge pattern of septal  Miller  during  mechanisms u n d e r l y i n g t h e r e l a t i o n s h i p  hippocampal  of  medial  same  1967) . R e t i c u l a r  peripheral sensory stimulation i n i t i a t e s pattern  The  P e t s c h e e t a l , 1965;  P e t s c h e , S t e r c and S t u m p f ,  discharge  rhythmic  manner  (Petsche  P e t s c h e and G o g o l a k , 1962;  Gogolak,  fire  i n the  and and unit  Electrical efferent to  the  seguence  and a s y n c h r o n i z a t i o n o f t h e  p a t t e r n d i s p l a y e d by m e d i a l s e p t a l  the basis of  these  data  they  suqgested  48  that  RSA  i s  "pacemaker the  1  not  simply  but that t h e  bursting  hippocampal  discharge  neurones v i a feedback loop These s t u d i e s of  the  pattern within  output of  the  based  septal  septal  region.  of the r o l e  o f BSA , The o n l y  t h e s e p t a l a r e a may i n f a c t i n i t i a t e  on  the  observations  that  2) some s e p t a l c e l l s c o n t i n u e  BSA  1) e l e c t r o l y t i c  l e s i o n s o f t h e s e p t a l a r e a b l o c k BSA and  initiate  medial  have prompted a r e - e v a l u a t i o n  s e p t a l area i n the generation  evidence that is  t h e consequence o f a s e p t a l  (reviewed  t o burst  above)  when RSA i s  not  present i n the v i c i n i t y of a recording  the  h i p p o c a m p u s ( P e t s c h e e t a l , 1962; R a n c k , 1 9 7 5 ) .  the  model p r o p o s e d by McLennan a n d M i l l e r  lesions  could  disrupting  electrode i n  (1976)  In  septal  be a b o l i s h i n g h i p p o c a m p a l RSA b y e i t h e r  m i d b r a i n a f f e r e n t s which  may  pass  through  the s e p t a l area t o r e a c h t h e hippocampus o r o p e n i n g t h e feedback  loop  observation when  through  the  septal  t h a t some s e p t a l c e l l s  area.  The s e c o n d  continue  to  burst  RSA i s n o t p r e s e n t i s h a r d e r t o a c c o u n t f o r u s i n g  McLennan and M i l l e r ' s  (1976) m o d e l , h o w e v e r , i t must be  remembered t h a t i n t h e e x p e r i m e n t s (1962) seizures  hippocampal  RSA  was  i n t h e hippocampus.  of  Petsche  eliminated Perhaps  a  by  et a l inducing  steady  input  f r o m h i p p o c a m p u s t o t h e l a t e r a l septum i s s u f f i c i e n t t o cause the b u r s t i n g discharge  Regardless  of  the  o f medial s e p t a l  mechanisms  involved,  apparent that the s e p t a l area i s o f c r i t i c a l i n the generation  o f RSA.  neurones.  i t is  importance  49  Role  Of  Pharmacologically  Distinct  C o n t r o l Of Septal-Hippocampal Many effective  investigations  particular  1966;  Anchel and L i n d s l e y , results  systems  of  have  anatomical  attempted t o c o r r e l a t e hippocampal  substrates 1972;  in  brainstem  regions  By  far  systems has  identification  1974).  without  basis  most  (Ach),  ascending  been of  studied but  the,  monoamine  prompted an i n v e s t i g a t i o n of t h e i r r o l e  hippocampal and  h±  of  the  the  putative transmitter i s acetycholine recent  RSA 1961,  s p e c i f i c n u c l e i . Another approach has  neurotransmitters.  more  (Torii,  Macadar et a l ,  to d e l i n e a t e these ascending systems on their  The  these s t u d i e s i n d i c a t e r a t h e r d i f f u s e  originating  implicating  In  Activity  brainstem s i t e s which e l i c i t  with  The  Systems  in  septal a c t i v i t y .  Acetycholine Bremer  and  Chatonnet  (1949) f i r s t  an i n t r a c o r o t i d i n j e c t i o n of Ach desynchronization was  obtained  i n r a b b i t s and  using  Rinaldi  Romanouski,  neocortical  cats. A s i m i l a r effect  of  and 1962).  (DFP)  Himwich, A  mediating the e f f e c t s of Ach  on  (eserine)  (Bremer and 1955b;  possible  at  acetycholinesterase  physostigmine  diisopropylflurophosphate 1949;  produces  by i n c r e a s i n g the a v a i l a b i l i t y of Ach  s y n a p t i c s i t e s by i n a c t i v a t i o n (AchE)  observed t h a t  Chatonnet,  Monnier  anatomical  neocortical  or  and system  'arousal'  50  was  described  using  histochemical  ( K r n j e v i c and S i l v e r , Shute be  and  Lewis,  showing  simultaneous  electrical  formation A the  an  with  of  by  r e l e a s e o f Ach  the midbrain  of  hippocampal  produced reticular 1968).  RSA. , I n t r a c a r o t i d  ( R i n a l d i and H i m w i c h , 1955a) a n d via  Romanouski,  1975) . E s e r i n e  a  variety  hand,  (atropine  and  routes  when elicits  (Brucke,  and N i c h o l s o n ,  also initiates  1962;  Sailer Monnier  scopolamine Nicholson,  of medial  septal units  the  bursting  muscarinic block  Hz)  antagonists  hippocampal  RSA  1962) and t h e b u r s t i n g p a t t e r n  (Stumpf e t a l ,  1962).  (1975) h a s r e c e n t l y r e p o r t e d (3-12  discharge  (Stumpf e t a l , 1 9 6 2 ) . On t h e  cholinergic  and  r e l a t e d RSA  eserine  1962; Stumpf e t a l , 1962; V a n d e r w o l f ,  (Bradley  Vanderwolf  of  species tested  p a t t e r n o f s e p t a l neurones other  provided  s y s t e m h a s a l s o been i m p l i c a t e d i n  S t u m p f , 1950; B r a d l e y  whereas  was  Jasper,1966; P h i l l i s ,  h i p p o c a m p a l RSA i n e v e r y  and  1967;  o f Ach o r DFP p r o d u c e l o n g t r a i n s o f RSA i n  administered  and  Shute,  increased c o r t i c a l  and  cholinergic  rabbits  activity  stimulation  production  and  neocortical desynchronization  { Celesia  injections  Lewis  1 9 6 7 ) . f u r t h e r e v i d e n c e t h a t Ach may  involved i n neocortical  studies  by  1965;  s t a i n i n g f o r AchE  i s not  blocked  However,  that  movement  by  atropine  i m m o b i l i t y r e l a t e d (4-7 Hz) RSA i s b l o c k e d .  the basis of these  data  Vanderwolf  On  (1975) s u g g e s t s t h a t  t h e r e a r e a t l e a s t two p h a r m a c o l o g i c a l l y  distinct  forms  51  of  BSA w h i c h h a v e d i f f e r e n t f r e q u e n c i e s  to  behaviour. The  of  effects  BSA  are  Following  o f Ach and e s e r i n e  dependent  septal  on  an  lesions  and  relations  on t h e  generation  intact  eserine  is  p r o d u c i n g RSA, h o w e v e r , i t c o n t i n u e s fast and  activity  o f t h e hippocampus  H i k l e r , 1966),  septo-hippocampal suggests that this  The  evidence  projection  eserine  may  area.  ineffective in  to  enhance  (Stumpf, 1965; for  a  formation release  Torii  cholinergic  (Reviewed i n S e c t i o n I I )  be e n h a n c i n g t h e a c t i v i t y  or  stimulation  the  medial  of  septal  i n t h e d o r s a l hippocampus  midbrain  the medial s e p t a l area block brainstem  stimulation  reticular  enhance  (Smith,  1972; D u d a r ,  lesions  the release  may  t h e e f f e c t s o f e s e r i n e on RSA  mediate  eliminate  the  strong  evoked  (Dudar, 1 9 7 7 ) . A l t h o u g h  the septo-hippocampal c h o l i n e r g i c  possibilities  that  s e p t a l a r e a o r 2) e s e r i n e  transmission septal  area.  i n synaptic  mechanisms  t h e y do n o t 1)  eserine input  enhances c h o l i n e r g i c intrinsic  The a b o v e s t u d i e s t a k e n t o g e t h e r  Ach i s i n v o l v e d i n t h e g e n e r a t i o n  anatomical substrates  this  system  e n h a n c e s t h e a c t i v i t y o f an e x t r i n s i c c h o l i n e r g i c the  Ach  of  o f Ach  suggests that  that  of  region  1975,1977;. F u r t h e r m o r e , e l e c t r o l y t i c  to  the  system. Electrical  by  septal  o f RSA,  to  the  suggest but  the  f o r t h e s e a c t i o n s a r e n o t known.  52  Bj. N o r a d r e n a l i ne The  first  suggestion  that adrenergic  systems  may  p l a c e a r o l e i n n e o c o r t i c a l or hippocampal ' a r o u s a l * i s b a s e d on t h e o b s e r v a t i o n s or  NA  produce  (Rothballer, or  NA  that  intravenous  neocortical  desynchronization  1 9 5 6 ) . However, i n j e c t i o n s  directly  adrenaline  of  adrenaline  i n t o the c e r e b r a l c i r c u l a t i o n  via  the  c a r o t i d a r e t e r y r a t produce a s i m i l a r  desynchronization  (Mantegazzini,  1959)  that  P a e c k and  systemic  effects  desynchronization. vasopressin  Santibonez,  The  (Capon,  1960)  pressure  desynchronization adrenaline  and  mediate  additional  descending t h o r a c i c aorta blood  may  and  (Baust  and  the  observed  observations  compression  produce the  act i n d i r e c t l y  that  of  e t a l , 1963)  have s t r e n g t h e n e d NA  suggesting  the  increase  neocortical proposal  to produce  that  cortical  'arousal'. More r e c e n t l y , a r o l e f o r originating and al  i n the  locus coeruleus  h i p p o c a m p a l a r o u s a l has (1973)  in  forebrain waking  dorsal (LC)  NA  lesioned  Jones  causing dramatic  NA  and  observed  a  time  and  cortical  activation.  depleting  desynchronization Jouvet,  1974) .  and  et  LC,  L i k e w i s e 6-hydroxydopamine i n j e c t i o n s i n t o the catecholamine  bundle  in neocortical  been p o s t u l a t e d .  electrolytically  depletion of decrease  the  drugs  waking  time  decrease  LC  and  cortical  (Lidbrink,  1974;  53  It  has  also  been  suggested  neurones o r i g i n a t i n g i n the production  of  RSA.  LC  This  t h a t NA c o n t a i n i n g  are  involved  suggestion  was  and  produce  ( B r a d l e y and  RSA  Vanderwolf,  1975;  unpublished related  systemic  results).  or  its  of  The  Barbour  the  (Macadar  amphetamine  N i c h o l s o n , 1962.; L o n g o ,  Assaf,  to i t s a b i l i t y  dopamine  injections  the  b a s e d on  o b s e r v a t i o n s t h a t e l e c t r i c a l s t i m u l a t i o n o f LC e t a l , 1974)  in  and  1962;  Miller,  e f f e c t o f a m p h e t a m i n e may  to increase release  direct  of  NA  be and  a c t i o n on d o p a m i n e r e c e p t o r s  (Moore, 1977).  £*. Dop_afflin e Although, evidence,  other  apomorphine RSA,  i t  at  this than  (Brucke  has  been  time, the  there  relating  suggested  to  "arousal  1  play  of  desynchronization Domaw,  L-Dopa  results  (Montegazzini 1970;  Hawer  and  effect  a p p e a r s t o be r e l a t e d  n o t t o NA  s i n c e i t i s not  prevents  the  1 9 7 0 ) . An  indirect  system  direct  Thut  and and  following in  1966). systemic  neocortial  Glasser,  1960;  Rech, 1972).  (Hawer and  This  DA  blocked with d i s u l f i r a m t o NA  to  a role i n the  t o an i n c r e a s e i n  c o n v e r s i o n o f DA  and  dopamine  (Hornykiewicz,  An i n c r e a s e i n b r a i n dopamine l e v e l s injections  no  e f f e c t s o f amphetamine  e t a l , 1957)  p r o d u c t i o n of c o r t i c a l  is  and which  Domer,  a c t i o n m e d i a t e d by t h e m e s o l i m b i c  p r o j e c t i n g t o the s e p t a l area  (Lindvall,  DA  1975;  54  Assaf  Pi.  and M i l l e r ,  1977)  i s more  likely.  Serotonin Serotonin  'arousal* cerebral cycle  on  the  levels  of  5-HT  electrolytic  and  sleep provided (Jouvet,  The r o l e o f 5-HT electrical  activity  (1962)  infusion resulted  the  in  recently,  observation  significantly  f u r t h e r support  In  f o r t h e above  the  control  is  a l s o c o n t r o v e r s i a l . Domer and  reported  5-HT  that  precursor  hippocampal  of  hippocampal  tha  intravenous  5-hydroxytryptophan  desynchronization.  produces c o r t i c a l Monnier,  a c t i v a t i o n and  1970),  More  electrical  raphe i n c a t s  d e s y n c h r o n i z a t i o n of hippocampal  c o n t r a s t , s t i m u l a t i o n o f t h e same s i t e  and  decreases  Macadar e t a l (1974) r e p o r t e d t h a t  in  nuclei  in  s t i m u l a t i o n i n the region of the midbrain results  raphe  that  1974).  first  of  that  during the d i u r n a l  of the midbrain  5-HT  cortical  observation  changes  destruction  relationship  Longo  initial  1974). The a d d i t i o n a l  forebrain  slow-wave  has been i m p l i c a t e d i n  based  (Jouvet,  reduces  (5-HT)  activity.  i n the r a b b i t  h i p p o c a m p a l BSA  However, t h e l a t t e r  study  (Pole d i d not  r e l a t e the e f f e c t s of s t i m u l a t i o n i n the r e g i o n of raphe  to  5-HT  methylsergide i.p.)  do  not  levels,  (10-20  in  fact,  large  m g / k g , i , p.) and p-CPA  block the a b i l i t y  r e g i o n of t h e r a p h e t o e l i c i t  BSA  the  doses (500  of  mg/kg  of s t i m u l a t i o n i n the (Bobinson,  1978).  55  T h e r e f o r e , some o f t h e s e o b s e r v e d s y n c h r o n i z i n g may  be  due  to n o n - s e r o t o n e r g i c systems passing  effects adjacent  t o the raphe n u c l e i .  Other  Transmitters  Glutamic activation  acid  may  be  involved  s i n c e the r e l e a s e  in  of glutamic  cortical  a c i d from  the  n e o c o r t e x i s r e d u c e d f o l l o w i n g l e s i o n s of  the  reticular  formation  and  increased  (Jasper,  following reticular glutamic the et  Khan and  electrical formation a c i d has  perforant al,1976),  and  path i n p u t has  as the  been  implicated  Electrical  perforant  generation  RSA  (Adey, M e r i l l e s and  The (GABA)  inhibitory may  also and  bursting  discharge  was  disrupted  GABA  Miller  by  antagonist  injection  (Assaf  p a t h d i d not  involved  i n the  (1974a)  and  (Nadler in  the  disrupt  pattern  shown  of  application  Miller,  1976)  unpublished  and  bursting  RSA. the  neurones of  b i c u c u l l i n e . I n a d d i t i o n , the  (Segal,  the  acid  that  of medial s e p t a l  electrophoretic  or  1977).  generation  have  of  Sunderland,1956;  Schwartzkroin,  of b i c u c u l l i n e d i s r u p t s the  of s e p t a l neurones  Although  amino a c i d g a m m a - a m i n o b u t y r i c  be  McLennan  the  stimulation  the  A n d e r s e n , B l a n d , M y h r e r and  in  transmitter  hippocampus  t r a n s e c t i o n of of  sites  to the  not  RSA.  of  Koyama, 1 9 6 9 ) .  been p o s t u l a t e d  of  1965)  stimulation  (Jasper  i t  generation  Elliot,  the  systemic discharge  hippocampal  observations)  .  RSA The  56  possibility of  t h a t GABA m e d i a t e s  hippocampal  t h a t i t may  neurones  the recurrent  inhibition  ( A n d e r s e n e t a l , 1964b)  be i n v o l v e d i n t h e g e n e r a t i o n o f  R e l a t i o n s h i p Of  Ser>tal  An d  Hippocampal  suqgests  RSA.  Activity  To-  Behaviour Hippocampal overt  movement  RSA  has  been  (Vanderwolf,  related  1969)  t o changes i n  and  to  inferred  processes i n c l u d i n g i n f o r m a t i o n processing (Routtenberg and  Kramis,  reward  1968),  and  (Konorski  punishment et  learning  attention  al,  (Elazar  Vanderwolf  (1969)  (Gray,  1968;  and  (Bennet  first  1970),  Grastyan  Adey,  e t a l , 1973),  1967;  et  motivation  al,  W i n s o n , 1978  observed t h a t  al,  RSA,  w h i l e o t h e r b e h a v i o u r s were n o t  1975  for  voluntary  review).. In  behaviours  such  the as  ).  accompanied  (Vanderwolf  freely walking,  rat  swimming  and  Hz  while i m m o b i l i t y or * stereotyped *  such  by  urination  relationship active activity 1971) .  (REM)  hippocampal 1973)  between sleep  consists  behaviours  RSA, as  and p e l v i c t h r u s t i n g a r e a c c o m p a n i e d  irregular  and V a n d e r w o l f ,  et  moving  m a n i p u l a t i o n o f o b j e c t s a r e a c c o m p a n i e d by 7-12  chewing,  and  certainovert  m o t o r b e h a v i o u r s of r a t s were c o n s i s t e n t l y by  1966)  .  One  major  (tfishaw  exception  to  o v e r t m o t o r b e h a v i o u r and RSA  since of  activity  RSA  the  hippocampal  (Vanderwolf,  the is  electrical  1971;  Harper,  57  The  above  hypothesis  relating  hippocampal  e l e c t r i c a l a c t i v i t y t o movement i s s t i l l c o n t r o v e r s i a l . Bennet  (1969)  and  others  observed that  movements  pressing  not  are  Whishaw and  ( F e d e r and such  as  R a n c k , 1975)  walking  a l w a y s a c c o m p a n i e d by  Vanderwolf  have  and  RSA.  lever  However,  (1973) have s u g g e s t e d  that  the  f a i l u r e t o o b s e r v e a c l o s e r e l a t i o n s h i p b e t w e e n RSA walking  or  lever  pressing  between t h e e l e c t r o d e  out  electrode.  RSA  due  p l a c e m e n t and  such that f a s t a c t i v i t y cancel  is  in  t o an i n t e r a c t i o n type  of  response  generated i n neighbouring  the  immediate  Another c h a l l e n g e  to the  and  vicinity movement  sites of  hypothesis  a r i s e s f r o m Klemm's (1970,1971,1976) o b s e r v a t i o n s RSA  can  be r e c o r d e d  during  Vanderwolf et a l (1975), pharmacological that there the  primarily  data  (reviewed  e x i s t s two  different  h i p p o c a m p u s , one  immobility  producing  (Type I ) and  which i s c o r r e l a t e d with  septal-hippocampal the  n e u r o n e s and overt  and  axis  activity attempting  on  the  ascending  low  higher  of  proposed  systems  freguency  has  RSA  to  during  freguency  RSA  to  been t a k e n t o r e l a t e the behaviour  is  that  o f s i n g l e h i p p o c a m p a l and to r e l a t e discharge Ranck  dorsal  hippocampal  unrestrained  d i v i d e d the recorded  g r o u p s on t h e b a s i s of t h e i r f i r i n g  of  septal  patterns  (19 7 3 ) ,  single units i n the  two  basis  movement (Type I I ) .  i n f e r r e d processes.  rats,  that  More r e c e n t l y ,  b e l o w ) , have  the other  Another approach t h a t  recording  immobility.  the  to  recording  formation  of  neurones i n t o  repertoire.  One  58  g r o u p , w h i c h he burst  containing  t y p e was  called  action Ranck  'complex s p i k e  different  'theta  potentials  cell'  which  firing  rate  movement'  related  r e l a t i o n s h i p of  there  cells  was  and  during  RSA  i s the best  was  and  cells*  ongoing  which i n c r e a s e  occurred  RSA  during  (1974)  of  these  pattern of  also reveal of  in  by  A s s a f and  studies  relating  t h e r a b b i t and  neurones to b e h a v i o u r a l  or  Miller  septal  'theta  only  during  whose  firing  *theta c e l l s '  Stumpf and  a  medial s e p t a l  rate  be  rate  behaviour.  I n the  s u g g e s t s t h a t t h e y may Petsche,  spike'  i n discharge  s p e c i f i c consumatory behaviours  by  Other  RSA,  'complex  ' t i g h t group c e l l s *  neurones recorded  rat.  to  most common  pattern  firing  the  contrast  c e l l s were i d e n t i f i e d  their  and  (1974).,The f i r i n g Ranck  discharge  major t y p e s o f  hippocampal  a  an i n c r e a s e  behaviour.  pointed  'voluntary  relation  i n the s e p t a l area  r e l a t i o n s h i p between t h e  RSA.  increase  In  successful appetitive  Similar recording  simple  and  o f t h e r a t . The of  a  other  description for  no s i m p l e  behaviour  behaviour  n u c l e u s two  'theta' c e l l s  a c o r r e l a t i o n between t h e f i r i n g  a p p r o a c h and  neurones  the  fired  'theta* c e l l s to behaviour.  the  and  i t  h i p p o c a m p a l RSA  r e l a t i o n s h i p between t h e f i r i n g cell  and  (1971) d e s c r i p t i o n o f  'complex s p i k e ' c e l l s had but  since  fire  were r e l a t e d t o o n g o i n g  during  that Vanderwolf's  cells',  size spikes  (1973,1975) o b s e r v e d t h a t  their out  called  (Ranck  recorded  by  same as  B-  the  Gogolak (1978)  the d i s c h a r g e  (1962) in  of  physiological states  the  septal suggest  59  an  increase  and  in  sensory At  time,  of  the  the  of  the  during  dehydration  anf Feldman, 1974),  relationships  between  septal-hippocampal  understood s u f f i c i e n t l y role  rate  stimulation(Hayat  this  activity  discharge  septum  t o allow and  axis  the  are not  an a p p r e c i a t i o n o f the  hippocampus  in  behaviour.  However, s e v e r a l t h e o r i e s which t r y to account f o r seme of  the  above  Vinogradova receives input  (1975)  do  stimuli  dendritic  contain  reaching  the  neurones  been  that  signals  not  b u r s t s of s e p t a l  have  postulated  generalized  which  about  observations  the  through  proposed. hippocampus  reticuloseptal  qualitative  information  hippocampus. The 'theta*  rhythmically  a c t i v i t y o f hippocampal  modulate  neurones  the  creating  the c o n d i t i o n s when comparison o r matching of i n p u t s will  be  possible  strictly  only  determined  for signals  time  guanta.  which  Nadel  and  (1974) suggested that the type o f i n f o r m a t i o n hippocampus theory, which  processes  is  used  by  concerning  deficits  animal  environment  spatial  environment.  the  This  and  relations theory  to  a  to  between  accounts,  0*Keefe  to t h i s  cognitive  move  in  which the  According  t h e hippocampus f u n c t i o n s as  locations i n i t s  map  to s p e c i f i c  solve  problems  o b j e c t s i n the in  part,  for  i n s p a t i a l l e a r n i n g f o l l o w i n g hippocampal and  septal lesions between  i s spatial.  come  the  {Hinson, discharge  1978)  and  the r e l a t i o n s h i p  p a t t e r n of hippocampal neurones  60  and unique places i n the animal's (Nadel and O'Keefe,  1974).  spatial  environment  61  IA.2 The  Present  On  the  different are  Study  basis  of  by  brainstem.  The  interposed  between  f o r m a t i o n and  medial  may  and  (NA)  the  RSA.  is  and  critically  the  serotonin  raphe  be  activity bundle  5-HT  in  the  ( c h a p t e r 4) from  the  A second will  that  the and  The  role  the  and  of  electrical (chapter  projection  the  3)  of  whether  of  activity.  anaesthetized r a t  control  locus  hippocampal a c t i v i t y  the  i n v o l v e d i n the g e n e r a t i o n  i n the urethane  nucleus  and  (5-HT)  o f sept al-hippocampal  t h e r o l e of t h e  hippocampal  suggest  s e p t a l area i n the g e n e r a t i o n of hippocampal  2)  activity  Meuroanatomical  hippocampus  may  patterns  area  p a r t o f t h i s t h e s i s e x a m i n e s 1) the  activity  above  f o r monoamine p r o j e c t i o n s t o  transmitters  Noradrenaline  electrical  brainstem  mediate  septal putative  septal  the  evidence  area  reviewed  a n a t o m i c a l l y d i f f u s e r e g i o n s i n the  neurochemical  first  evidence  p a t t e r n s of h i p p o c a m p a l  initiated  distinct  the  from  3)  median  septal-hippocampal the  dorsal  NA  c o e r u l e u s produces r h y t h m i c a l  (chapter  5).  f e a t u r e of the hippocampal f o r m a t i o n  that  be e x p l o r e d i n t h i s t h e s i s i s t h e p o t e n t i a t i o n  neuronal  t r a n s m i s s i o n between the e n t o r h i n a l c o r t e x  the dentate conditioning  gyrus.  P r e v i o u s s t u d i e s have i n d i c a t e d  stimulation  of  the p e r f o r a n t path  the e n t o r h i n a l p r o j e c t i o n to the dentate, marked  p o t e n t i a t i o n of the f i e l d  of and  that (PP) ,  results in  responses  e v o k e d by  a a  62  s u b s e q u e n t t e s t v o l l e y . However i t i s not activity  of o t h e r a f f e r e n t s  to  the  dentate  monoamine s y s t e m s a f f e c t P P - e v o k e d f i e l d second 1)  part  o f t h i s t h e s i s was  c h a r a c t e r i z e the  field  features  of  (chapter  6)  and  particularly alter  the  t e s t PP  2)  the  if  (chapters  7-9).  recorded  i n order to v e r i f y  obtained  PP  the  t h e PP  following systems synapses.  determining  whether  above,  d e n t a t e by a  synapses  this  w h i c h do not This  input  input  be  that the  effects  of  on  field  compared t o  results  p r o j e c t to the may  heterosynaptic i s a feature  be  in  stimulation  approach  a  laminar  previous suggestions  will  the  t o the d e n t a t e w i l l  conditioning  neuronal transmission formation.  of  the  afferents,  d e n t a t e g y r u s . The  stimulation  e v o k e d by  monoamine the  of  in  of t h i s  extrinsic  t h i s i n p u t t e r m i n a t e s a d j a c e n t t o PP layer  to:  to study  In chapter 7  presented  responses  designed  r e s p o n s e s evoked i n the  the c o m m i s s u r a l i n p u t  conditioning  The  monoamine p r o j e c t i o n s d e s c r i b e d  p r o f i l e of  molecular  responses.  potentiation  determine  field  volley  as  s t i m u l a t i o n and  homosynaptic  the  such  therefore  potentials  d e n t a t e g y r u s f o l l o w i n g PP  known how  of  be  of area  the of  useful  in  potentiation  of  the  hippocampal  63  ZsSL GENERAL METHODS  2., 1 S u r g i c a 1 P r e p a r a t i o n : Male  Wistar r a t s  weighing  between  recording with  ( R o o d l y n Farms, G u e l p h ,  250-400  experiments.  interperitoneal  (urethane produce  necessary  injections and  light  though  a  probe  heating  (EKEG  for  acute  a  of  ethyl  supplemental  previously was  carbamate  were  doses  to  given  as  implanted  monitored  by  jugular a  rectal  and m a i n t a i n e d b e t w e e n 36.5-37 C u s i n g  pad r e g u l a t e d by a t e m p e r a t u r e  control  unit  Electronics). The  frame  a n i m a l s were  (Model  incisor  bar  placed  the  midline incision  4.5-5.0 mm skull  in  a  Kopf  below  the  stereotaxic fixed  zero  by t h e thereby  horizontal  plane.  A  a p p r o x i m a t e l y 15 mm i n l e n g t h was made  t h r o u g h t h e s c a l p and s k i n with  in  1204) w i t h t h e head r i g i d l y at  positioning  held  used  anaesthesia  c a n n u l a . Body t e m p e r a t u r e thermistor  were  The a n i m a l s were a n a e s t h e t i z e d  1.0-1.5g/kg)  a state of  g  Ontario)  mosquito  flaps  were  retracted  and  f o r c e p s . The s u r f a c e o f t h e s k u l l  was t h e n s c r a p e d and d r i e d r e v e a l i n g bregma, lambda and t h e s a g g i t a l s u t u r e . One o r two p i e c e s of bone were  removed  underlying  and  cortical  the  dura  tissue  incised, was  so  exposed  (7x7 mm)  that over  the areas  r o u g h l y c o r r e s p o n d i n g t o b o u n d a r i e s 2.0 mm a n t e r i o r  to  bregma, 4.0 mm p o s t e r i o r t o bregma and 4.0 mm on e i t h e r  64  side and  of  the  s a g g i t a l suture f o r f o r e b r a i n placements  t o b o u n d a r i e s 2.0 mm  posterior  to  saggital Extreme  lambda  suture care  anterior  to  taken  not  in  to  the  The  e x p o s e d c o r t e x was c o v e r e d  t o keep t h e a r e a  mm  brainstem.  damage t h e s u p e r i o r  s a g g i t a l s i n u s when r e m o v i n g t h e bone o r dura.  3.0  a n d 3.0 mm on e i t h e r s i d e o f t h e  f o r placements  was  lambda,  incising  the  w i t h warm s a l i n e  moist throughout the experiments.  p o o l i n g o f s a l i n e was n o t p o s s i b l e warm m i n e r a l  When  o i l was  used.  2j>_2 S t i m u l a t i n g And E e c o r d i n g Stimulating lowered  into  electrodes  various  s u b s e q u e n t method holder.  in  were  regions,  sections,  For microelectrode  microdrive  Procedures stereotaxically  which a r e d e t a i l e d i n  using  a  Kopf  p l a c e m e n t s a Kopf h y d r a u l i c  (Model 607W) was u s e d t o l o w e r  the electrode  1 uM s t e p s . The a n t e r i o r - p o s t e r i o r (AP)  zero  for  a l l forebrain  electrode  while  brainstem  s t e r e o t a x i c zero  sinus  and  a l l these Klippel  suture  and  p l a c e m e n t s were m e a s u r e d  from  and  from the m i d l i n e p o s i t i o n o f vertical  measured f r o m t h e s u r f a c e for  was  at t h e t i p of the ear bar. A l l l a t e r a l  p l a c e m e n t s were t a k e n sagittal  stereotaxic  placements  measured from t h e j u n c t i o n o f t h e s a g g i t a l bregma  electrode  the  coordinates  were a l l  o f t h e c o r t e x . The  positions  p l a c e m e n t s were m o d i f i e d  from t h e Konig  (1963) a t l a s o f t h e r a t b r a i n .  65  Concentric instruments)  bipolar  having  electrodes  (SNE  100,  Rhodes  a t i p s e p a r a t i o n o f 0.5 mm  and  r e s i s t a n c e i n n o r m a l s a l i n e o f 75-100 K ohms were for  electrical  stimulation.  monophasic r e c t a n g u l a r isolated  stimulator  specified  otherwise  in duration  and  stimulators programmer from  Single  pulses  were  (Digitimer pulse  controlled  electrodes  0.15-0.5 mm  from  the  a  Single Unit Activity  were  containing  4M  prepared  a  when  under  unit  NaCl having  from  activity using  tips  1. 5 mm)  and  under  31  gauge  field  micropipettes  pyrex  microelectrodes  capillary  tubing  w h i c h were h e a t e d and p u l l e d and  the  broken back t o t h e d e s i r e d  width  observation.  puller  The  electrodes  were  a d i s s e c t i n g m i c r o s c o p e by i n j e c t i n g t h e  e l e c t r o l y t e i n t o the s h a f t of long  with  1976).  evoked  glass  microelectrode  were  microscopic  spread  t i p d i a m e t e r s o f 1-2 uM and  Corning  Canberra-type  filled  channel  stimulating  (Bagshaw and E v a n s ,  recorded  diameter  resultant  four  The  t o range between  DC r e s i s t a n c e b e t w e e n 2-5 M ohms. T h e s e  in  uA) .  And E v o k e d P o t e n t i a l s  Extracellular potentials  was e s t i m a t e d tip  i n t e n s i t i e s o f 10-100uA  (outside  0.05-0.1 msec  (20-400  by  an  unless  ( D i g i t i m e r M o d e l D4030).,The c u r r e n t  these  were  by  t y p e 2533) a n d  intensity  used  repetitive  delivered  p a r a m e t e r s were  1-20 V  were  and  BC  hypodermic  the needle.  pushed f u r t h e r down t h e s h a f t u s i n g  electrode The  using  a  s o l u t i o n was  a pyrex probe  until  66  capillary The pole  action  drew i t t o t h e t i p of the e l e c t r o d e .  m i c r o e l e c t r o d e was connected t o  of  a  custom  made  voltage  follower  i n s u l a t e d s i l v e r wire. The reference was  grounded  to  the  stereotaxic  or  and  and d i s p l a y e d  Tektronix  D13  positive using  negative  pole  Tektronix  5A22N  on a Tektronix D4 4 o s c i l l o s c o p e  dual  beam  storage  E x t r a c e l l u l a r u n i t a c t i v i t y was f i l t e r e d  oscilloscope. using  a 100Hz-  10kHz bandpass, while evoked p o t e n t i a l r e c o r d i n g s filtered unit  using  and  evoked  potentials  s i m u l t a n e o u s l y on the two beams outputs  were  voltage  which  discriminator  compared  predetermined  the  of  were  the  connected  audiomonitor. The a m p l i f i e d a  were  a 10Hz-3KHz bandpass. I n some cases both  activity  Amplifier  an  frame. The recorded  e l e c t r i c a l a c t i v i t y was l e d through a amplifier  the  to  recorded  oscilloscope. a  custom made  s i g n a l s were a l s o l e d  into  (HP.I Instruments, Model 120) recorded  triggering  signals  potential  so  p o t e n t i a l s having a minimum amplitude were  with that  a  action  represented  by an output s i g n a l . The s i g n a l s from the d i s c r i m i n a t o r were  fed  into  a  Schmidt  trigger  and the r e s u l t i n q  p u l s e s were subseguently l e d i n t o a PDP 11/10 Corp.)  computer  described plotted  programmed  to analyze the records as  i n the next s e c t i o n . The analyzed on a v i s u a l d i s p l a y t e r m i n a l  digital plotter  (Tektronix  (Digital  data  were  or an i n t e r a c t i v e  model 4662).  67  Electrical The  A c t i v i t y Of Tlje HiEPO£§fflEi§i EQJEfflatiGn  electrical  dentate  gyrus  was  steel electrodes Fig.  2-1,  activity  the  of  recorded  the  using  hippocampus  bipolar stainless  { t i p s e p a r a t i o n = 0 , 5 mm). signals  As  shown  r e c o r d e d from t h e s e  were f i l t e r e d  (2-30 H z ) , a m p l i f i e d  oscilloscope  and r e c o r d e d on a p o l y g r a p h  and d i s p l a y e d  on  (Gilson  used  to  discharges  P o l a r o i d camera resulting  2 ..3 D a t a  SiBgle  was  t h e r e c o r d e d e l e c t r i c a l a c t i v i t y and  s e c o n d beam was u s e d t o  neuronal  an  model  One beam o f a d u a l beam s t o r a g e o s c i l l o s c o p e  the  in  electrodes  MSP).  display  and  in  display  the  the  simultaneous  s e p t a l area.  A  Tektronix  (model C-5) was u s e d t o p h o t o g r a p h  oscilloscope  the  sweeps.  Analysis:  Unit  Activity  were  used t o  analyze t h e spontaneous discharge pattern  of a  neurone  and  by e l e c t r i c a l  determine  Several  methods  w h e t h e r i t was i n f l u e n c e d  stimulation  of a  particular  discharge  rate  was  i n t e r v a l histogram preferred  interval  Similarily  the nth  region.  analyzed  using  (IHT) . A peak between order  The  on  spontaneous  a an  first IHT  order  shows  f i r i n g s i n a spike  interval  histogram  a  train. i s the  d i s t r i b u t i o n o f t h e i n t e r v a l s b e t w e e n a g i v e n s p i k e and the  nth+1 s p i k e .  is  known  as  peaks i n d i c a t e  The sum o f t h e s e I H T ' s o f o r d e r  the autocorrelation the  preferred  function  periods  of  1 to n  whereby t h e the  spike  68  2-  l i  Schematic  Illustration  Of  Extracellular  Recording Technique., Slow e l e c t r i c a l a c t i v i t y i s recorded the  dentate gyrus using  electrodes.  Single  micropipettes are  amplified  bipolar stainless steel  unit  simultaneously from the  a c t i v i t y i s recorded  s e p t a l area using  f i l l e d with 4M and  displayed  NaCl. The on an  f o r photography or p l o t t e d on an terminal.  from  glass  signals  oscilloscope x-y  graphics  Dual-Beam Oscilloscope  A  r\  W  r  A  y y \j v 1' I r I i "> \i  V  "I I  r A  I  v  ,f  Filter D.I-3KHZ  ii  THPI t  J500/JV  200msec  Win dow Discirimin. v PDP-11  Computer  Plotter  70  train. an  Rhythmical  neuronal  autocorrelogram  displaying  whereas t h a t c o r r e s p o n d i n g is  flat  (Perkel,  patterns result i n  a  damped  and  measure  Uring  and  Gerstein,  neurone  Moore,  1967),  of  spontaneous  w h i c h was u s e d i s t h e j o i n t  (Rodieck,  oscillation  t o a randomly f i r i n g  Gerstein  additional statistical discharge  discharge  the  interval  1962)  in  An  density  which  the  a b s c i s s a v a l u e o f each p o i n t i s t h e d u r a t i o n o f a g i v e n i n t e r v a l and the c o r r e s p o n d i n g  ordinate  duration  interval.  of  the  gives a clear  subsequent  indication  of  the  value  i s the  This a n a l y s i s  bursting  discharge  p a t t e r n o f a neurone. In (PST)  stimulation  histogram  activity region  experiments,  a post  was u s e d t o a s s e s s  r e s u l t i n g from against  a  of  of  particular  time  t h e s t i m u l u s was summed o v e r many r e p e a t e d  presentations shows  a  stimulus  time  peak  a  lack  of  on  a  of discharge  ( G e r s t e i n and K i a n g ,  s t i m u l u s data whereby  or epochs. A  preferred  indicates  dots  a  spontaneous  n e u r o n e s . The d i s t r i b u t i o n o f s p i k e s i n to  time  t h e changes i n s p i k e  stimulation  background  stimulus  PST  firing relative stimulus  histogram  r e l a t i v e t o the  1960) whereas a f l a t  response  to the stimulus.  were a l s o d i s p l a y e d i n  a  rastered  PST Pest form  each s p i k e a p p e a r s a s a d o t and t h e d e n s i t y o f  before  probability  and that  after  the  stimulus  indicates  the background d i s c h a r g e  the  rate ofthe  n e u r o n e was a l t e r e d by p r e s e n t a t i o n o f t h e s t i m u l u s .  71  Evoked  Fields  photographed  Evoked from  field  digital  »ere  used.  The  averaging  was  by c o n v e r t i n g the analog a m p l i f i e r output t o voltage  microsecond  values  bins  which  by the PDP  were  sampled  11/10 computer.  t h i r t y consecutive stimulus presentations were  either  the s t o r a g e o s c i l l o s c o p e or p l o t t e d  when computer averaging was performed  potentials  used  to  L a t e n c i e s were  obtain  a  measured  typical from  35  Twenty t o  (ISI=1-5  average  the  in  sec)  response.  beginning  of  the  s t i m u l u s a r t i f a c t s to the peak o f the evoked wave (peak latency)  and/or to the onset of the evoked  l a t e n c y ) . The evoked responses with  negative  polarity  amplitude of each baseline  to  upwards  field  peak.  evoked f i e l d s was  In  were  always  as  response  wave (onset displayed  i n F i g . 2-2.  was  measured  The from  addition  the  r a t e of r i s e of  measured as the  net  voltage  change  from the onset of the f i e l d t o a predetermined i n t e r v a l (usually was  1.0-1.5 msec) a f t e r  measured  whenever  onset.  amplitude  The r a t e of measurements  rise were  l i k e l y t o be contaminated by s p i k e d i s c h a r g e s o c c u r r i n g near  the  peak  of  EPSP's ( F i g , 2-2). measure  the  the evoked Special  amplitude  of  field  care  as i n the case of  was  compound  also spikes,  p o p u l a t i o n s p i k e s d e s c r i b e d i n chapter 6 , sometimes Fig.  2-2,  measured  superimposed  on  the amplitude of as  d e f l e c t i o n to  the the  evoked the  taken  to  such as  which  were  waves. As shown i n  population  spike  was  v o l t a g e change from maximum p o s i t i v e peak  negative  deflection  of  the  72  O G J L  ;  2- 2:  Measurements Of Amglitudes  Of Evoked F i e l d  hz  field  EPSP  And Rate Of  Rise  Potentials,  p o t e n t i a l s such as the e x t r a c e l l u l a r  were  analysed  amplitude  and  rate  msec a f t e r  onset.  with of  respect  to  r i s e measured 1.0-1.5  B: compound s p i k e s which were  superimposed  evoked  with  waves  t h e i r amplitude positivity) ,  were  peak  analysed  on  respect t o  (maximum n e g a t i v i t y t o  maximum  73  74  spike.  This  method  amplitudes  was  previously  used  of  found  measuring  to  be  by Steward  as  population reliable  spike  as  et a l (1976) who  that  expressed  the spike amplitude as the average of the height of the ascending and descending limbs of the p o p u l a t i o n spike. In  a d d i t i o n , the present method i s  automated  data  analysis.  more  suitable  alterations  in  for  evoked  responses were expressed as a percentage of the c o n t r o l amplitude or r a t e of r i s e .  Bhythmical E l e c t r i c a l The slow dentate  wave  gyrus  Activity  activity was  of  analyzed  the  hippocampus  with  respect  to  freguency, amplitude and shape. The e l e c t r i c a l was  classified  consisted  as r h y t h m i c a l slow a c t i v i t y  Electrical  made  Hz and  activity  was c l a s s i f i e d  to  subclassify  average amplitude electrical to  the an  (SSa) i f i t  was  minimum amplitudes of 0.3  that  did  not  meet  as i r r e g u l a r . irregular often  No  noted  a l l three attempt  activity,  spontaneously  was  although i t s  ( F i g . 3-1).  When  occurring  used  electrical  used to time the onset and t e r m i n a t i o n of  the s t i m u l u s t r a i n BSA was  mV.  event marker on a separate channel of the  polygraph was  of  activity  s t i m u l a t i o n or drug a d m i n i s t r a t i o n was  alter  activity  its  of roughly s i n u s o i d a l waves with a frequency  v a r y i n g from 3-12  criteria  and  or i n j e c t i o n  computed by manually  s i n u s o i d a l •theta*  waves  period.  The  freguency  counting the number of  occurring  during  1  second  75  sampling  periods.  Typically,  beginning  one m i n u t e b e f o r e t h e  r e c o v e r y t o background Statistical  rates  were  stimulus  f o r c o m p a r i s o n s o f d a t a were a l l  disprove  the  hypothesis.  evoked used.  and  tests  the  which  designed  For comparisons  two i n d e p e n d e n t p o p u l a t i o n s s u c h a s before  until  activity.  were u s e d  RSA  train  A n a l y s i s : the s t a t i s t i c a l  null  calculated  to  between  freguency  of  during stimulation o r potentiation of  responses a  conventional Students t - t e s t  was  When c o m p a r i s o n s were made b e t w e e n two d e p e n d e n t  measures , such as whether  or n o t a p o p u l a t i o n o f c e l l s  i s i n h i b i t e d , t h e b i n o m i a l d i s t r i b u t i o n was u s e d .  2iii Lesioning All  Technigues  l e s i o n s were p e r f o r m e d when t h e  anaesthetized  with  (50 mg/kg i . p , ) .  sodium  The a n i m a l s  were  s t e r e o t a x i c frame and t h e s k u l l the  previous sections.  calvarium was  used  lesioning  (1.0-1.5 M to  positioned  exposed a s d e s c r i b e d i n i n the  sharp  underlying  dura  needle and t h e  e l e c t r o d e o r c a n n u l a was t h e n s t e r e o t a x i c a l l y  lowered t o the desired depth, A l e s i o n  was  u s i n g one o f t h e methods d e s c r i b e d b e l o w . lesions  i n the  S m a l l h o l e s were d r i l l e d  the  were  pentobarbital  i n d i a m e t e r ) and a  puncture  animals  the  incision  was  sewn  up  then  made  Following the  and  the animals  allowed to recover i n a temperature c o n t r o l l e d  cage.  76  Electrolytic The  l e s i o n i n g e l e c t r o d e s were made by s c r a p i n g t h e  insulation under the  Lesions  a  o f f t h e i n n e r p o l e o f an dissecting  device  The  (Model  positive LM5A)  to the t a i l  between t h e n e g a t i v e  pole  was  i n n e r t i p o f t h e e l e c t r o d e and t h e connected  electrode  m i c r o s c o p e s o t h a t 0.5-0. 75 mm o f  t i p was e x p o s e d .  lesioning  SNE-100  of  a  connected t o the  negative  o f t h e animal.  Grass  pole  A good  p o l e and t h e a n i m a l  connection  was s e c u r e d  w r a p p i n g a m o i s t c o t t o n swab a r o u n d t h e a n i m a l * s The  lesioning  before  current  (1.0-1.5  surgical  blade  before  course  complete  holder.  preadjusted  the  0.5 mm  surface  of  from  the  to  The  dura  modified  overlying gently  the  in  To  the  removed  transect  position  4.5 mm  posterior  to  t h e m i d l i n e and 4.0 mm b e l o w t h e  cortex;  the  saggital  the  the  the v e n t r a l psalterium t h e  blade  was  then  moved  s i n u s t o a p o s i t i o n 2.0 mm  a n t e r i o r t o bregma. To t r a n s e c t b r a i n s t e m forebrain  a  w h i c h was mounted on a  transection.  commissure  bregma;  using  was s t e r e o t a x i c a l l y l o w e r e d a n d moved  J c n i f e was l o w e r e d t o a  parallel  made  o f t h e t r a n s e c t i o n was  the blade  hippocampal  were  (1.0 mm X10.0 mm)  stereotaxic  intended  the  tail.  Transections  Acute t r a n s e c t i o n s  to  was  by  a n o d a l DC c u r r e n t was p a s s e d f o r 10-15 s e c o n d s .  A c u t e And C h r o n i c  Kopf  mA)  was  saggital  sinus  was  afferents tied  to  o f f and  77  removed before the k n i f e was lowered 3.0  mm  behind  mm  below  bregma; 4.5  the  mm  to a p o s i t i o n  from the m i d l i n e  s u r f a c e of the c o r t e x . As the k n i f e  moved across the c o r o n a l plane i t was  gradually  f u r t h e r r e a c h i n g a depth of 7.0-8.0 mm At  this  point  it  was  gradually  approached the c o n t r a l a t e r a l s i d e . necessary s k u l l and  to  at the  The  one  performed by d r i l l i n g positioned  midline  and  1.0  bregma 5.0  mm  from  and  mm  the  the  midline  other  posterior  to  1.0  hole  and  through  one  the o t h e r . The two  and  mm  was  carefully  skull, 2.0  from  bregma,  lowered  mm the  A sterile thread  was  brought up  ends of the thread were then  thereby t r a n s e c t i n g the o v e r l y i n g f i b r e s .  The curve of t h e needle mm  it  commissure  two s m a l l holes i n the  with attached  4.5  as  arteries.  (6-0)  gently l i f t e d  midline.  procedure  curved s u r g i c a l needle  through  was  account f o r the shape of the base of the  avoid damaging t h e b a s i l a r  a n t e r i o r to  2.5  lowered  retracted  Chronic t r a n s e c t i o n of the hippocampal was  and  2.5-  assured  a  minimum  at the l e v e l of the v e n t r a l p s a l t e r i u m .  depth  of  78  Neurochemical  Lesions  Chemicals Hamilton  30  gauge  stereotaxic special was  were  injected  intracerebrally  microsyringe  h o l d e r . The  attached  microsyringe  care t o e l i m i n a t e a i r bubbles.  stereotaxically  tissue  damage.  A  lowered  very  predetermined  u s i n g a micrometer a t the r a t e of t h e end  of the i n j e c t i o n  place f o r at l e a s t diffusion was  was  of  10  to  the s o l u t i o n  a  filled  The  Kcpf taking  microsyringe  slowly  to  minimize  volume  was  injected  1.0  ul/10 minutes.  period the cannula minutes  using a  to  was  allow  away f r o m t h e  At  left  in  undisturbed t i p before i t  withdrawn,. The  V=-4.5  d o r s a l noradrenergic bundle below  bilateral  cortex)  injections  was  with  0.2mg/ml  have s u g g e s t e d  selectively  acid).  axons  subsequent d e s t r u c t i o n .  (Tranzer  and  the  degree  Sachs  and  tissue  damage a t t h e i n j e c t i o n  Jonsson,  needle  penetration  0.25  i n any  1975)  and  intragastric  (p-CPA, 400  Previous  0.15M  studies  the  resulting  site  by  in  their  Thoenen,  1967;  of n o n s p e c i f i c  resulting  injection  from  d i d not  the  exceed  penetration.  Central serotonin using  u l of  t h a t 6-OHDA i s s p e c i f i c a l l y t a k e n up  catecholamine-containing  mm  using  hydrobromide  6 ug d i s s o l v e d 2.0  ascorbic  L=+1.1;  destroyed  o f 6-hydroxydopamine  (6-OHDA, R e g i s C h e m i c a l ; NaCl  (AP=+2.6;  (5-HT) was  injections  mg/kg; P f i z e r  Inc.)  of  selectively  depleted  p-chlorophenylalamine  suspended  i n 2-3  ml  of  79  saline.  The  suspension  was  p r e p a r e d b y a d d i n g a few  d r o p s o f p o l y s o r b a t e (Tween 80) t o wet t h e p-CPA  was t h e n c o m p l e t e l y d i s s o l v e d a t pH  5 M NaOH. The s u s p e n s i o n was t h e n d i l u t e d and  saline to f i n a l  CPA h a s b e e n f o u n d by  inhibition  The  11 by a d d i n g u s i n g 5M  HC1  pH o f 7.0. G i v e n i n t h i s manner p-  t o b l o c k 5-HT  of  solid..  enzymatic  biosynthesis  possibly  tryptophan hydroxylation  (Koe and W e i s s m a n , 1966) . The r e s u l t i n g d e p l e t i o n o f 5HT i s m a x i m a l 2-4 Cell using  days f o l l o w i n g t h e i n j e c t i o n .  bodies i n  direct  the  septal  Kainic acid  e x c i t a n t amino a c i d g l u t a m a t e  injection  destroy  cell  i s an  (1.0-3.0 ug i n  analogue  of  the  has been c l a i m e d t o  bodies  i n t h e area of the  without d e s t r o y i n g axons  McGeer a n d McGeer,  destroyed  which  passing through the i n j e c t i o n s i t e 1974;  were  i n j e c t i o n s of k a i n i c acid  1.0 u l o f s a l i n e ) .  specifically  area  1977).  terminating  in  or  ( O l n e y , Ho a n d R h e e ,  80  2 5 Neurochemical  Assays  A  The e f f e c t i v e n e s s o f 6-OHDA and p-CPA i n d e p l e t i n g central  noradrenaline  ,respectively, concentrations  was of  (NA)  evaluated  these  nucleus, t h e hippocampal At t h e t e r m i n a t i o n o f experiments  and  serotonin  by  (5-HTj  assaying  substances  i n the  the caudate  f o r m a t i o n and t h e s e p t a l a r e a .  t h e acute  electrophysiological  t h e a n i m a l s were d e c a p i t a t e d and t h e above  b r a i n a r e a s p r o m p t l y removed. The c o n c e n t r a t i o n  of  NA  was  measured u s i n g a r a d i o e n z y m a t i c assay a c c o r d i n g t o  the  methods  of  concentration to  Coyle  and  Henry  (1973).  o f NA i n 6-OHDA t r e a t e d r a t s was c o m p a r e d  l e v e l s i n animals that  t h a t were a l s o a n a e s t h e t i z e d  and u s e d f o r e l e c t r o p h y s i o l o g i c a l e x p e r i m e n t s as t o v a l u e s o b t a i n e d from u n o p e r a t e d Serotonin  concentration  spectrofluorometric previously  assay  described  by  electrophysiological  was  morning.  well  and  and  using  to  immediately  were d i s s e c t e d o u t a n d f r o z e n a t -40 following  measured  Richardson  experiments  as  controls.  according  ( 1 9 7 3 ) . The a n i m a l s were k i l l e d  the  The  methods Jacobowitz after  the brain  degrees  a  C  the areas until  They w e r e them h o m o g e n i z e d a n d  a s s a y e d on a T u r n e r m o d e l 430 spectroflourometer»  81  ZtJk Si§i2l53i£§2 The passing  location of stimulating sites l o w DC a n o d a l c u r r e n t  through small  the iron  deposits spots  Analysis  stainless deposits  were  perfused  with  Prussian  observed under positions sky  visualized  reaction  the light  product  The  as b l u e / g r e e n was  mixture  r e a c t s w i t h Fe++ r e s u l t i n g  in  which i s e a s i l y  microscope.  Microelectrode  were d e t e r m i n e d b y e i t h e r e j e c t i n g p o n t a m i n e  b l u e d y e ( 2 0 % w/v i n 4a  (Thomas  tip.  a potassium f e r r o c y a n i d e / f o r m a l i n  blue  by  resulting i n  s e c t i o n s when t h e p r e p a r a t i o n  (1g/100 m l ) . The c y a n i d e the  electrode  the electrode  subsequently  in histological  marked  ( 1 0 - 1 5 uA f o r 10 s e c o n d s )  steel  from  was  and  Wilson,  e l e c t r o d e t i p so t h a t  NaCl) e l e c t r o p h o r e t i c a l l y  1965) the  or  by  electrode  visualized after the fixation  breaking track  o f f the could  be  ( f o r e x a m p l e See F i g . 3-  2) . The  animals  anaesthetic 200  were  killed  agent and p e r f u s e d  by  an overdose o f t h e  intracardially  ml o f 0.9% N a C l f o l l o w e d b y 100 ml o f 1 0 %  formalin,,  Histological  verification  s i t e s was made by c u t t i n g 50  uM  s t a i n i n g them w i t h c r e s y l v i o l e t  w i t h 100buffered  of the e l e c t r o d e  frozen  sections  or s a f f r a n i n .  and  82  CHAPTER • 3s - ROLE OF THE SEPT AL • ,ARE& -1H THE GENERATION- OF • HIgPQCAMPAL ELECTRICAL A C T I V I T Y  Introduction As of  reviewed  i n chapter  t h ehippocampal  formation consists of a  s l o w and f a s t waves h a v i n g related  to  ongoing  (RSA)  stimulation midbrain  or  direct  reticular  hippocampal  or  i s recorded activation  formation.  activity  of  et  a l  (1962)  observed  neurones f i r e  p h a s e o f RSA  desynchronization  the  that  electrolytic  sensory ascending  lesions  RSA  i n b u r s t s which  waves,  same  {MS) r e g i o n .  during  whereas,  neurones  i r r e g u l a r o r random manner. The a d d i t i o n a l that  slow  h a s been r e l a t e d t o t h e d i s c h a r g e  Petsche  during a certain  regular  In rabbits, rhythmical  neurones i n t h e medial s e p t a l  MS  most  the  of  of  septum  hippocampal  'paces'  during  fire  i n an  observation  of the s e p t a l area  formation  electrical (Petsche  et  a  occur  abolish  RSA ( B r u c k e e t a l , 1959) h a s l e d t o t h e p r o p o s a l the  of  The  during  pattern  population  mixture  states.  i s a synchronous  which  activity  v a r y i n g a m p l i t u d e s which a r e  physiological  conspicuous a c t i v i t y activity  1, t h e e l e c t r i c a l  activity  that  of the  a l , 1962; Stumpf,  1965). A  t r u e pacemaker i n t h e s e p t a l area  t h e h y p o t h e s i s t h a t RSA i s g e n e r a t e d inputs  which  produce  periodic  would  support  by p h a s i c a f f e r e n t depolarization  of  83  hippocampal Recently,  neurones  McLennan  and  electrophysiological bursting  discharge  conseguence This MS  (Ton  Miller  rather  Green,  (1976)  evidence  pattern of  and  that, MS  1960).  have in  provided  the r a t , the  neurones  may  be  a  than the c a u s e o f h i p p o c a m p a l  RSA.  prompted a r e - e v a l u a t i o n o f t h e e v i d e n c e t h a t  the  initiates The  RSA.  purpose  of  the  present  c h a r a c t e r i z e the discharge in  Euler  the  urethane  patterns  to  hippocampus  and  2)  is  p a t t e r n s of s e p t a l  anaesthetized  ongoing  chapter  rat  electrical describe  and  to  1)  neurones  r e l a t e these  activity  mechanisms  of  the  which  could  u n d e r l i e the observed r e l a t i o n s h i p s .  3JL2 E x p e r i m e n t a l  Procedures  Slow e l e c t r i c a l a c t i v i t y  from the  CA1  r e g i o n of the d o r s a l hippocampus or  the upper blade  of  the  technigues  dentate  i n chapter  g y r u s i n 71  2.  The  neurones i n the posterior 6.0  mm  simultaneous  surface  extracellularly.  stereotaxic  were  mm  into  from the  n e u r o n e s were c l a s s i f i e d position  of  of  single  midline; was  recording the  detailed  a n t e r i o r t o 0.3  of the cortex)  Several made  discharge  (0.2  t o bregma; 0.1-0.5 mm  penetrations  recorded  r a t s using  s e p t a l area  below the  individual  was  septal  mm 3.5-  recorded electrode  region  and  on t h e b a s i s o f  the  the r e c o r d i n g e l e c t r o d e ,  the  r e s p o n s e t o s t i m u l a t i o n of the  fimbria  (McLennan  and  84  Killer,  1974a)  and  t h e d i s c h a r g e p a t t e r n of neurones  analyzed as outlined  i n c h a p t e r 2.  Hippocampal e l e c t r i c a l a c t i v i t y in  animals  which  electrolytic  previously  lesion  of  the  electrolytic  (1.5 mfl a n o d a l  neurotoxin  MS l e s i o n s ,  without i n t e r f e r i n g a). at  recorded  (3-20 days) had e i t h e r  seconds) or an i n t r a s e p t a l i n j e c t i o n saline)  was a l s o  current  for  an  10-15  (1-3 ug i n 1 u l o f  kainic acid  which,  destroys neuronal  w i t h axons o f passage  unlike  perikarya  (See a p p e n d i x  I n 4 a d d i t i o n a l r a t s an a c u t e t r a n s e c t i o n was made the  level  of  contribution  of  pattern of septal  the  hypothalamus  brainstem  to  evaluate  the  afferents to the discharge  neurones,  3.3.3 R e s u l t s  Spontaneous E l e c t r i c a l The D e n t a t e  Of The Hipfiocamjaus  JLfid  Gyjrus  Electrical pyramidal c e l l granule c e l l these  activity  activity  was  recorded  from t h e CA1,  l a y e r and t h e upper b l a d e o f t h e d e n t a t e  r e g i o n . The r e c o r d s o b t a i n e d f r o m b o t h  sites  consisted  of  either  of  1) a n i r r e g u l a r o r  desynchronized  activity  consisting  of  waves  varying  amplitudes  ( F i g 3-1B  o r 2) a  having  constant  having  rhythmic  pattern  of  amplitudes  and  (Fig  The l a t t e r  3-1a).  slow  frequencies  waves which  pattern,  slow  ranged  referred  and  fast  f r o m 3-7  t o as  RSA  Hz or  85  :  ll  From  Patterns The  Of E l e c t r i c a l A c t i v i t y  Dentate  Gyrus  O f A  Recorded Urethane-  Anaesthetized Rat. IxPi  spontaneously o c c u r r i n g RSA shown at f a s t  and slow sweeps., Bxll  desynchronized  electrical  recorded from the same p o s i t i o n  activity  3 minutes a f t e r  the previous r e c o r d s , Ci  somatosensory s t i m u l a t i o n  s o l i d line)  ( i n d i c a t e d by the  s h i f t s the e l e c t r i c a l  activity  from  d e s y n c h r o n i z a t i o n t o RSA. I i . records o b t a i n e d f o l l o w i n g t h e death of animal  indicating  electrical  noise.  minimal  contribution  the of  86  87  •theta',  could  stimulation 1C).  The  also  such  be  always  dentate  with  similar respect  obtained dentate  to  tail  activity  that  ( F i g 3-  recorded  recorded  from  from the  and f r e g u e n c y .  r e c o r d e d i n CA1, i n t h e a b s e n c e  the dentate. F o r t h i s  from  somatosensory  t o i t s synchrony  Moreover, RSA was n e v e r ESA f r o m  by  as p i n c h i n g the animal's  pattern o f e l e c t r i c a l  CA1 was  of  elicited  histologically  ( F i g . 3-2) w i l l  be  reason  only  verified  presented  records  sites  i n the  the  present  in  urethane  in  thesis. ,  The  frequency  of  RSA  anaesthetized  rats  the freguency  o f RSA i n f r e e l y  previously effects in of  of urethane  RSA  was  of  be  activity, urethane i.v.)  (3-12 Hz)  on RSA f r e g u e n c y have been  observed  1965).  The spontaneous  t o the depth  RSA c o u l d  be  at  movement a r t i f a c t s  with  5  previously  in  contribution  did  of  electrical  not rats. noise  with  (20 mg/kg,  The s p o n t a n e o u s  p a t t e r n s of e l e c t r i c a l  non-immobilized  which  anaesthetized  ventilated.  conditions  wide  the patterns of e l e c t r i c a l  were t h e n i m m o b i l i z e d w i t h f l a x e d i l  these  a  In order to e l i m i n a t e the  associated animals  occurrence  o f a n a e s t h e s i a , but  demonstrated  o f any e x t r a n e o u s  and a r t i f i c i a l l y  obtained  rats  than  Similar  related  sensory-evoked under  Vanderwolf  a n a e s t h e t i c doses.  possibility might  by  moving  lower  (1 9 7 5 ) .  ( Stumpf,  sensory-evoked range  (3-7 Hz) i s s i g n i f i c a n t l y  reported  rabbits  observed  activity  differ  recorded  from  those  Furthermore, generated  and  by  the the  88  EIGj.  3- • 2^. L o e a t i o n  Of  Dentate Gyrus, Ai  A  gecording  drawing  formation showing  of  the  The  hippocampal  pyramidal c e l l l a y e r  of  the  proper ( t r i a n g l e s ) and the granule  c e l l s of the dentate gyrus B_i C o r o n a l s e c t i o n of electrode  Xs.  y  schematic  hippocampus  Electrode  positions  recorded i n the  the  gyrus. Abbreviations: Pyramidal c e l l  CC  Corpus Callosum  DG  Dentate Gyrus  Ffl  Fimbria  HF  Hippocampal  H  Dentate H i l u s  rat  brain  showing  (arrow) from which ESA  upper  CA1-3  (circles),  layer  Fissure  blade  of  the  was  dentate  89  90  equipment  and  recording  from  shown  in  room  Sep_tal O n i t  checked  routinely  after  death.  by As  3- 1f, s u c h a r t i f a c t s d i d n o t c o n t r i b u t e t o the recorded  activity.  Activity_  Action potentials greater  was  the animal immediately  Fig  substantially  fixtures  than  4:1  with  signal  (160:40 uV)  to  noise  ratios  were r e c o r d e d f r o m  431  n e u r o n e s i n t h e m e d i a l s e p t a l - d i a g o n a l band r e g i o n . A l l neurones  were  discharge  spontaneously  frequencies  active  and  exhibited  r a n g i n g between 2 and  50  Hz.  the b a s i s of t h e i r d i s c h a r g e p a t t e r n s  septal  were  (I - n e u r o n e s )  classified  bursting  as  (B-neurones).  an  irregular  any  c o n s t a n t phase  hippocampal neurones, which  either irregular  or  I-neurones  random p a t t e r n w h i c h relationship  electrical  always  observed (Fig.  D) .  This  the  (Fig.,3-3  exhibited  or  as  A-C).  E)  wave  and  of B-  manner  were  also spikes  occurred  of  sensory  a c o n s t a n t f r e q u e n c y and  A g i v e n B - n e u r o n e may 'theta'  result  •theta'  in  desynchronized  p a t t e r n , which a  or  exhibit  patterns  ( F i g . 3-3  bursting  r e l a t i o n s h i p to hippocampal  the  d i d not  with the  activity  spontaneously  stimulation,  of  discharged  t o d i s c h a r g e i n r h y t h m i c b u r s t s o f 2-10  3-3  either  neurones  i n an i r r e g u l a r  associated  p a t t e r n of hippocampal  to  activity  i n addition to f i r i n g  was  always  On  phase  waves.  discharge during f o r each c e l l  any  phase  the discharge  91  3-  3_i  P.iffergnces  In The  Discharge  RM£hmical  S e p t a l Neurones Recorded During Desynchronized  Hi££ocamDal  Single  oscilloscope  the  trace  is  a c t i v i t y and  Or  Activity  AxB^DxIl top  P a t t e r n s Of  sweeps i n which  hippocampal  the lower t r a c e the  electrical  simultaneously  recorded  septal  unit  d i s c h a r g e s . A and D were  recorded  during  RSA  whereas  recorded  during i r r e g u l a r  C fi  Inter-spike  x  (corresponding  to A and  C  and  E  were  activity. interval  D)  histograms  indicating  irregular  discharge of the I-neurone (C) and the b u r s t i n g bimodal discharge p a t t e r n of the B-neurone (F). Number of s p i k e s i n each histogram the bin width i s 3 msec.  i s 2000  and  92  :93  ZIILL  2-  4.1  Local i z at i o n  o f B-neurones In - The-Septal-  Area. Ai  Coronal  sections  from  stereotaxic  atlas  showing the d i s t r i b u t i o n of neurones which were i d e n t i f i e d as B-neurones.. Bc x  of  Histological the  pontamine  v e r i f i c a t i o n of the p o s i t i o n  recording sky  electrode  non-bursting  was l e f t a t the  neurones  of  neurones were f i r s t  recorded  medial s e p t a l r e g i o n .  site  i n the dosal septum  and the lower d e p o s i t was l e f t  the  ejection  blue dye ( i n d i c a t e d by arrows) .  Note t h a t the top d e p o s i t of  by  where  bursting  i n a t r a c k through  00 CD  <  95  distribution  as  remained  fairly  F i g . 2).  In  revealed constant  contrast  by  serial  correllograms  (see a l s o Petsche et a l ,  to  the  conclusions  1962  drawn  by  Petsche et a l (1962) f o r s e p t a l b u r s t s i n the r a b b i t , a small  proportion  (20-30%)  of  B-neurones  i n the r a t  d i s p l a y an amplitude decrement within a b u r s t . However, intracellular guantitative to the  recordings a n a l y s i s and  are  necessary  for  a  comparison of t h i s decrement  ' i n a c t i v a t i o n response* o f hippocampal pyramidal  c e l l s described patterns  by von E u l e r and  Green (1960) . S i m i l a r  of neuronal discharges  have been d e s c r i b e d i n  the r a b b i t . (Petsche  et a l , 1962;  Stumpf e t  al,  1962;  Apostol and C r e u t z f e l d t , 1974), Of the 431  neurones recorded  throughout the s e p t a l  r e g i o n i n t h i s s e r i e s of experiments 202 were  classified  as  I-neurones  neurones. However, there was  and  the septum In  229  B-  a regional distribution  of  was  (53%)  recorded  that were i n the ventro-medial  aspects  addition  to  their  characteristic  s e p t a l neurones were c l a s s i f i e d on the  B-neurones  tested,  activated following single dentate  of  discharge  of t h e i r response t o s t i m u l a t i o n of the dentate 51  in  ( F i g . 3-4) .  patterns,  Of  (47%) as  B-neurones whereby a high p r o p o r t i o n penetrations  neurones  at  a c t i v i t y was  24  pulse  were  basis gyrus.  antidromically  stimulation  of  the  the same e l e c t r o d e p o s i t i o n from which  RSA  recorded  one  ( F i g . 3-5).  In c o n t r a s t , only  96  fISi.  2z S i . C h a r a c t e r i s t i c s Of A S e p t a l hz  Single  oscilloscope  spontaneous b u r s t i n g  sweep  B^neurone.. displaying  the  pattern.  B£ Antidromic a c t i v a t i o n of the same neurone i n response to s t i m u l a t i o n (DG).  the  Collision-extinction  occurring Ci  of  spike  Inhibitory  following  antidromic  of  i n middle t r a c e . the  activation  B-neurone of  superimposed sweeps), Arrows i n d i c a t e artifacts.  gyrus  with spontaneously  is illustrated response  dentate  DG  (25  stimulus  ^Jo.2 mV 2 0 0 msec  M"0.2 mV 2 msec  0.1 mV 50 msec  98  of  96  I-neurones  activated. spikes  Several  were  constant  could  criteria  latency (3-5  evoked:  antidromically  (a)  {1.0-3,0 msec) volts),  (b)  i n the c o n f i g u r a t i o n  ability to 150 Hz),  short  at  neurones  threshold  follow  Single  high  the  presence  with  of  freguency  stimulation  (100-  p u l s e s t i m u l a t i o n of the f i m b r i a  a  shorter  latency  the  same  also  septal  (0.5-1,5 msec) than gyrus.  spontaneous discharge of B-neurones was i n v a r i a b l y  i n h i b i t e d f o r periods fimbria 1  o f 30-100 msec f o l l o w i n g  stimulation  antidromically  evoked.  used  for  the  even  when  they  ( F i g . 3-5). T h i s  s i m i l a r t o t h a t reported and  IS-SD  o f t h e evoked spike and (d)  that observed during s t i m u l a t i o n o f the dentate  or  and  collision-extinction  resulted i n antidromic a c t i v a t i o n of  The  that  a spontaneous and the evoked s p i k e a t c r i t i c a l  i n t e r v a l s up t o 4.0 msec, (c) break  be  were used t o v e r i f y  antidromically  stimulation between  examined  dentate were  inhibition  by McLennan and M i l l e r  identification  of  medial  not is  (1974a) septal  neurones. Two a d d i t i o n a l c h a r a c t e r i s t i c s o f MS response patterns  f o l l o w i n g s t i m u l a t i o n of the  fimbria  or  the  dentate gyrus were b r i e f low amplitude burst  discharges  having  period  low  amplitudes  i n h i b i t i o n and a  high  would  begin  burst  period  ( F i g . 3-6).  Although activated  to  probability  I-neurones  following  preceding  at  the  were  stimulation  the that  MS  of  neurones  end of the i n h i b i t o r y  not  antidromically  of the f i m b r i a , they  99  IIS*.  3z  §k  Bursting  p i s charge  M§U£ones F o l l o w i n g  Pattern  Septal  Hippocampal S t i m u l a t i o n .  Az r a s t e r e d d i s p l a y o f spontaneously bursts  Of  ;  occurring  (upper r a s t e r ) which are synchronized  s i n g l e pulse s t i m u l a t i o n  (arrow) i n the  by  dentate  (lower r a s t e r ) . Bi  post  stimulus  time  shown i n A i n d i c a t i n g pattern.  a  histogram of the rhythmical  cell  discharge  001  101  could  be  (42$)  synaptically  by  stimulation  activated  activated  (37%)  of  that  sites  After  K a i n i c Acid L e s i o n s Qf The. S e p t a l  Electrolytic  compares the e l e c t r i c a l a c t i v i t y  DG  of  unoperated  r a t s , the  two  patterns  of  electrical  were  recorded.  control  distinct  i n F i g . 3-7B)  40,100 Hz) contrast,  in  or  activity, RSA  was  also  or e l e c t r i c a l  region  hippocampal  of the  and  initiated the  by  animal*s  stimulation  {1-  was  was  recorded i n  rats. not  However,  significantly the  medial s e p t a l r e g i o n  ( F i g . 3-7D,G), In f a c t , there  were  no e a s i l y d e t e c t a b l e  d i f f e r e n c e s between the  recorded  from  electrolytic  not  In  of  activity  and  occurring  locus c o e r u l e u s .  lesioned  activity  In  desynchronized  such as p i n c h i n g  kainate  a l t e r e d by k a i n a t e  r a t s having  spontaneously  spontaneous or evoked RSA  electrolytic irregular  the  r a t s and  recorded  l e s i o n s of the s e p t a l area.  somatosensory s t i m u l a t i o n (T.P.  And  Area  3-7  control  tail  antidromically  Fig.  e l e c t r o l y t i c or k a i n a t e  BSA,  inhibited  B-neurones.  SiEEScamrjal Response P a t t e r n s  from  or  the  dentate  k a i n i c or e l e c t r o l y t i c l e s i o n s of the The that  extent of  resulted  in  kainate the  and  lesions  of  r a t s having  HS.  electrolytic  d i s r u p t i o n of BSA  F i g . 3-8A,B . In both c a s e s , the damage was to the medial s e p t a l - d i a g o n a l  electrical  lesions  are shown i n restricted  band r e g i o n . L o c a l i z a t i o n  102  FIG...  3-  E f f e c t s Of E l e c t r o l y t i c Of  The  Septal  Area On  And  Kainate L e s i o n s  fliP£2£ J2Eal a  Electrical  Act.iyity.i_ A D G i spontaneously o c c u r r i n g x  A  the  periodic  appearance  activity  of  RSA  showing  only  in  animal's  tail  controls. D ,EH;_ it  f  effect  (T.P.) during  of the  pinching period  the  indicated  by  solid  lines. CjJgxLl  electrical  evokes RSA  s t i m u l a t i o n of the  in control rats  only.  brainstem  KAINIC  ELECTROLYTIC  G j* spont.  J 1  0.2 SEC.  mV  104  of the k a i n i c a c i d l e s i o n , as i n d i c a t e d by of  neuronal  glia 0.7  perikarya  and  (Fig. 3-9) , revealed mm  anterior  to  bregma. F i g . 3-9 perikarya  in  marked p r o l i f e r a t i o n of  that i t  extended  bregma to 0.7-1.0 mm  from  MS  of  a  kainate  0.5-  posterior  also shows that the number  the  significantly  the  degeneration  of  to  normal  lesioned rat i s  l e s s than i n a c o n t r o l s e c t i o n  taken  at  the same l e v e l . Inasmuch as m i c r o s c o p i c i n v e s t i g a t i o n r e v e a l s of  perikarya,  terminals kainic  the  or axons of  injections  eliminate  this  was  previous  to  lesioned  studies  was  r a t s but  (Assaf  was  damaged  by  In order  to  of  the  efficacy  have  was  selected  shown  through the  the  s e p t a l area  M i l l e r , 1978c), e f f i c a c y in  control  and  o f the  s e p t a l area.  by  histologically  not  abolish  RSA  kainate  verified Control  l a t e r a l v e n t r i c l e s , which caused  neuronal degeneration i n a r e s t r i c t e d did  a  markedly attenuated i n r a t s with  only blocked  into  since  that  i n j e c t i o n s o f k a i n i c a c i d i n t o the s e p t a l area. injections  dentate  ( H a l a r i s et a l , 1976). As  and  the same  e l e c t r o l y t i c destruction RSA  the  p r o j e c t i o n was  i n the dentate  of t r a n s m i s s i o n  also  be r u l e d out.  of i t s axons p r o j e c t  reported  presynaptic  median raphe nucleus to the  examined. T h i s  terminate  previously  not  that  were  possibility,  anatomical  proportion  passage  can  p r o j e c t i o n from the gyrus  possibility  loss  recorded  region  i n the  of  CA3,  dentate gyrus.  105  jr  8«  Extent Of  Electrolytic  Lesions In The Ai  coronal  widest  Kainic-indjuced  Sep_tal Ar ea  section  extent  And  of  of the  the  forebrain  electrolytic  at  the  lesion  showing l o s s of t i s s u e r e s t r i c t e d to the  septal  area. Bz_  section  the  i n t r a s e p t a l i n j e c t i o n of k a i n i c  "9) •  taken  at the same l e v e l  following acid  {2.0  107  3-  9^  Neuronal  Degeneration  Following  Kainic  I n j e c t i o n s Into The S e p t a l Area^Aj.  a  photomicrograph  nucleus  taken  abundance o f Bj.  medial  injection and  from  of a  the  medial  control  septal  rat  showinq  followinq  Kainic  neurones. septal  nucleus  indicating  proliferation  of  l o s s of normal p e r i k a r y a glia.  s t a i n e d with c r e s y l v i o l e t  Sections  were  and magnified 1 0 0 X .  Control  109  Therefore the e f f e c t s of not  due  to  intraseptal  diffusion  of  injections  kainic  acid  were  into  the  ventricles.  Discharge  P a t t e r n Of S e p t a l N e u r o n e s  In  The  Isolated -  Forebrain In  the  previous  section  i n t a c t septo-hippocampal generation  is  septal  at  f o r the  is  synaptically  by p h a s i c , b r a i n s t e m i n f l u e n c e s , t h e d i s c h a r g e  (n=22) a c o m p l e t e  the  shown t h a t an  necessary  neurones  p a t t e r n o f B - n e u r o n e s was r e c o r d e d after  was  o f BSA. I n o r d e r t o i n v e s t i g a t e w h e t h e r t h e  bursting pattern of relayed  axis  i t  level  recordings  (n=43)  and  t r a n s e c t i o n of the diencephalon  o f the hypothalamus  were  before  obtained  up  to  ( F i g . ... 3-10) . . S t a b l e 4  hrs  after  the  transection. In  4  of  6 animals the i n t e g r i t y of the s a g i t t a l  s i n u s and t h e b a s i l a r a r t e r y d a t a from  t h e k n i f e c u t 31 o f 43 (72%)  a c t i v e neurones  5.3±0.5 Hz.  at  recorded  medialis  rhythmical  (23%)  preserved  and  only  t h e s e a n i m a l s were i n c l u d e d i n t h e a n a l y s i s .  Before  nucleus  was  bursts After  septi at  in  the  average  aspects  of  t o discharge i n freguency  of  t h e k n i f e c u t o n l y 5 o f 22 n e u r o n e s  were r e c o r d e d i n t h e b u r s t i n g  a freguency  medial  were o b s e r v e d an  spontaneously  (4,3±0.4 Hz) w h i c h  <0.01) l o w e r t h a n t h a t o b s e r v e d  mode  of  discharge  i s significantly  before the  knife  { p cut.  110  EISA.  I z l Q L Acute T rjinsee t i on Of F oj:ebra_i n.. hz  A  knife  schematic cut  showing  (dotted  the  line)  l o c a t i o n of the  in  relation  to  at about 200  um  i n d i c a t e d a n a t o m i c a l landmarks. B:  a saggital section  from the midline. of  the  of b r a i n  The arrow i n d i c a t e s  recording  electrode  in  the l e v e l  the  region. Abbreviations CA1  Pyramidal c e l l r e g i o n  CC  Corpus Callosum  AC  anterior  CP  Caudate  DG  Dentate Gyrus  FM  Fimbria  FX  Fornix  HTA  of  hippocampus.  Commissure Nucleus (Fascia  Hypothalamus  LM  M e d i a l Lemniscus  LV  Lateral  B  Red Nucleus  S  Septal  Ventricle  Area  Dentata)  septal  Ill  112  Direct  activation  of  s t i m u l a t i o n d i d not septal  neurones  preparation were  alter  the  recorded  in  ( F i g . 3-11). On  obtained  continued  in  or  discharge  pattern  the  two  sensory of  isolated forebrain  occasions  F i g . 3-11C,  recordings  and a f t e r the one  of  those  t o b u r s t a f t e r the k n i f e c u t . In cases  where b u r s t i n g was observed the  brainstsm  from the same c e l l before  k n i f e cut and as shown cells  the  i n the i s o l a t e d  forebrain,  s p i k e s w i t h i n a burst were not r e g u l a r as shown by  the wide i n t e r v a l histogram Since  i t has  (eserine) neurones  been  enhances (Petsche  unpublished  shown i n  results),  burst  was  physostigmine  activity Assaf  t h e response  injection  F i g . 3-11A,  that  a l , 1962;  i n the i s o l a t e d f o r e b r a i n intravenous  shown  the et  shown i n F i g . 3-11B.  of and  septal Miller,  o f t h e 22 neurones  recorded  following  an  o f physotygmine (0.1 mg/kg). As 13  of  the  22  neurones  (591)  e x i h i b i t e d the b u r s t i n g mode of discharge f o l l o w i n g the i n j e c t i o n . The response 100  seconds  injection.  and  was  t o e s e r i n e had a l a t e n c y of 90maximal  15-20  minutes  post  113  EIG±..  :  DiSSkarae  I r l l l "  Before And Aj_  The  Patterns  Of  Septal  Neurones  A f t e r T r a n s e c t i o n Of The F o r e b r a i n  number  (expressed  of  medial  septal  as a percentage  . of c e l l s recorded)  neurones  of the t o t a l number  d i s p l a y i n g the b u r s t i n g mode  of discharge. E_i I n t e r v a l histogram before  and  discharge  after as  of the  a  neurone  knife  cut.  Bursting  by  the  bimodal  indicated  d i s t r i b u t i o n continued a f t e r C  A  discharge  sweeps) and recorded  a  transection  of  the cut, a  corresponding  from  before and  injected  pattern  recorded  neurone slow  (bottom  potentials  the same e l e c t r o d e (top sweeps)  at  the of  the  indicated  times  after  f o r e b r a i n , ,, E s e r i n e  15 minutes a f t e r  the  r e - i n s t a t e bursting discharge.  transection  a was to  115  3j__£  Discussion These data i n d i c a t e  discharge  pattern  activity  of  the  anaesthetized the  of  septal  et  1974).  populations  in  between  neurones and in  electrical  the  urethane  al,  In  the  1962;  addition,  medial  Apostol  at  septal  whether or not  region  Discharge Pattern  they p r o j e c t to the  Of S e p t a l  hippocampal  may  manner  activity.  In  which are  contrast  and  s t i m u l a t i o n of antidromic  activated  discharge i n a random or unrelated  to  hippocampal  B-neurones discharge i n b u r s t s  are  sites  observation  that  of  to  may  interneurones  classified evoked  activated  by  suggestion.  to  The  precede  proportion  by  those  I-neurones.  discharges  supports the l a t t e r  followed  perhaps  as  by  Since  or  neurones  stimulation  is  BSA.,  postulated  that a  synaptically  the  be  i n h i b i t i o n of B-neurones and are  of  activated  generate  B-neurones  collateral  inhibitory presently  antidromically shown  activation  i n h i b i t i o n an axon  cells  is  patterns  phase r e l a t e d to e l e c t r i c a l a c t i v i t y  hippocampus  activate  that  be  hippocampus.  antidromically  stimulation,  irregular  cell  Neurones  I-neurones, which are not by  and  l e a s t two  d i f f e r e n t i a t e d on the b a s i s of t h e i r d i s c h a r g e and  the  s i m i l a r to that p r e v i o u s l y shown i n  (Petsche  Creutzfeldt,  relationship  hippocampus  rat  rabbit  a  of  the I-  hippocampal  116  C o r r e l a t i o n s With Mor£ho103i c a 1 S t u d i e s Studies o f the h i s t o l o g i c a l medial  septal region  Stephan,  1964)  types  also  (1)  indicate two  small  axon c o l l a t e r a l s  neurones  whose  axons  ovoid  cells  could  the  be  other cells  Andy and  different profusely  medium medial  terminals  of  to  large  septum i n a the  small  and  Petsche  (1969)  hand  the  large  projecting  hippocampal  between  hippocampal RSA (Petsche,  to  neurones are presumably  the  observed  et a l , 1962;  in  together  these  could  be  of  RSA  this  and  with  zones  activated i n the  neurones  output  by Tombol and Petsche  irregular firing  the i n t r i n s i c c e l l  I-neurones may  population.  studies and  the f a c t t h a t only  antidromically  generating  described  close  Apostol  gyrus suggests t h a t these cells  output  The  other  Gogalak et a l , 1962;  1974)  stimulation  the  discharge of B-neurones and  Creutzfeldt, cells  regions.  the  suggest  neurones are i n t r i n s i c to the s e p t a l area. On  relationship  The  cell  t r a c e d to the d e n d r i t e s of  l a r g e r c e l l type, Tombol these  (2) the  the  heterogenous  neurones with  and  leave  Since  a  fundamentally  ovoid  branching  dorsal direction.  of  (Tombol and Petsche, 1969;  p o p u l a t i o n c o n s i s t i n g of cell  organization  correspond  by  dentate to  the  (1969).  r e f l e c t a c t i v i t y in  117  Regulation  Of HiEP.ocjirap.al A c t i v i t y .  Petsche e t a l (1962) emphasized the the  medial  septal  transforming  region  influences  discontinuous  pulse  hippocampus. The  present  since  abolished  rhythmical The  bodies  data  additional  and  tends of  patterns  to  that  septal bursts  generating  brainstem  septal  area  that  chronically  to  pons may  septal in  the  septal the  generation  synaptically  neurones.  However,  isolated  forebrain  continued  rhythm.  to  fire  i t s e l f , are Removal  in  peripheral  isolated  of  tonic  incidence  generation  stimulation.  of  ;  the  Recent  p e r s i s t s i n c a t s with  forebrains  provides  the  capable  i n the i s o l a t e d f o r e b r a i n and  that hippocampal RSA  V i l l a b l a n c a , 1977) that  the  kainate  intact  i n f l u e n c e s would e x p l a i n the lower  observations  in  suggests t h a t mechanisms w i t h i n  *theta*  lack o f responses  proposal  the  necessary f o r the  neurones  of b u r s t i n g discharge  and  this  activity  f o r e b r a i n , p o s s i b l y the s e p t a l area of  a  i n the  not d i r e c t brainstem a f f e r e n t s to  observation  rhythmical  into  hippocampal a c t i v i t y .  relay bursting  preparation  station  support  observation  Neurones i n the midbrain and  the  of  to  suggests t h a t  hippocampus are a b s o l u t e l y of r h y t h m i c a l  relay  brainstem  electrical  RSA  a  which i n i t i a t e s RSa  destruction  i n j e c t i o n s also block cell  the  train  suggestion  hippocampus.  of  as  importance  (Olmstead  f u r t h e r support f o r the rhythmical  activity  is  118  d e p e n d e n t on  B o l e Of  forebrain  Cholinergic  The  pattern  Petsche  et  on  cerveau  and  1975). E s e r i n e cholinergic activity  could  observation  Monnier  the  following  septal  of e s e r i n e  action  mechanisms.  Since  eserine  bursting  o f s e p t a l n e u r o n e s i n the  it  enhancing the  may  be  B-neurones  onto  BSA  i n urethane  Assaf  and  production  that  role  of r h y t h m i c a l  area  of  or  the The  Stumpf,  i s dependent  on the  isolated forebrain,  septal  rats  neurones.  blocks  of The  hippocampal  (Vanderwolf,  results;  cholinergic activity.  is  19 65)  of the c o l l a t e r a l s  unpublished of  action  potentiates  atropine  anaesthetized  Miller  emphasizes the  activity  neighbouring  additional observation  in intact,  septal lesions eserine  suggests septal  potent  neurones.  ( T o r i i , 1966  the  have  Vanderwolf,  the  i n e f f e c t i v e i n p r o d u c i n g BSA that  forebrain  Bomanowski,  1977;  cholinergic  also  preparations  and  potentiating to  septal that  forebrain  Villablanca, be  bursting  isolated  o f h i p p o c a m p a l BSA  1962;  afferents of  the  i n i n t a c t (See  and  isolated  and  anticholine-  anticholinesterases  Nicholson,  Olsmstead'  the  elicited  1962)  production  isole  of  B-neurones  Likewise,  the  and  of  al,  preparations.  (Bradley  injection  physostigmine,  discharge  1962;  System.,  intravenous  esterase,  actions  mechanisms.  chapter  systems  in  1975; 5) the  119  3«_5. Summary A  summary  the s e p t a l results  of  area  the proposed r e l a t i o n s h i p s between  and  the  of the present  hippocampus  based  on  the  experiments i s shown i n F i g . 3-  12, S t i m u l a t i o n of a RSA  generating zone i n the  gyrus  activates  antidromically  only  dentate  B-neurones  i n d i c a t i n g t h a t these c e l l s p r o j e c t to the hippocampus. Furthermore, I-neurones  i t i s the d i s c h a r g e of B-neurones but not which  relationship  shows  to  RSA  a  phase  waves.  Since  and  freguency  the  antidromic  a c t i v a t i o n of B-neurones i s followed by i n h i b i t i o n , axon  collateral  inhibitory presently that  system  may  interneurones classified  as  gamma-aminobutyric  or  be p o s t u l a t e d to a c t i v a t e perhaps  those  I-neurones. acid  1976}  elicited Miller,  by  and  the  antagonists  inhibition  hippocampal  1974a)  suggests  observations  evidence  block  Miller,  1974;  (McLennan  t h a t t h i s compound may  that  the  of s e p t a l neurones  stimulation  i n h i b i t o r y t r a n s m i t t e r o f the The  cells  Recent  b u r s t i n g of s e p t a l neurones (McLennan and Segal,  an  and be  the  interneurones. electrolytic  or  kainate  induced l e s i o n s of the medial s e p t a l d i a g o n a l band area abolish  hippocampal  RSA  suggests  that the s e p t a l area  i s c r i t i c a l f o r the generation o f r h y t h m i c a l a c t i v i t y i n the hippocampus. Furthermore discharge p a t t e r n of s e p t a l neurones may local  forebrain  mechanisms  and  is  the  electrical bursting  be mediated by  not  synaptically  r e l a y e d by  midbrain a f f e r e n t s .  121  FIG..  3-12:,  Schematic  £Slationshijg  Illustration  arriving  The  Bet ween The B r a i n s t e m  And The Hi££ocam£al The  Of  septal  rhythmical bursts  S e p t a l Area  Formation area  signals  x  Proposed  from which  transforms the are  randomly  brainstem relayed  into  to the  hippocampal f o r m a t i o n by B-neurones and i n t u r n generate  BSA. ,  ant i d r o m i c a l l y subsequently discharge  via  Stimulation activates  inhibits recurrent  of  the  B-neurones their  and  spontaneous  collaterals  interneurones i n the s e p t a l area.  dentate  onto  o  Hippocampal Formation  v  A  O  i-  Neuronel B-Neurone +V  6  Septal Area  V -  Brainstem  123  CHAPT EE 4 i ROLE OF A BAPHJzSEROTONIN  SIS-  SYSTEM I N  CONTROL OF SEPTAL HIPPOCAHPAL  ACTIVITY  Introduction In septal  the previous chapter area,  significant  particularly role  in  i t was  shown  that  the medial r e g i o n ,  the  control  of  the  electrical  of  and F u j i m o r i , et  and  hippocampal  elicit  activity  of  these  systems,  that  ( T o r i i , 1961; Yokoto  elicits  1972;  regions  i d e n t i f i e d monoamine-containing neuroanatomical  the brainstem  et  a l  (1974) of  and p o n t i n e r e g i o n s  hippocampal  correspond  Macadar  stimulation  mesencephalic  the c h a r a c t e r i s t i c  these  Macadar  electrical  anatomically distinct  from  contrasting  1964; A n c h e l and L i n d s l e y ,  demonstrated  of  brainstem  a l , 1 9 7 4 ) , I n an a t t e m p t t o l o c a l i z e  origins  suggested  s t i m u l a t i o n o f ascending systems  hypothalamus  patterns  plays a  hippocampal  e l e c t r i c a l a c t i v i t y . E a r l i e r e x p e r i m e n t s have that  the  patterns.  to  Some  histochemically  nuclei.  Since  d a t a have shown t h a t t h e s e c e l l  recent groups  h a v e e x t e n s i v e t e r m i n a l p r o j e c t i o n s upon t h e s e p t u m and hippocampus (see C h a p t e r arises that these may f o r m  1 f o r review)  pharmacologically  the n e u r a l s u b s t a t e s through  the p o s s i b i l i t y  #  distinct which  systems  patterns of  a c t i v i t y i n t h e s e p t u m and h i p p o c a m p u s a r e c o n t r o l l e d . Of serotonin  particular  interest  f i b r e system  in  whose c e l l  this  chapter i s the  bodies are located i n  124  the  mesencephalic  substantial nucleus  raphe  projection  nuclei.  (Conrad,Leonard and P f a f f ,  result  with in  a  serotonin serotonergic  The the  1974; H a l a r i s e t  significant and  aim  observed  a  involved  function.  stimulation  in  activity  effects  suggest that  t h e p r e s e n t c h a p t e r i s t o 1) e x a m i n e  discharges  hippocampal  forebrain  o f t h e septum may be  effects of electrical  neuronal  a l , 1976}  of  197 4)  o f sep t a l - h i p p o c ' a m p a l of  a  l e s i o n s o f t h e MR  depletion  Guldberg,  innervation  i n the control  of  t h e septum and hippocampus  the observations that  (Lorens  presence  o r i g i n a t i n g i n t h e median r a p h e  (MR) a n d i n n e r v a t i n g  together  The  the  and  septal  2)  of  the  MR  on  a r e a and r e l a t e d  determine  whether  a r e d e p e n d e n t on s e r o t o n i n  the  containing  s y s t e m s o r i g i n a t i n g i n t h e MR, ,  4^2 E x p e r i m e n t a l  Procedures  Experiments anaesthetized  with  were  performed  urethane  p r o c e d u r e s and r e c o r d i n g  on  54  (1.0g/kg i . p . ) .  Surgical  placements  i n the  h i p p o c a m p u s a n d t h e s e p t a l a r e a were i d e n t i c a l  t o those  described  in  concentric  the  into  (0.8  anterior  mm  previous  bipolar  lowered  the  electrode  rats  chapter.  electrode region to  was  In  addition, a  stereotaxically  o f t h e median r a p h e  stereotaxic  zero;  nucleus  0.0-0.5 mm  l a t e r a l t o the midline;  6.0-6,7 mm b e l o w t h e s u r f a c e  the  stimulation  cortex).  Electrical  o f t h e MR  of  consisted  125  o f e i t h e r s i n g l e p u l s e o f 0.05-0,1 20 msec  duration  and  msec d u r a t i o n and 10-  10-20 V i n t e n s i t y  or r e p e t i t i v e  v o l l e y s o f 40-100 Hz f o r 1-3 s e c a t i n t e n s i t i e s  of  1-  9V. The  signals recorded  septal unit  activity  were f i l t e r e d  and  2-50  Hz  (0.1-3 KHz f o r  for  hippocampal  activity)  and d i s p l a y e d on a d u a l beam o s c i l l o s c o p e and  analysed  using  Special care  the  had  discriminator  to  to  be  window  stimulus a r t i f a c t s discharge  method  taken  to  eliminated  in  the  in  5-HT,  a total  para-chlorophenylalanine  ensure  the  the  of  analysis  of  septal  unit  o f 6 r a t s were p r e t r e a t e d by (p-CPA).  5-hydroxytryptophan  piperazinyl)-guinoline was  guipazine supplied  previously  serotonin-containing and  the  An  additional  t h e r o l e o f s e r o t o n e r g i c m e c h a n i s m s was  presumed a g o n i s t  compound  that  2.  c o n t r i b u t i o n cf  made f o l l o w i n g t h e i n t r a v e n o u s i n j e c t i o n precursor  Chapter  during r e p e t i t i v e pulse s t i m u l a t i o n . I n order  deplete  evaluation  outlined  Drucker-Colin,  shown  (5-HTP)  by to  the  5-60  (0.5-2.0 Pfizer  5-HT  mg/kg and  mg/kg; 2 - ( 1 Inc.).,This  activate  systems (Rodrigues,  1973).  of  central  fiojas-Ramirez  126  Results Since least  i n the previous  two  populations  classified  chapter  of  i t was  septal  shown t h a t a t  neurones  on t h e b a s i s o f t h e i r d i s c h a r g e  can  be  p a t t e r n and  i t s r e l a t i o n s h i p t o h i p p o c a m p a l RSA,  the e f f e c t s of  s t i m u l a t i o n were a n a l y z e d  f o r I - n e u r o n e s and  separately  MR  B-neurones.  Response  Of I - N e u r o n e s  The d i s c h a r q e were e x a m i n e d  To j^aphe S t i m u l a t i o n  p a t t e r n o f a t o t a l o f 202  f o l l o w i n g s i n g l e pulse s t i m u l a t i o n of the  MR  at stimulus i n t e n s i t i e s ranging  One  h u n d r e d and f i f t y - n i n e c e l l s  for  periods  duration  of  of  single The  inhibition  i f t h e MR  pulses  pulses  between (78.7%)  10-15  were  volts.  inhibited  30-200 msec(mean=75.2±U0.5 S.D.).  the  considerably successive  I-neurones  was  (100 Hz)  at  could  be  increased  s t i m u l a t e d w i t h two o r more at  threshold  suprathreshold  intensity  (1.5 x T)  or  intensity.  l a t e n c y t o the onset of the observed i n h i b i t i o n  always  less  than  25 msec  following  the  the r i g h t  after  the s t i m u l u s a r t i f a c t  i n F i g . 4-1).  stimulation  sites  Histological  which  (e.g. c e l l  the  r e s p o n s e i n d i c a t e d t h a t t h e y were l o c a l i z e d (Fig.  4-2B).  Electrode  sites  medial l o n g i t u d i n a l f a s c i c u l u s  in and  began  verification  elicited  the the  was  stimulus  (mean=12.5 msec) and i n some c a s e s t h e i n h i b i t i o n immediately  The  on of  inhibitory to  region dorsal  the  MR  of the raphe  127  FIG..  Hz  II  Response  Of  Septal  I r n e u r o n e s To Raphe  Stimulation,.. i x M i response of two neurones recorded medial  septal  i n the  nucleus of t h e same animal. The  top records show 25  superimposed  oscilloscope  sweeps  records  r a s t e r e d PST  and  bottom  are  responses of the corresponding c e l l s . Note that in  A the onset  after  of  inhibition  the s t i m u l u s a r t i f a c t  the r a s t e r s ) while i n B t h e longer.  is  immediately  (vertical lines i n onset  latency  is  syood3  129  nucleus short  were  e i t h e r i n e f f e c t i v e o r sometimes  latency  (3-8 msec) s p i k e  amplitude  field  electrode  was  neurones (Fig.  lowered  previously  4-2  located  response.  A). on  a c t i v a t i o n with  When  into  the  t h e same  the  unaffected  When  MR  for  stimulating  were  then  stimulating  electrode  the  inhibitory  observed.  component  of  for activation  related  to  between  electrode  and t h e c e n t r e o f t h e MR .  the  effects gyrus  distance  of and  CA3  total  area  on  inhibited  by MR s t i m u l a t i o n . by  a  stimulating  examined  both  of  96  the  hippocampus,  and  these was  stimulating  region  of the  that  were  MR and h i p p o c a m p a l s t i m u l a t i o n , an  by  and  and  The  Some n e u r o n e s (41.7%) were  by  MR  the  I-neurones  (35.5%)  influenced  was  o f t h e h i p p o c a m p u s were  approximately egual proportion the  septal  inhibited  r e s p o n s e s was l o w e r t h a n t h a t  inhibited  small  t h e p e r i m e t e r o f t h e MR, a m i x t u r e o f b o t h  threshold  dentate  a  proper,  a c t i v a t i o n and i n h i b i t i o n s e g u e n c e s was  The  elicited  activated the  remainder  by h i p p o c a m p a l  were  inhibited  stimulation (20.8%)  stimulation.  of  were  the not  130  IISx,.-  U-  Localization  2z  Of S t i m u l a t i n g E l e c t r o d e s I n  T h e l e g i o n Of The Raphe And  The  Corresponding  Response Of I-neurones. Az  photomicrograph showing s m a l l i r o n  made at the s i t e of an i n e f f e c t i v e the  d o r s a l raphe  the  median  deposits  placement i n  (top arrow) and a placement i n  raphe  that  produced  inhibition  (lower arrow). Bz_  frontal  indicating sites  s e c t i o n s through the raphe nucleus the  and  activity:  distribution  their  effects  (0) i n e f f e c t i v e ,  of on  stimulating septal  (•*) a c t i v a t i o n ,  inhibition. ABBREVIATIONS! DR  D o r s a l Raphe Nucleus  LH  M e d i a l Lemniscus  MR  Median  PCS  S u p e r i o r C e r e b e l l a r Peduncle  Raphe Nucleus  unit {-)  131  A 160/J  1  ^ \  P 100/J  132  Response Of B-neurones To Baghe In  contrast  Stimulation  to t h e i n h i b i t o r y responses  described  above, s i n g l e pulse  s t i m u l a t i o n of MB r a r e l y i n f l u e n c e d  the  identified  discharge  Inhibition recorded  was  observed  during  discharge did  of  the  Likewise,  in  only  irregular  .Increasing  not a l t e r  B-neurones  or  bursting  MB  d i d not  of B-neurones that were i n h i b i t e d .  repetetive  intensity  (2-9 V) and f r e g u e n c i e s  stimulation  i n the d i s r u p t i o n of b u r s t i n g firing  pattern  of  the  MR  o f 4 0-100  which was r e p l a c e d by  an  ( F i g . 4 -4B) . Of 220 B-neurones  during t h e b u r s t i n g mode, 185 (84.1%) began to  i n an i r r e g u l a r p a t t e r n . I n t h e majority  this  response  stimulation,  did  not  however,  to f i r e  termination  of  in MB  was  not  an  irregular  stimulation  with  rate  during  an  the  neurones  consistently  neurone may f i r e freguency  outlast some  C) . The average discharge train  at low  Hz r e s u l t e d  fire  continued  of  of B-neurones i n f l u e n c e d .  However,  irregular  mode  i n t e n s i t y (20-35 V)  double pulse s t i m u l a t i o n o f the  a l t e r the p r o p o r t i o n  recorded  5 of 229 B-neurones  t h e stimulus  the p r o p o r t i o n  ( F i g . 4-3).  o f cases  period (4  manner  of  of 220)  after  the  (e.g. c a l l i n F i g . 4-4 during  the r e p e t i t i v e  altered  i n t h a t a given  increased  subseguent  response of B-neurones described  or  stimulus above  a  decreased  trains.  was  unigue  The to  s t i m u l a t i o n o f MB nucleus s i n c e s t i m u l a t i o n of adjacent areas (Fig.  d i d not 4-5)  and  r e s u l t i n d i s r u p t i o n of burst sometimes  changed  the  activity irregular  133  FIG  a-  3z  C h a r a c t e r i s t i c s Of  A  B^neurone  During  S i n g l e Pulse S t i m u l a t i o n Of MR • A  A  A  rastered  d i s p l a y of 60 s u c c e s s i v e  presentations during 1-25)  and  bursting  both non-bursting (epochs  26-60)  stimulus (epochs modes o f  discharge, §xQl s i n g l e  oscilloscope  sweeps  r e l a t i o n s h i p of the same u n i t hippocampal e l e c t r i c a l a c t i v i t y  showing  (lower  the  t r a c e s ) to  (top t r a c e s ) .  134  Epochs  o  o  -i  3  00 CD O * . •  •  •••••  •  *•  • * • • * * • till • I | \ •i 5  • • - '..  O O  o  O  3  3  <  •  t" • •  • « i ••  ... • •  o  i  en  <  !' 'ii i !  I  *  I  •  ««••*• I . : ,«•: ... : «• 'j: ;  ' i  1.1! *  4:.J  J  *  135  discharge  of  rhythmical  bursts  stimulation, trial.  B-neurones often  persisting  Stimulation  longitudinal  of  into  rhythmical  outlasted until  the  sites  fasciculus  the  the  The  period  of  s t a r t o f the next  such  or  bursts.  as  the  superior  cerebral  peduncle also a c t i v a t e d 1-neurones which were i n the medial s e p t a l area  Effect  Qf  medial  recorded  ( F i g . 4-2 and 4-5).  Rajahe S t i m u l a t i o n  On Hi2£OGameal^Jlestrijsal-••  Activity. The  spontaneous  hippocampus  was  electrical  recorded  activity  simultaneously  d i s c h a r g e of s e p t a l neurones. As shown the  bursting  pattern  BSA, S i n g l e p u l s e  in  CA1,  in  stimulation  or  ongoing  the  stimulation  of  MB  4-4 A,  bursting were  possible  gyrus.  desynchronized  4-6C, D).  stimulus  did  any  3,  not  detectable  recorded from repetitive  The  hippocampal  disruption  200 msec  presentation.  determine  which  of  desynchronization  MB  B-neurone  electrical  activity  (average b u r s t  interval)  However, occurred  results  independent  activity  of  important to note that low v o l t a g e stimulation  chapter  However,  and d e s y n c h r o n i z a t i o n of  to  the  o f MB caused a s h i f t from ongoing RSA to a  observed w i t h i n  o f the  with  which  electrical activity  dentate  f a s t low v o l t a g e (Fig.  the  of B-neurones was accompanied by  i n f l u e n c e B-neurones a l s o d i d not e l i c i t changes  of  of  (less in the  it  was  first., than  not Iti s  5.0 V)  hippocampal mode  of  the  136  £22*  4- Hi  III gets Qf B e j j e t i t i y e MR S t i m u l a t i o n On  Bursting Control A B :_  Discharge And  top  t  activity  Pattern  £:CPAtrgated. traces  and  are  Of  fiats ~ A  traces  are  discharges.„MR s t i m u l a t i o n occurs two  arrows and  portion  of  the stimulus  results  hippocampal cellular  in  a  septal  unit  between  the  a r t i f a c t s obscure a  (3 V,  100  Hz,  desynchronization  activity bursting  stimulation  electrical  the s p i k e s i n the lower t r a c e s . In  (A) r e p e t i t i v e s t i m u l a t i o n msec)  B^neuronesin  hippocampal  lower  The  and  blockade  pattern.  In  of of  (B)  600 the the  the  MR  i s ineffective.  Cz a r a s t e r e d d i s p l a y o f the  discharge  pattern  of  a B-neurone recorded i n a normal r a t before  and  a f t e r a t r a i n of s t i m u l i  sec)  indicated  that, i n irregular  by  contrast  the to  discharge  o u t l a s t s the stimulus  (3 V, 100  Hz,  3. 2  s o l i d white bar.  Mote  response pattern train.  in  {A),  elicited  by  the MR  138  preceding  spontaneously occurring  Stimulation perimeter  of of  intensity,  adjacent MR  but  resulted at  desynchronization  Effects  Of  areas  and  in  higher  electrical  RSA  sometimes at  low  intensities  synchronization  the  stimulus  (5-7 V)  seguence  P-chlorqphe nylanine  activity .  a  occurred.  On S e g t a l - Higp,oeam p a l  Activity Pretreatment with  p-chlorophenylanine  (p-CPA)  days p r i o r t o e l e c t r o p h y s i o l o g i c a l experiments in  60-80%  depletion  rats  (n=4) o n l y  7 of  were  inhibited  by  202  of forebrain  5-HT.  24  I-neurones  (29.2%)  did  not  the  treated  vicinity rats  pulse  intensities  (2-5v)  bursting  the  binomial  MR. 9  from  (19.6%)  which in  the  The  p-CPA  short  latency  stimulation  were  points  influenced  of  the  resulted  in  the  i n controls  majority  of B-neurones  disruption (84.1%)  ( T a b l e 1) . A s  of  of B-  indicated of  (p<0.001) and d i s r u p t i o n o f t h e (p<0.05) were  lower than those observed i n c o n t r o l As shown i n F i g .  fay  MR a t t h e same  d i s t r i b u t i o n , both the occurrence  i n h i b i t i o n of I-neurones bursting  examined  Of 46 B - n e u r o n e s r e c o r d e d i n  stimulation  discharge  neurones recorded by  of  only  repetitive  In the treated  (Table 1).  abolish  e x c i t a t o r y responses e l i c i t e d in  resulted  MR s t i m u l a t i o n , c o m p a r e d t o 159 o f  (78.7%) i n c o n t r o l a n i m a l s  pretreatment  3  significantly rats.  4-5, p-CPA p r e t r e a t m e n t  d i d not  139  TABLE 1 COMPARISON OF SEPTAL NEURONES INFLUENCED BY MR STIMULATION IN CONTROL AND p-CPA TREATED RATS  CELL TYPE  CONTROL (n=29)  p-CPA (n=4)  I-NEURONES  159/202  (78.7%)  7/24  (29.2%)  B-NEURONES  185/229  (84.1%)  9/46  (19.6%)  p-CPA (400 mg/kg) was administered i n t r a g a s t r i c a l l y days b e f o r e r e c o r d i n g experiments. for  F l u o r e m e t r i c assays  f o r e b r a i n s e r o t o n i n l e v e l s were performed  f o l l o w i n g the r e c o r d i n g s e s s i o n s . number o f c e l l s influenced/number percentages o f t o t a l ) .  3  Entries  immediately  indicate  o f c e l l s t e s t e d (and  140  Elis.  .Hz 5 i  Effects  Of  R e p e t i t i v e MR S t i m u l a t i o n On-  MifiROcamgal E l e c t r i c a l A c t i y i t j . I n C o n t r o l P.C.PA Treated  Rats  spontaneously activity  And  occurrinq  electrical  showing that RSA i s recorded  in  both  c o n t r o l and pCPA t r e a t e d r a t s , Ixfi~  RSA  recorded  following  a  tail  pinch  <T.P.) . Cxi2.tO4.Ii e f f e c t s o f 4 and {100  Hz)  activity evoked  of  5  volt  the MR on hippocampal  stimulation electrical  i n d i c a t i n g that pCPA e l i m i n a t e s the MR desynchronization.  CONTROL  MM  pCPA  SPONT.  SPONT.  rtWi^Ugiillili T.P.  MR  T.P.  4V  MR  4V  H MR  5V  MR  5V  0.6 mV  2  Sec  142  significantly of  a l t e r t h e spontaneous e l e c t r i c a l  urethane anaesthetized  r a t s . As i n c o n t r o l r a t s 8SA  occurred spontaneously or as a r e s u l t of stimulation  such  as  activity  tail  pinch  (t.p. i n F i g . 4-5).  However, MR s t i m u l a t i o n  did  voltage  a c t i v i t y w h i c h was o b s e r v e d i n  desynchronized  control rats. treated  rats  In  addition  MR  result  in  stimulation  d i d n o t a b o l i s h o n g o i n g RSA  a s e p a r a t e group o f 9 r a t s injection  not  somatosensory  which  hydroxydopamine,  MR  desynchronization  RSA  suggesting  a  that  guipazine them  rats  received  an  reliably  spontaneously occurring  intravenous  to  desynchronization  2  resulted  not  Activity. i n j e c t i o n of  rats  produce  of  desynchronization a any  o c c u r r e d 2-4  dose  of  4  of  i n disruption of  RSA and a s h i f t  low v o l t a g e  In t h e r e m a i n i n g necessary  and  (0.5-2.0 mg/kg) i n s a l i n e s o l u t i o n . I n  to  in  o r dopamine.  0.6-1.0 mg/kg  activity  6-  the e f f e c t s  E f f e c t s O f Q u i p a z i n e On S e p t a l - H i p p o c a m p a l Six  central  resulted  p r o d u c e d by p-CPA were due t o t h e l o s s o f 5-HT noradrenaline  p-CPA  neurotoxin,  stimulation  of  in  low  (Fig.4-5). I n  received  o f the catecholamine-specific  the  ( F i g , 4-6).  2.0  effects.  mg/kg  The  minutes  hippocampal  onset  following  of the  injection  and p e r s i s t e d  RSA  d e m o n s t r a t e d i n 3 r a t s w h i c h were s t u d i e d f o r  up  was  6 hours f o l l o w i n g  sensory-evoked  RSA  f o r 1-3 h o u r s . F u l l  was  the  injection.  In  r e c o v e r y of  a l l animals  r e c o v e r e d b e f o r e the appearance of  143  Zl^i.  4-  6z  Effects  Electrical kz_  J2sA£§zine-  Of  On  Hipp oca j£al  Activity  spontaneous  occurring  activity  prior  to  guipazine i n j e c t i o n . Bx£i  activity  recorded  following  intravenous i n j e c t i o n o f guipazine E>i  recovery  of  BSA  f o l l o w i n g the i n j e c t i o n .  recorded  the  (1.0 mg/Kg). 40  minutes  CONTROL  QUIPAZINE  B  +2min.  +5min.  +40min. (Recovery)  500 uV 1 sec.  145  spontaneously o c c u r r i n g RSI. An i n j e c t i o n  of the s a l i n e  v e h i c l e d i d not procduce any e f f e c t s s i m i l a r of  guipazine  and  a  subsequent  to  those  i n j e c t i o n of e s e r i n e  through t h e same cannula r e s u l t e d i n the appearance RSA,  The l a t t e r i n j e c t i o n  not i r r e v e r s i b l y  of  v e r i f i e s that g u i p a z i n e does  damage mechanisms which mediate RSA,  The e f f e c t s of systemic i n j e c t i o n s o f guipazine on the d i s c h a r g e p a t t e r n o f 4 HS neurones(2 I-neurones and 2 B-neurones)  were  examined,  Quipazine  significantly  lowered t h e spontaneous d i s c h a r g e o f the I-neurones and attenuated the b u r s t a c t i v i t y o f B-neurones, The e f f e c t of  guipazine  on  a l l septal  units  was  overcome by  somatosensory s t i m u l a t i o n .  Effects  Of  Electrical Some  5 h y d r o x y tryptophan  Hippocampal  Activity rats  (n=5) r e c e i v e d an intravenous i n j e c t i o n  of t h e s e r o t o n i n precursor 5-HTP unlike  On  (5-80  mg/kg)  5-HT, passes t h e b l o o d - b r a i n b a r r i e r  which,  (Doner and  Longo, 1962). Doses lower than 20 mg/kg d i d not  result  i n any d e t e c t a b l e change i n t h e spontaneously o c c u r r i n g or evoked patterns o f hippocampal e l e c t r i c a l activity.  electrical  Higher doses (40-80 mg/kg) produced a gradual  desynchronization  which o c c u r r e d 5-7 min f o l l o w i n q the  s t a r t of the i n j e c t i o n . At 15-20 minutes post the amplitude of the e l e c t r i c a l reduced  ( F i g . 5-8E).  activity  was  injection greatly  Recovery to t h e normal amplitude  146  Ii  Jff§£is 2 f 5-HT On  Hippocampal  Elecjtrieal-  Actiyity.. A:  spontaneously  occurring  a c t i v i t y recarded  from the dentate gyrus before BACJL  records o b t a i n e d  2-5  injection.  minutes  after  the  i n j e c t i o n of 5-HTP (60 mg/Kg). Pi  low  voltage  activity  recorded 40 minutes  f o l l o w i n g the i n j e c t i o n  and  the  at  animal's  injection.  death  persisting 55  minutes  until post-  CONTROL  5 HTP +2 min.  +5 min.  +40min. 500 uV  148  during  the remainder of the r e c o r d i n g  observed. higher  Three  was  not  o f the four animals t h a t r e c e i v e d the  doses ( i . e . >40 mg/kg) of 5-HTP died w i t h i n  180 minutes post  4j_4  session  30-  injection.  Discussion These  data suggest that e l e c t r i c a l s t i m u l a t i o n of  the MR r e s u l t s septal  in  neurones  inhibition  (I-neurones),  of  irregularly  firing  d i s r u p t i o n of r h y t h m i c a l  a c t i v i t y of b u r s t i n g s e p t a l neurones  (B-neurones)  and  desynchronization  activity  the  of  electrical  of  hippocampus.  Effect  Of MR S t i m u l a t i o n  On • I-neurones. -,  S i n g l e p u l s e s t i m u l a t i o n r e s u l t e d i n short (mean=12. 5 msec) considering recording velocity are  the sites  of  of  distance  between  (8-10 mm)  allows  I-neurones  of  with  previously  unmyelinated  5-HT  for a  reported fibres  i g h a j a n i a n , 1977) . The r e l a t i v e constancy of of  inhibition  direct  together  (Conrad, Leonard and P f a f f , that  monosynaptic  this  input  and  conduction velocities conduction (Wang the  and onset  with anatomical evidence f o r a  p r o j e c t i o n from the  suggests  and  stimulating  between 0.5 and 1.5 m/s. These  compatible  velocities  inhibition  latency  MB  to  the  medial  septum  1974; H a l a r i s et a l . , 1976)  response  directly  onto  i s mediated I-neurones.  by  a  The  149  absence  of  clear  inhibitory  s t i m u l a t i o n of l o c i outside observed  inhibition  the MR  i s not  responses  following  indicates  that  mediated by an  the  extra-raphe  system.  E f f e c t Of MR  Stimulation  In c o n t r a s t  to  the  neurones were u n a f f e c t e d the  MR  On  regardless  B-neurones-  response  of  I-neurones,  B-  by s i n g l e pulse s t i m u l a t i o n  of  of whether they were i n b u r s t i n g  or  non-bursting mode of d i s c h a r g e (See F i g . 4-3).  However,  the  disrupts  observation  the  that  bursting  repetitive  of  B-neurones  altering their firing relationship  stimulation  rate  between  the  without  indicates MB  and  significantly  a  more  those neurones than  t h a t suggested f o r I-neurones. R e p e t i t i v e temporally septal  summate to i n h i b i t interneurones  Mclennan  and  classified  Miller,  as  1974a)  and or  is  septal  o f RSA  conceivable  generating  zones i n the  that a proportion  interneurones  collaterals hippocampus. effectiveness  1968;  presently  monosynaptically a c t i v a t e d  are I-neurones which are i n h i b i t e d by It  involving  Petsche,  neurones  may  I-neurones. I t i s i n t e r e s t i n g t h a t seme  s e p t a l neurones that are stimulation  stimuli  local circuits,  (Tombol  complex  of  that  are  B-neurones  An of  mechanisms within  alternate repetitve the MR  itself  MR  hippocampus stimulation.  of I-neurones are  excited  which  project  explanation  be  by  axon to  the  for  the  is  that  initiated  only  stimulation may  by  150  by  repetitive  stimulation.  However, t h i s i s u n l i k e l y  s i n c e s i n g l e p u l s e s t i m u l a t i o n of inhibition  of  I-neurones  the  and  t r a n s m i s s i o n i n the dentate gyrus  ME  results  alters  in  neuronal  (See Chapter 8 ) .  Regulation Of Hiepocampal a c t i v i t y Chapter 3 has emphasized medial  septal  region  the  importance  of  as a r e l a y s t a t i o n t r a n s f o r m i n g  i n f l u e n c e s of the brainstem i n t o a d i s c o n t i n u o u s train  which  i n i t i a t e s hippocampal  RSA.  the present chapter show that a system the of  MS  neurones  desynchronized  and hippocampal  turn  hypothalmus.  Wilson  in  a  et  al  known  to  bundle,  of  of  the  Since p r o j e c t i o n s from the ME to  are  forebrain  activation  response  results  activity.  in  a s i m i l a r e f f e c t on s e p t a l neurones  d e s y n c h r o n i z a t i o n observed the  originating  a c t i v i t y following stimulation  the medial septum medial  in  hippocampal  (1975) demonstrated  lateral  which  pulse  The r e s u l t s of  i s capable of d i s r u p t i n g the b u r s t i n g  septal  the  course  it  is  through possible  by these authors was  fibres  of  passage  of  due  the that to  neurones  o r i g i n a t i n g i n the MB . A l t e r n a t e mechanisms mediating a d e s y n c h r o n i z a t i o n of hippocampal Lindsley  activity  (1972)  have been proposed. Anchel  observed  that  blocked s y n c h r o n i z a t i o n but not elicited  from  hypothalamic  and  l e s i o n s of the f o r n i x the  sites  desynchronization thereby c o n c l u d i n g  151  t h a t the l a t t e r e f f e c t was  mediated by an  system. McLennan and M i l l e r qating  mechanism  (1976) proposed a frequency  i n the l a t e r a l septum which  the d i s c h a r g e p a t t e r n o f medial that  either  bursting  septal  the  fimbrial  pathway.  At  the  mechanisms r e g u l a t i n g the a c t i v i t y and  patterns  sufficiently  of  hippocampal  controls  neurones  or i r r e g u l a r f i r i n g  depending on t h e l e v e l o f hippocampal by  extra-septal  will  such result  output  mediated  present  time the  septal  neurones  of  activity  have not been  e l u c i d a t e d to e l i m i n a t e any o f  the  above  proposals.,  P o s s i b l e Role Of Serotonin The system  present  results  mediates  stimulation. observation forebrain elicited  This that  5-HT by MR  stimulation  the  responses suggestion  p-CPA blocks  of  MR  in  elicited is  based  pretreatment the  In  p-CPA  of  which  inhibition  stimulation.  disrupt the bursting hippocampal  suggest that a s e r o t o n e r g i c  B-neurones  or  MR  on  the  lowers  of I-neurones  addition, treated  by  rats  repetitive does not  desynchronize  a c t i v i t y . The a d d i t i o n a l o b s e r v a t i o n s that  g u i p a z i n e , a presumed agonist of s e r o t o n i n (Rodriques e t al,  1973)  strengthens  desynchronizes the  proposal  that  hippocampal  activity  a s e r o t o n e r g i c system  mediates the observed d e s y n c h r o n i z a t i o n . , The o b s e r v a t i o n that the e f f e c t s of g u i p a z i n e  are  152  r e v e r s i b l e inasmuch as RSA can be subsequently produced by  eserine  suggests  injection  that  nonspecific  or  somatosensory  desynchronization and  is  permanent  that  due  to  of  BSA  p-CPA  does  a b o l i s h BSA i n d i c a t e s an i n t a c t septal-hippocampal  a x i s . The proposal the  not  destruction  generators. Likewise the observation not  stimulation  generation  to block  that s e r o t o n i n i s not e s s e n t i a l f o r  o f BSA i s a l s o supported by the f a i l u r e  BSA i n f r e e l y  systemic  moving  animals  following  i n j e c t i o n of the 5-HT antagonist  the  methysergide  (Robinson, 1978). The  r e s u l t s following  the i n t r a v e n o u s i n j e c t i o n of  5-HTP were not as c l e a r c u t as  the  produced  injection.  by  guipazine  desynchronization was  observed  of  hippocampal  following  the  l a r g e doses were r e g u i r e d Similar Longo  observations  desynchronization  electrical  doses  activity  i n j e c t i o n of 5-HTP, very  to produce r e l i a b l e  effects.  were p r e v i o u s l y made by Domer and  (1962) i n t h e r a b b i t . Thus, i t i s  these  Although  reguired  to  produced s y s t e m i c e f f e c t s  elicit  possible  that  desynchronization  which  ultimately  have  also  kill  the  animals. Previous serotonergic activity.  studies system  Stefanis  in  the  control  (1964) r e p o r t e d  a p p l i c a t i o n o f 5-HT i n h i b i t s the neurones.  More  recently,  implicated of  that  septal  unit  iontophoretic  discharge  Segal (1976)  a  of  observed  septal that  153  raphe  stimulation  50 msec)  results  a  long  latency  (20-  i n h i b i t i o n of s e p t a l neurones. In the present  experiments no i n h i b i t i o n 25 msec  in  was  observed.  with  Although  account f o r t h i s discrepancy inhibition,  the  fact  pretreatment blocked e f f e c t s were mediated  latencies i t is  between the  that  in  both  longer  than  d i f f i c u l t to latencies  instances  to  p-CPA  the i n h i b i t i o n suggests that t h e s e by  serotonin.  The  observation  t h a t s t i m u l i of low i n t e n s i t y i n h i b i t e d I-neurones only if  the  s t i m u l a t i n g e l e c t r o d e was i n the centre of the  ME provides observed system  f u r t h e r support f o r the suggestion  inhibition  is  mediated  originating  in  the  preliminary  observation  MB  that  by .  a  serotonergic  Furthermore,  systemic  injection  the of  guipazine  decreases  attenuates  t h e b u r s t i n g o f B-neurones a l s o i m p l i c a t e 5-  HT i n the c o n t r o l of these  effects  can  the f i r i n g  t h a t the  septal be  r a t e of I-neurones and  unit  activity.  However,  more d i r e c t l y evaluated  iontophoretic  a p p l i c a t i o n o f guipazine  on i d e n t i f i e d  s e p t a l neurones.  and 5-HT  by the itself  154  4.5 Summary A  model  o f t h e p r o p o s e d r e l a t i o n s h i p between  s e p t a l a r e a and t h e hippocampus t h i s and t h e p r e v i o u s c h a p t e r Single of  pulse  non  b a s e d on t h e r e s u l t s o f i s shown  in  s t i m u l a t i o n o f MR c a u s e s d i r e c t  bursting  ME,  I-neurones  without  F i g . 4-8, inhibition  inhibiting  neurones suggesting  that  only  monosynaptic  from  MR. The d e s y n c h r o n i z a t i o n  of  and RSA may be  by  the  input  bursting  temporal  o f B-neurones  summation  of  I-neurones  B-  receive  mediated  i n h i b i t e d I-neurones.  a  S i n c e B-  n e u r o n e s a r e a n t i d r o m i c a l l y a c t i v a t e d by s t i m u l a t i o n o f RSA g e n e r a t i n g formation. suggests  The  they  the  inhibition  give  o f f axon  some I - n e u r o n e s w h i c h  are  activated  by  suggests that a population inhibitory  antagonism  to  the  of I-neurones Recent  of  and M i l l e r ,  inhibitory  rhythmicity. somatosensory Miller,  Manipulations or  in  the  that i n i t i a t e  fimbrial  1974a) may p r o v i d e  I-neurones.  by  MR  stimulation  are  stimulation  may i n f a c t be evidence  o f MS  1974a) e m p h a s i z e s t h e  mechanisms  to  observation  transmitter  aminobutyric acid dissrupts the bursting (McLennan  The  inhibited  inhibitory  B-neurones  collaterals  hippocampal  interneurones.  of  hippocampal  of  i n h i b i t o r y interneurones.  synaptically  the  project  subseguent  that  neighbouring that  zones they  that gamma-  neurones  importance  generation RSA  of  including  (McLennan and  a net e x c i t a t o r y d r i v e  onto  155  F I G 4 -  8j_ A Schematic I l l u s t r a t i g n Synaptic  Arrangements  Of  The  Proposed  Between The MR  Segtumj,  And Hippocampal Formation MB neurones neurones  directly  inhibit  septal  I-  which i n t u r n may i n h i b i t B-neurones,  Stimulation  o f t h e dentate gyrus a n t i d r o m i c a l l y  activates  B-neurones  and  inhibits  spontaneous d i s c h a r g e v i a r e c u r r e n t innervating circles  collaterals  i n t e r n e u r o n e s i n the septum.  represent  excitation.  their  inhibition,  white  Black  circles  I B- neurone  •  —  MR  I-neurone  Septum  Hippocampus  157  CHAPTER 5_l THE  DOE SAL  NC^ADBENERGI C SYSTEM  AND  HIPPOCAMPAL ELECTRICAL- ACTIVITY  5.S.I I n t r o d u c t i o n Previous  studies  (reviewed  shown that s t i m u l a t i o n elicits  rhythmical  hippocampus. ascending of  of  in  diffuse  electrical  Further  chapter  1) have  brainstem  regions  activity  characterization  pathways and  in  the  of  these  the l o c a l i z a t i o n of these  o r i g i n i s e s s e n t i a l for understanding  which u n d e r l i e hippocampal and c o r t i c a l  cells  the mechanisms activation.  The o b s e r v a t i o n that e l e c t r i c a l s t i m u l a t i o n i n the vicinity  of the l o c u s c o e r u l e u s , the s i t e  noradrenaline  containing  f o r e b r a i n , e l i c i t s RSA that  this  of o r i g i n  neurones which i n n e r v a t e the  (Macadar et a l , 19 74)  pharmacologically  distinct  suggests  system  i n i t i a t e the g e n e r a t i o n o f r h y t h m i c a l a c t i v i t y septum in  and  part,  in  may the  hippocampus. T h i s suggestion i s supported, by  injections  the  observations  reliably  e l i c i t RSA  that  amphetamine  (Vanderwolf,  1975)  t h a t e l e c t r o l y t i c l e s i o n s o f the l o c u s c o e r u l e u s in  of  a decrease  and  result  i n e l e c t r o c o r t i c a l a r o u s a l (Jones et  al,  1973) . However, a d e t a i l e d a n a l y s i s of the r o l e of t h i s pathway  in  the  control  of  rhythmical  a c t i v i t y has not yet been c a r r i e d The effects  hippocampal  out.,  aim of the present chapter  i s to 1)  test  the  of e l e c t r i c a l s t i m u l a t i o n of LC on hippocampal  158  electrical  activity,  are dependent 3)  2) determine whether these e f f e c t s  on the d o r s a l noradrenergic  determine  whether  this  pathway  and  pathway mediates the well  known e f f e c t s of amphetamine on hippocampal  electrical  activity.  5_j.2 Experimental Procedures Electrical electrodes vicinity  stimulation:  were of  Bipolar  stereotaxically  the  stimulating  positioned  locus c o e r u l e u s (1.5 mm  in  the  p o s t e r i o r to  s t e r e o t a x i c zero; 0.9-1.3 mm l a t e r a l ; 5.5-7.0 mm  below  cortical  anaesthetized  rats.  S t a i n l e s s s t e e l r e c o r d i n g e l e c t r o d e s were lowered  into  the  surface)  in  urethane  CA1 pyramidal c e l l l a y e r or the upper blade of the  dentate gyrus t o a spontaneous  or  position  sensory  which  evoked  s t i m u l a t e d with a 3-10 second  reliably  RSA,  The LC was then  t r a i n of pulses (0,1 msec  duration,  1-5  V) at a frequency of 10-300 Hz  effects  on  hippocampal  determined. recording  The  positions  electrodes  l e s i o n f o r subsequent  electrical of  the  responses  and  the  activity  were  stimulating  and  were marked by producing a s m a l l histological  Lesion experiments: In order observed  produced  were  mediated  verification. to  examine  i f the  by the ascending NA  p r o j e c t i o n , 9 r a t s r e c e i v e d a b i l a t e r a l i n j e c t i o n of 6hydroxydopamine(6-OHDA, 6 ug) d i r e c t l y i n t o the NA bundle  dorsal  (AP=+2.6; L=+1.1; V=-4.5). I n a d d i t i o n the LC  159  of  5  using  rats  was  electrolytically  1.0-1.5mA a n o d a l c u r r e n t  least  5 days w e r e a l l o w e d  r a t s were a n a e s t h e t i z e d experiments. lesioned and  The  for  10-20  with  occurrence  urethane of  RSA  (0.08-0.1  peripheral  mg/kg)  seconds.  At  f o r recording i n c o n t r o l and  spontaneous sensory  i n t r a v e n o u s i n j e c t i o n o f amphetamine eserine  bilaterally  f o r recovery a f t e r which the  r a t s was n o t e d d u r i n g  following  lesioned  conditions stimulation,  (0.5*2.0  and a t r o p i n e  mg/kg),  sulphate  (1-5  mg/kg).  5_s.3  Results  SRO&taneous And Sensory. E v o k e d P a t t e r n s  Of  Electrical  Activity..; The  spontaneous  electrical  activity  hippocampus i n r a t s w i t h e l e c t r o l y t i c or  6-OHDA  different  lesion  of  the dorsal  o f the  l e s i o n o f t h e LC NA  bundlewas n o t  from t h a t r e c o r d e d i n c o n t r o l r a t s . A m i x t u r e  o f f a s t a n d s l o w waves w i t h t h e p e r i o d i c a p p e a r a n c e RSA  was  freguency control recorded treated there or RSA.  recorded of  RSA  i n a l l three following  (mean=5.6±0.2)  i n electrolytic (mean=5. 3 + 0. 2,  were no d e t e c t a b l e  shape  rats  g r o u p s ( F i g . 5-1).  sensory  stimulation  d i d not d i f f e r  (mean=5.3±0.4)  ) rats  of  from  or  The in  that  6-OHDA  ( F i g . 5-2). I n a d d i t i o n  differences i n  of spontaneously occurring  t h e amplitude  and s e n s o r y - e v o k e d  160  5-  I i Rhythmical E l e c t r i c a l  Activity  Recorded In  The Dentate Gyrus Of C o n t r o l An£Treated RSA pinch line.  was e l i c i t e d i n each animal by a  Bats  A  tail  during the period i n d i c a t e d by the s o l i d  NORMAL  6-OHDA  LC LESION  1 sec.  16 2  FIGJS.  5- 2 i F r e c j u e n c y Of Elicited  Spontaneously  And-  RSA A  Each freguency  histogram  represents  o f RSA r e c o r d e d  OHDA-treated  (n=9)  g r o u p s . The v e r t i c a l of  Occurring  the  mean.  significant  i n normal  and  are  differences  However, RSA r e c o r d e d  (T.P.)  or  spontaneously  (n=7),  standard no  eserine  o c c u r r i n g RSA.  6-  (n = 5) errors  statistically  between  groups.  following  mean  LOlesioned  bars a r e  There  the  experimental  during t a i l was f a s t e r  pinch than  164  In order  to  verify  activity  is  freguency  o f RSA was e x a m i n e d  intravenous treatment  generated  that in  rhythmical  each  group  of  rats  (0.08-0.1 mg/kg).  i n t h e continuous  min  and  2  lesioned  RSA,  there  i n t h e freguency  rats  of  no  of  4-7 Hz.  of elicited  stimulation.  On Hi£j20camj_al A c t i v i t y ^  At  As  stimulation  elicited shown  following The  RSA  (1-6 V) i n  RSA  i n  having  F i g . 5-3,  RSA was r e l a t e d t o t h e lower  a the  intensity  s t i m u l a t i o n i n t e n s i t i e s (1-  2 V) t h e e v o k e d RSA was s t i m u l u s bound intensities  significant  o f RSA b e t w e e n c o n t r o l and  t h e r e g i o n o f t h e LC r e l i a b l y  freguency  were  control rats e l e c t r i c a l  freguency  between  ( F i g . 5-2) .  E f f e c t Of LC s t i m u l a t i o n In  RSA  h r s . As i n t h e c a s e o f s p o n t a n e o u s and  sensory-evoked differences  This  appearance of  i n a l l three groups o f r a t s f o r p e r i o d s ranging 20  the  (2-60 min.), f o l l o w i n g t h e  injection of eserine  resulted  electrical  persisted  , but at  f o r up  to  30  higher seconds  t e r m i n a t i o n of the t r a i n . s t i m u l u s freguency  was s e l e c t e d  intensity  and  duration  analyzing  RSA  a t a range o f s t i m u l u s f r e q u e n c i e s ( 1 0 -  300  of  Hz). A stimulus freguency  the  train  by k e e p i n g t h e constant  and  o f 100 Hz was f o u n d t o be  o p t i m a l a t 3-4 V i n t e n s i t y and t h i s f r e q u e n c y i n the remainder of the a n a l y s i s .  was  used  165  fi^Ls.  5- J i - E f f e c t s Of S t i m u l a t i o n I n Thg Region Of The. Locus Coeruleus On E l e c t r i c a l A c t i v i t y  Of  The  Dentate Gyrus The tail  top  pinch  the e f f e c t s indicated  record  shows  RSA e l i c i t e d  by a  (T.P) and t h e remaining records  show  of s t i m u l a t i n g LC with the voltages  on t h e l e f t  by the s o l i d bar.  during the  period  shown  167  As  shown  in  diffuse regions RSA.  An  F i g . 5-4, e l e c t r i c a l s t i m u l a t i o n of  i n the v i c i n i t y of  analysis  of  histologically  verified  electrode  the  revealed  and  several  effective  as  LC  LC  the r e l a t i o n s h i p site  current  of reguired  ventral  which  were  proper.  These  regions  movements  which  stimulating  at  least  nerve  also  could i n d i r e c t l y  as  include the (MBS V) and  i n nucleus p o n t i s  Placements i n t h e area o f MES V  the  t o i n i t i a t e BSA  regions  placements  initiated  between  the  mesencephalic nucleus o f t h e f i f t h more  also  caudalis.  elicited  facial  i n i t i a t e RSA through  sensory-motor pathways (Vanderwolf, 1972).  E f f e c t s Of 6 2 O H D A On RSA I n i t i a t e d  By LC Stimulation-  In c o n t r o l r a t s the c o n c e n t r a t i o n hippocampal  formationwas  concentration  depletion)  was  NA  i n the  0.41.t0.0 5 ug/kg. F o l l o w i n g a  b i l a t e r a l i n j e c t i o n of 6-OHDA i n t o the  of  reduced  the  dorsal  bundle  to 0.02±0.3ug/kg (94%  which i s s i g n i f i c a n t l y lower  (p<0.01)  than  normal. Electrical  stimulation  rats  (Fig, 5 - 5 ) e l i c i t e d  and  amplitudes  to  that  RSA  of  LC  i n 6-OHDA t r e a t e d  of  comparable  recorded i n c o n t r o l r a t s . As  shown i n F i g . 5 - 6 , the stimulus-response OHDA  rats  i s not  significantly  normal curve, d e s p i t e hippocampal  formation.  freguency  curve  different  of 6from the  l e s s than 10% NA remaining i n the  16.8  S  FIG._  L o c a t i o n Of S t i j m u l a t i n g  5-  R e g i o n Of LC  And I n t e n s i t y  G e n e r a t i o n Of  RSA  Ai  of  Drawings  coronal  E l e c t r o d e s In  Threshold  sections  e f f e c t i v e n e s s of  stimulating  indicated  key on t h e l o w e r  Bi  by t h e  Coronal  The arrow  section  indicates  of  at  the t i p o f  e l e c t r o d e on the p e r i m e t e r of  the  For  The  showing  each  t h e pons at  The  the  site  as  left. about P  2.0.  stimulating  LC.  Abbreviations Cer  Cerebellum  DTN  Dorsal  NV  mesencephalic  LC  Locus  RPOC  Reticularis  IV  Fourth C e r e b r a l V e n t r i c l e  Tegmental  Nucleus  nucleus  of  the f i f t h  Coeruleus Pontis  Oralis  Caudalis  nerve  169  170  Z1Q.3.  5- 5: E l e c t r i c a l A c t i v i t y  Recorded In The Dentate  Gyrus Of A 6-OHD_A T r e a t e d Rat Rhythmical pinch LC  was  evoked  by t a i l  (T.P.) and s t i m u l a t i o n i n t h e reqion  with  shows  activity  the i n d i c a t e d  continous  following eserine  RSA  voltaqes recorded  injection.  of  (B and C). D 5  minutes  172  E f f e c t s Of Amphetamine In  c o n t r o l r a t s the intravenous  amphetamine (2-5 mg/kg) manner. T h i s response  evoked  2-5  of  amphetamine induced RSA  was  D-  had an onset l a t e n c y  minutes and p e r s i s t e d f o r 2-4 h r s . The frequency ranged  between  5-7  Hz  and  injection  not r e s u l t i n any o v e r t movement, although the r a t e v e n t i l a t i o n o f t e n i n c r e a s e d during the f i r s t  post  electrolytic  min  lesion  of  the  RSA i n r a t s which had an LC or a 6-OHDA i n j e c t i o n  i n t o the d o r s a l bundle. The l a t e n c y to freguency of BSA significantly  It  has  And - Evoked- A c t i v i t y •  atropine  series  of  a n a e s t h e t i z e d r a t s , RSA atropine  cases  (Vanderwolf,  such  1975).  experiments,  independent  of  stimulation  in  by  the  a d d i t i o n , a t r o p i n e pretreatment 2-5  In  using  was always blocked  spontaneously o c c u r r i n g , e l i c i t e d by  in  as  to c o n c u r r e n t movement RSA i s r e s i s t a n t  blockage by  initiated  the  been suggested t h a t under some c o n d i t i o n s  related  present  and  between groups.  RSA i s blocked by a t r o p i n e whereas those  onset  produced by amphetamine d i d not d i f f e r  E f f e c t s Of A t r o p i n e On Spontaneous  mg/kg  5  injection. Amphetamine a l s o e l i c i t e d  to  of  dose-dependent  remarkably constant f o r each animal. The  did of  RSA i n a  ( F i g , 5-7)  of  injection  urethane by  2,0—5.0  whether a  it  tail  region minutes  the  pinch of  was or  LC. In  prior  to  173  FIG^  5-  6.1  Freguency  Stimulus Lesioned The  Of  Intensity  RSA In  As  A  Control  F u n c t i o n Of And  LC  6-OHDA  Rats vertical  e r r o r s o f t h e mean.  bars  represent  standard  174  I  Stimulus Intensity (Volts)  175  fJG-A  5-  7t  I f f gets  Of  Amphetamine  On  Electrical  A c t i v i t y Of The Dentate Gyrus The ongoing  top  sweep  electrical  following  a  saline  lower sweep  shows  following  the  amphetamine  cases.  each record  activity  5.0  vehicle injection the  activity  intravenous  5.0  shows the minutes and the minutes  injection  (2.0 mg/Kg). Note that  i n i t i a t e d rhythmical three  of  of  amphetamine  electrical activity in a l l  CONTROL Saline  Amph.  6-OHDA Salime  Amph.  ELECTROLYTIC Saline  Amph.  US sec.  177  amphetamine  injection  RSA  for periods  5jJ5  Discussion  was f o u n d t o c o m p l e t e l y  prevent  o f up t o 2,0 h r s ,  Does The D o r s a l NA B u n d l e U n d e r l y RSA ? The  results of  the present  that the dorsal noradrenergic  chapter  demonstrate  bundle o r g i n a t i n g i n the  locus coeruleus  d o e s n o t p l a y an e s s e n t i a l r o l e i n t h e  generation  RSA  rats. for  of  recorded i n urethane  I f t h edorsal noradrenergic t h e generation  expect  that  abolishe  1)  of  rhythmical  rhythmical those  of  depletion  electrical  BSA  would  electrical  would  initiate  i n t e n s i t i e s lower  sites.  However,  than  6-OHDA  t h e d o r s a l bundle which r e s u l t e d i n 90-95%  or  sensory-evoked  activity.  thestimulus  from  bodies o f o r i g i n  adjacent  one would  projection  o f NA i n t h e h i p p o c a m p u s d i d  spontaneous  increase  at  critical  activity  a n d 2) d i r e c t  a c t i v i t y at threshold  required  lesions  this  activity  stimulation of thec e l l  b u n d l e were  rhythmical  destroying  anaesthetized  electrode  not a l t e r  patterns  the  o f hippocampal  I n a d d i t i o n 6-OHDA l e s i o n s d i d n o t intensity  required  to  initiate  p l a c e m e n t s l o c a l i z e d t o LC p r o p e r  r e l a t i v e t o placements s i t u a t e d i n adjacent  areas.  These r e s u l t s support the s i m u l t a n e o u s f i n d i n q s of Robinson e t a l bundle  (1977) w h i c h show  i s not  that  the dorsal  e s s e n t i a l for t h eqeneration  NA  o f RSA i n  178  freely low  moving r a t s .  threshold  RSA  and  containing  RSA.  as  may the  generation  of  and  those  e l i m i n a t e the  other  and  A4  than  The  according  recent  lesions  hippocampus but  taken  to  ascending be  various  systems  region  the  f o r the  and  regions with of  bundle  the  Moore totally  partially  (48%)  groups  may  RSA. abolish  together  a r e a may  NA  only  RSA  with  by the  d i f f u s e areas i n brainstem i n i t i a t e multiple  groups  to Dahlstrom  content suggest that caudal  influence  failure  cell  observation  NA  The  generation  associated  deplete  indirectly  coursing  extra-hippocampal  t h a t 6-OHDA l e s i o n s o f d o r s a l  s e p t a l NA  those  containing  of  possibility  a r o l e i n the  (1978)  lower  of  present chapter  s e p t a l a r e a which are  i n the  initiation  NA.  influence  RSA.  any  following  axons  ( i . e . A2  f o r the  find  RSA  I t i s p o s s i b l e t h a t NA t o LC  d i d not  block  d o r s a l bundle play  F u x e , 1964) such  to  e t a l (1977) do n o t  through the  caudal  unable  r e s u l t s of the  Robinson  of  also  of hippocampal  The  t h a t NA  s i t e s w i t h i n t h e LC  were  depletion  These r e s e a r c h e r s  systems  site  of  and  may  generation  making  observation RSA  modulate  suggests RSA.  interactions thus of  RSA.  be  specific  the  that that  The  septal  between  these  only  critical  179  4£tipn Of Ampheta mine The i n t r a v e n o u s i n j e c t i o n o f amphetamine was shown to  produce  RSA  destruction  in  of  rats  which  had  electrolytic  LC, 6-OHDA l e s i o n of the d o r s a l bundle  and c o n t r o l r a t s . The mechanisms mediating t h i s of  amphetamine  are  enhanced  synaptic  dopamine  and  not  known  release  and may be r e l a t e d to  of  noradrenaline  action  the  catecholamines  (reviewed by Moore, 1977).  The e f f e c t of amphetamine i s u n l i k e l y t o be mediated by enhanced NA r e l e a s e from since  RSA  was  the  demonstrated  l e s i o n s of LC. Amphetamine of  the  mesolimbic  i n n e r v a t e the Assaf  and  septum  DA  rhythmical  been  burst  axons  electrolytic  could enhance  septal  area  implicated discharge  the  activity  (Lindvall,  1975;  in  the  generation  of  of medial s e p t a l neurones  1974a, 1976).  I t i s not known to are  following  LC  1977). The neurones of the l a t e r a l  (McLennan and M i l l e r ,  amphetamine  of  system which has been shown t o  lateral  Miller,  have  terminals  what  dependent  extent on  the  actions  of  septal-hippocampal  c h o l i n e r g i c neurones. The p r e l i m i n a r y o b s e r v a t i o n s t h a t in  urethane  amphetamine role  of  anaesthetized can  be  cholinergic  possibility release of  that  the  action  of  blocked by a t r o p i n e emphasize the systems.  amphetamine  acetycholine  there i s no d i r e c t  rats  There  is  injections  ( Moore,  197 7).  also  the  enhance the However,  evidence that Ach i n the s e p t a l area  180  is  e n h a n c e d by  amphetamine.  P o s s i b l e C o n t r i b u t i o n Qf The in  results  urethane  arises  that  these  o f LC  urethane  narrows  of  LC  the  i n driving  Hz.  of  RSA  Hz and  chapter  any  the p o s s i b i l i t y  Hz  will  not  be  Kelly  t h a t NA l o w e r s t h e t h r e s h o l d  o f RSA  a t an o p t i m a l f r e q u e n c y driving  has  occurrence  of  not  f r e q u e n c y range  this  yet  RSA  e t a l (1977) i n f r e e l y o f RSA  of been  and  the  moving  rats  (i.e. NA.  3-  However  f r e g u e n c y band o c c u r s i n t h e  n o r a d r e n e r g i c system that  Hz i n  H c N a u g h t o n , James and  the evidence that the f u l l LC  3,  contribution  occurs i n the absence o f hippocampal  of  potential  f r o m 3-12  related to physiological  suggest t h a t the f u l l  the  range  septal  of Robinson  possibility  in  do i n f a c t s u g g e s t  7.7  absence  mask  f r e q u e n c i e s a b o v e 7.0  'septal driving*  12 Hz)  the  As p o i n t e d o u t  r e s u l t s o f Gray,  However,  and  conditions  on RSA.  for  results  rats  moving r a t s down t o 3-7  s e e n . The (1975)  o f t h e p r e s e n t c h a p t e r were o b t a i n e d  anaesthetized  influence  freely  Orethane Anaesthesia  system  does not e l i m i n a t e modulates  l o w e r i n g the t h r e s h o l d f o r c e r t a i n f r e g u e n c i e s . ,  RSA  by  181  5._5  Summary The  results  p o s s i b i l i t y that plays  an  of the present chapter the  essential  LC role  proposed that amphetamine other than enhanced NA  noradrenergic i n generation elicits  BSA  e l i m i n a t e the system  plays  of BSA.  It is  by  mechanisms  r e l e a s e i n the hippocampus.  182  CHAPTER 6: CHARACTERIZATION OF THE PER FOR ANT  PATH-  DENTATE PSOJECTION  6j_1_ I n t r o d u c t i o n As  reviewed  i n chapter 1, h i s t o l o g i c a l s t u d i e s of  the hippocampal  formation r e v e a l two major c e l l  the  c e l l s of the' hippocampus proper and  pyramidal  granule c e l l s cells  form  ( G - c e l l s ) of the dentate  a curved sheet of c e l l  gyrus.  bodies with  o r i e n t e d d e n d r i t e s r e a c h i n g the o b l i t e r a t e d fissure  highly  of  dendrites  organized  termination 6-1,  cortex  The  of  laminar  from in  clear  c e l l bodies, there i s a distribution  the  the  G-  hippocampal  of  the major a f f e r e n t f i b r e s .  afferents  terminate  and  the  apically  (chapter 1, F i g . 1). In a d d i t i o n t o t h i s  segregation  Fig.  types,  As shown i n  ipsilateral  cuter  d i s t a l d e n d r i t e s wheras commissural  the  entorhinal  molecular l a y e r and  onto  associational  a f f e r e n t s terminate more proximal to the c e l l bodies i n the  inner  molecular  layer.  While  o r g a n i z a t i o n of other e x t r i n s i c a f f e r e n t s known,  histochemical  studies  the is  precise not  suggest t h a t monoamine-  c o n t a i n i n g systems terminate i n the v i c i n i t y of the cell  yet  bodies and the dentate h i l u s  G-  (reviewed i n s e c t i o n  1. 1. 1) The most massive  of the above i n p u t s i s t h a t  from  the  e n t o r h i n a l c o r t e x which p r o j e c t s v i a the p e r f o r a n t  path  (PP)  t o the  outer  two-thirds  of  the  dendritic  183  ll  L arain_a.E  O r g a n i z a t i o n Of A f f e r e n t s - To The-  Dentatgi, Afferents regions  of  from  the  the  lateral  and  medial  e n t o r h i n a l cortex p r o j e c t v i a  the p e r f o r a n t path onto the outer two-thirds o f of  the dentate molecular  the  dendrites  associational  of  G-cells,  which  and  (not shown here) f i b r e s from  the  and  ipsilateral  r e s p e c t i v e l y , terminate Cholinergic  i n t h e inner  and  hilus.  of  the  cell  CA3, molecular  monoamine-containing  f i b e r s p r o j e c t t o more d i f f u s e r e g i o n s vicinity  contains  Commissural  contralateral  layer.  layer  i n the  body l a y e r and dentate  > Entorhinal (PP)  Commissural  Septal (Ach) • Raphe ( 5 - H T ) L C (NA)  185  tree.  According  t o Nafstad  ( 1967), t h e s m a l l  a x o n s o f t h e PP make e n - p a s s a g e s y n a p t i c many  spines o f t h e profusely branching  cells.  system  revealed  results i n extracellularly having  contact  that  field  a topographical organization  Andersen  and  Lomo,  this  strictly  stimulation  recorded  with  d e n d r i t e s o f G-  E l e c t r o p h y s i o l o g i c a lanalysis of  laminated  diameter  of  PP  potentials  ( G l o o r e t a l , 1964;  1966; Lomo, 1 9 7 1 a ; McNaughton and  B a r n e s , 1977) Electrodes s i t u a t e d i n the outer of  the  which  dentate  record a negative  reflects  dendrites  the  and  i s termed  1971a) . A t t h e c e l l consists  of  synaptic  a  body  layer  extracellular  current  the  the  wave  with  field  generated  population  layer  positive  molecular  EPSP  evoked a  by  (Lomo,  response  superimposed  negative  spike representing  neuronal  a c t i o n p o t e n t i a l s and i s t h e r e f o r e r e f e r r e d t o  as t h e p o p u l a t i o n An  spike  important  the synchronous  firing  (Lomo, 1 9 7 1 a ) ,  feature  of  the  above  projection  system i s t h e p l a s t i c i t y  of synaptic transmission  is  i s stimulated  o b s e r v e d when t h e PP  freguencies.  of  Relatively  brief  at  tetanic  which  particular stimulation  r e s u l t s i n an enhancement o f b o t h t h e  population  and  f o r h o u r s and on  spike  occassions Bliss  and  response f o r several  which days  Gardner-Medwin,  persists (Bliss  and  Lomo,  EPSP  1973;  1 9 7 3 ; D o u g l a s and G o d d a r d ,  1975). In c o n t r a s t , a s i n g l e c o n d i t i o n i n g pulse  to  the  186  PP  results  only  in  short  term  ( l e s s then 1 second)  p o t e n t i a t i o n of the response t o a subsequent t e s t (Lomo, 1971b; Steward e t a l , 1976). The paradigm,  commonly  potentiation paired  referred  (PTP)  as  well  pulse f a c i l i t a t i o n ,  invitrp  to  as  mentioned  post-tetanic  the l a t t e r ,  known as  have a l s o been confirmed  hippocampal s l i c e s  unpublished o b s e r v a t i o n s ) ,  as  first  pulse  (Dudek et a l , 1976; The  in  Miller,  mechanisms which mediate  the above forms of f u n c t i o n a l p l a s t i c i t y are not known. Andersen  (1975) suggests  ability  of  transmitter.  the  of the  may  reflect  t e r m i n a l to r e l e a s e more  possibility  postsynaptic  of  of  G-cells  the  evaluate  thesis  these  to  examines  the  stimulation  of  the  this  r o l e of e x t r i n s i c response  of  p e r f o r a n t path. Such whether  changes  the e f f i c a c y of the c o r t i c a l i n p u t v i a the  PP occur  result  postsynaptic  of  the  cell  activity  in  The  purpose  the  entorhinal-dentate  anaesthetized the  of the  PP-evoked  afferents  elements of the t e s t  present  r a t and  of  to  a d d i t i o n to those p o s t u l a t e d  occur i n the p r e s y n a p t i c  of  altered  possibilities,  a n a l y s i s i s e s s e n t i a l f o r determining  as a  an  elements i s j u s t as  a f f e r e n t s to the dentate i n modifying the  in  the  (Dunwiddie et a l , 1978).  In order to part  they  presynaptic  However, the  responsiveness likely  that  chapter i s t o  projection  in  responses.  The  to  pathway.  characterize  the  analyze p a i r e d pulse  the  urethane  facilitation  following chapters  examine the e f f e c t s of s t i m u l a t i n g e x t r i n s i c  afferents  187  originating 7),  K  t h e c o n t r a l a t e r a l hippocampus  median raphe n u c l e u s  coeruleus  62  in  (chapter  Experimental  (chapter  9) on t h e s e  8)  and  (chapter  the  locus  response,  Procedures  E x t r a c e l l u l a r r e c o r d i n g e x p e r i m e n t s were performed on  a  total  Concentric  in  to  urethane  anaesthetized  stimulating  the angular  4.2-4.4 mm  surface)  94  bipolar  positioned bregma;  of  activate  electrodes  bundle  lateral;  (8.1 mm  3.0-3.5  the  recorded  NaCl  t h e p e r f o r a n t path a s i t l e a v e s  gyrus.  using  subiculum  resistance) (9-12  or  Mohm) ,  electrode from  both  amplified  2, T y p i c a l l y  presentations  the  and  were  w i t h 4M  sharpened  the  and  used  to  cell  body  analyzed  average  of  20-30  The  stimulus  were p l o t t e d . The  subseguent  through  delivered  ,  as described i n  of  e l e c t r o d e was a n a l y z e d  than  record  layer  effects of conditioning stimulation volley,  more  s y n a p t i c region i n the  ( I S I 2.5-4.0 s e c o n d s )  test  tungsten  I n some c a s e s  were  l a y e r and from t h e were  potentials  either glass micropipettes f i l l e d  simultaneously molecular  enters  dentate  recording  chapter  the  the  (2-5Mohm  signals  Extracellular  from t h e d o r s a l hippocampus  microelectrodes one  cortical  t o t h e h i p p o c a m p a l f i s s u r e where t h e PP  dentate  gyrus  were  posterior to  below  the i p s i l a t e r a l e n t o r h i n a l cortex or i n adjacent  rats.  the  using the paired-pulse  This c o n s i s t e d of comparing the amplitudes  PP the  on  a  same  paradigm.  and r a t e s o f  188  r i s e of the response  evoked by the f i r s t  pulse t o t h a t evoked by the second  (test)  pulse.  The  test  pulses  (C-T  interval  between  interval)  ranged between 0-1500 msec,  6^3  conditioning  {conditioning)  and  Results Fig.  evoked  6-2  by  shows the e x t r a c e l l u l a r f i e l d  low  intensity  (1-2V) s t i m u l a t i o n o f the  and recorded at t h e i n d i c a t e d gyrus.  potentials  depths  in  the  dentate  The l o c a t i o n of the e l e c t r o d e at each r e c o r d i n g  s i t e can be approximated by the corresponding of  PP  the upper and  lower  blades of the dentate.  schematic As  shown  by Lomo (1971a) i n the r a b b i t and Gloor e t a l (1964) i n the  cat,  middle  a s h o r t l a t e n c y negative  wave i s recorded i n  molecular l a y e r with a maximum at the  level  the PP synapses (Nafstad, 1967). At the c e l l the  response  body l a y e r  r e v e r s e s to a p o s i t i v e wave on which the  d i s c h a r g e s of i n d i v i d u a l G - c e l l s are superimposed. mirror  images  blade of the As shown intensity  of  these  responses  occur i n the  The lower  dentate. in  F i g . 6-3,  enhances  negative f i e l d and of  the  increasing  amplitude  of  the the  s i g n i f i c a n t l y increases  stimulus dendritic  the  number  s p i k e s recorded on t h e p o s i t i v e c e l l l a y e r f i e l d .  higher s t i m u l u s i n t e n s i t i e s synchronously  of  giving  rise  (3-7 V) to  At  the u n i t s d i s c h a r g e  a large negative spike  which f o r the reasons o u t l i n e d below i s r e f e r r e d  to  as  189  Z 2.L Dejoth  £rofiles  Of  The  Field  Potentials  E v o k e d I n The D e n t a t e G y r u s By A Weak Path  Volley  Az_  Extracellular  field  along a v e r t i c a l track  potentials  surface.  Ej.  of  measured  1.0-1.5  (indicated Cj_  profile  dentate  the  evoked  after  depths  potentials  their  onset  by v e r t i c a l b a r s i n A ) .  Schematic  positions  msec  recorded  at the indicated  below t h e c o r t i c a l Depth  Perforant  representation  of t h e  approximate  o f the upper and l o w e r b l a d e s o f  gyrus.  the  191  IISL*.  6-  3z_  Field Potentials  Evoked In The Dentate. By.  PP S t i r a u l a t i o n At V a r i o u s Ai Field potentials distances following  above  recorded at  the  a weak PP  granule  the  indicated  c e l l body  layer  volley.  B i Depth p r o f i l e as i n A volley.  Intensities  with  a  stronger  PP  > £  92  193  the p o p u l a t i o n spike response  I d e n t i f i c a t i o n Of Dentate  KJL * M o l e c u l a r  Iai§£  n e g a t i v e response in  the  middle  from  Responses^  As  shown i n F i g , 6-4,  i s recorded by an e l e c t r o d e molecular  negative response um  -  of dentate granule cells....  layer  Nafstad,  PP  1967).  directly  this  related  The time from discharge  onset  msec  of  it  freguency  of  150-190  response  (Blackstad,  this  following  negative  stimulation  and  its  rise  to s t i m u l u s i n t e n s i t y  time  ( F i g . 6-4B,C).  to  the  earliest  response  was  f o l l o w e d moderate (100-200 Hz) In  evoked  monosynaptically  (up to 50 Hz)  stimulation addition,  of  but not high  the  perforant  i t s onset l a t e n c y was  r e l a t i v e l y c o n s i s t e n t and thus u n l i k e l y t o r e s u l t polysynaptic a c t i v a t i o n similar  al,  1964)  negative  response  and r a b b i t s  was  previously  coincided  with  the  (Gloor  (Lomo, 1971a). Lomo (1971a)  observed that the onset of the wave  from  ( F i g . 6-4A) .  recorded i n the dentate molecular l a y e r of c a t s et  are  G - c e l l s ranged between 1.5-2,5 msec. The  (Fig.6-4D).  A  of  msec. The l a t e n c y t o  the onset of t h i s f i e l d  above negative  path  The  terminate  and reaches a peak a t 4-6  the onset of  since  i s maximal  G - c e l l body l a y e r i n the r e g i o n of the d i s t a l  response occurs at 2-4 the  situated  of the dentate. T h i s  (N2 i n F i g . 6-4B)  d e n d r i t e s where the PP synapses 1958;  a large  extracellular  onset  of the  negative  intracellular  194  OSA  Hi  6_r  Identification  Recorded In The  hi  Of  The  Field  Dentate Molecular  5 superimposed o s c i l l o s c o p e  the  small  initial  Lay,e.r  A;  sweeps  deflection  prominent n e g a t i v e response  Potentials  (N1)  showing and  the  (N2) .  B i e f f e c t s of i n c r e a s i n g the stimulus i n t e n s i t y on the above  responses.  Cz_ expanded p l o t s showing the s i z e rate  of  rise  of  N2  at  of  various  N1  and  stimulus  intensities. P i i n a b i l i t y of the l a r g e negative t o f o l l o w high freguency  stimulation  that i t i s produced s y n a p t i c a l l y .  field  (N2)  suggesting  195  196  EI .*. £6  5z_ R e l a t i o n s h i p Between PP  And  Amplitude  Of  Responses  Stimuljus In t e n s i t y Recorded  In  The  D e n d r i t i c Region Of The. Dent ate Each point r e p r e s e n t s the average responses  recorded i n the  oftwenty  d e n d r i t i c r e g i o n of  the dentate gyrus. The amplitude of the EPSP was measured while increasing  (0)  and  decreasing  i n t e n s i t y t o e v a l u a t e the response.  (,)  variability  stimulus of  the  0.0  1.0  2.0 3.0 Stimulus Intensity (Volts)  4.0  198  EPSP. S i n c e t h i s negative  monosynaptic wave i s  i n the l a y e r of t h e p e r f o r a n t path synapses, called  the  i n accord  extracellular  maximal  i t w i l l be  EPSP, T h i s i n t e r p r e t a t i o n i s  with that of G l o o r  et  al  (1964)  and  Lomo  (1971a) . In  some  molecular  extracellular  layer a  F i g . 6-4C)  small  precedes  records  negative  the  onset  obtained  i n the  deflection of  the  (N1 i n  EPSP by 0.4-  0.6 msec. T h i s s m a l l d e f l e c t i o n i s only recorded restricted  zone  in a  i n the v i c i n i t y of the PP synapse and  i s l i n e a r l y r e l a t e d to stimulus i n t e n s i t y  ( F i g . 6-5) .  U n l i k e the EPSP, t h i s e a r l y component i s not attenuated by  high  freguency  actually  enhanced  stimulation  ( F i g . 6-4D)  and  is  a t a s h o r t pulse i n t e r v a l s when the  EPSP i s r e f r a c t o r y . I t i s ,  therefore,  concluded  that  the e a r l y negative component i s the PP f i b r e v o l l e y and thus  does  response this  not  show  characteristics  d e s c r i b e d above. A s i m i l a r  response  o f the s y n a p t i c  interpretation  was p r e v i o u s l y proposed by Lomo  In a d d i t i o n , Lomo  (1971a) observed  (1971a).,  t h a t the p r e s y n a p t i c  v o l l e y was not as r e s i s t a n t to anoxia as response. ,  of  the  synaptic  199  ISSt. §.Z 6±  Identification  Of  The  Evoked  Potential  S§£2ES§d At G - c e l l Body Lai§£i A: Components of the response cell  body  layer  with a s t r o n g average  of  following  (10 V) v o l l e y . 20  trials  recorded stimulation The  Relationship  recorded image  G-  of PP is  an  and peaks are l a b e l l e d  according to t h e i r p o l a r i t y and Bj.  plot  at  between  the  latency. evoked  EPS P  i n the d e n d r i t i c l a y e r and the mirror  positive  wave  recorded  at  cell  body  layer. Cj_  Rate  of  r i s e o f P1 response and d e n d r i t i c  EPSP as a f u n c t i o n  of stimulus i n t e n s i t y .  201  Bj_  Cell  Layer  : F i g , 6-6&  extracellular perforant  field  path  shows the components of the  potential  volley  evoked  by  a  strong  (10V) and recorded at the c e l l  body l a y e r . These components are l a b e l l e d a c c o r d i n g their  polarity  and  latency  t o onset.  P1 i s recorded  simultaneously with t h e r i s e o f the negative EPSP  and  appears  Discharge but  as  i t s mirror  dendritic  image ( F i g . 6-6B).  of G - c e l l s r a r e l y occurs at the s t a r t  rather  1.5-2.0 msec  of  P1  a f t e r i t s onset. The r a t e of  r i s e of the P1 i s s i m i l a r t o t h a t o f the EPSP 6D)  to  ( F i g . 6-  and i s most l i k e l y the e x t r a c e l l u l a r r e f l e c t i o n of  the d e n d r i t i c EPSP recorded a t the c e l l body l a y e r . The o b s e r v a t i o n that i t i s the  opposite  EPSP  by the discharge of G - c e l l s  and  suggests  is  not  caused  to  the  that i t a c t s as a source p r o v i d i n g c u r r e n t  the d e n d r i t i c  EPSP s i n k  Component  N2  is  bodies and i s recorded the  polarity  perforant  positive  path  wave  following sufficient  is  low to  (Lomo, 1 971 a) . maximal i n the r e g i o n o f G - c e l l only  following  with  higher  recorded  by  stimulus  stimulation  intensity. the  same  intensities  Only  of a  electrode (0.5-1.0 V)  the  dendritic  EPSP.  is  gradually  increased  (1.0-  2.0 V) s i n g l e u n i t s are recorded on the p o s i t i v e  wave.  stimulating  The  is to  intensity  number  intensities  evoke  to  of  units  increase  with  ( F i g . 6-7) u n t i l a prominent  recorded.  As  higher N2  The l a t e n c y t o the peak of N2  the  stimulus component  corresponds  the mean l a t e n c y t o discharge of i n d i v i d u a l  G-cells  202  II£A,; 6 -  7z  Development  Of  The  Dentate  jPjJfiulation  Sjgikej, Responses following voltages.  PP  recorded stimulation  Note  in  with  recruitment  discharge to form a compound stimulus i n t e n s i t y .  the  G-cell the  of spike  layer  indicated  single at  unit higher  204  8z_ E f f e c t s Of Stimulus I n t e n s i t y On Am£litude M S MtSliSx Of %k§ O - c e l l Layer  response  The peak l a t e n c y and amplitude of  the  N2  component of the c e l l l a y e r response i s p l o t t e d as a f u n c t i o n  o f stimulus i n t e n s i t y .  2 05"  5.0  Stim. Intensity (V)  206  (Andersen,  Skrede  and  related to stimulus S i n c e the layer  N2  ( F i g . 6-9)  cells,  i t  most  activation 1964;  of  (>100  of  N2  Hz)  and  d i s c h a r g e of  i s r e l a t e d to the represents  population  i s that  caused  by  stimulation  of  the  F i g . 6-11,  the  freguency  latency  N2  was  (MF)  G-cell  component  units  pathway.  N2  wave, t h i s  spike  stimulation  (>150  shift  latency  in  amplitude enhanced the  of by  Hz)  low  frequency  spike.  could  (5-7 not  be.  of  and  hereafter  in  the  referred  shown MF  localized  to  by  high  In  freguency appreciable  addition  component Hz)  As  the  show an  6-11D). N2  following  could  stimulation The  N2  the  be  may  number  t e r m i n o l o g y of t o as  the  whereas  component  monosynaptic a c t i v a t i o n of a  G-cells  (1971a) w i l l be  does not  synaptic  antidromic spike  dentate  and  by  s y n a p t i c a l l y evoked  influenced  (Fig.,  the  t h u s r e p r e s e n t the of  i s not  the  is  obtained  stimulation  body l a y e r . U n l i k e  shifts  ( F i g . 6-10).  pathway r e s u l t s i n a s h a r p n e g a t i v e s p i k e the  et a l ,  high  same  intensity  (Gloor  follow  the  mossy f i b r e  low  monosynaptic  synaptic  discharge  activating  G-  the  shows  that  G-cell  of  monosynaptic responses  G-cell  antidromically  the  support  and  evidence  the  of G-cells  i t does n o t  stimulation  Additional  i s inversely  in  likely  of  and  component i s m a x i m a l  a  characteristic  1971)  i n t e n s i t y (Fig.,6-8).„  Lomo, 1 9 7 1 a ) . F u r t h e r  nature  in  Bliss,  Lomo  population  207  6-  9i The C e l l Layer Response Recorded At Various Depths In The Each  Dentate^  point  are the averages  and  corresponding  potentials  of 20 responses recorded along  the same d o r s a l - v e n t r a l e l e c t r o d e t r a c k .  Distance above G-Cell Layer  O CO  209  FIG._  6-1 Oj.  Presynaptic  Following Aj.  And  S t i m u l a t i o n Of The  effect  B: f i b r e  volley and  spike  G-cell  at  population  175  Hz.  spike,  from  the  attenuated  by  Ci  superimposed  5  is  (lower  the not  stimulation.  oscilloscope the  (top  unlike  volley  high freguency  characteristic  on  entorhinal  that,  PP  i n d i c a t i n g v a r i a t i o n of latency  PP  l a y e r response  Note  the  x  freguency  sweep) f o l l o w i n g s t i m u l a t i o n of the cortex  Path ~  response.  recorded  the  Responses  Perforant  of i n c r e a s i n g s t i m u l u s  PP evoked p o p u l a t i o n  sweep)  Postsynaptic  sweeps  population  of  a  spike  monosynaptic  response. pi  histogram showing the d i s t r i b u t i o n  latencies  following  seconds).  The  first  PP  stimulation  vertical  constancy o f the stimulus  bar  artifact.  of  peak  (ISI=2.5 indicates  o  1  5 "> o o X  1 o O-i  3 CD O  012  Spikes  CJl  o J  8  X M  211  Component at  threshold  P2 i s recorded a t the G - c e l l body  layer  intensities  of  f o r tne  production  d e n d r i t i c EPSP. Since P2 i s always recorded  a  with the P1  component i f may also be i n t e r p r e t e d as an image of the d e n d r i t i c EPSP. However with  P1  and  may  have  along i t s length evoked not  neurones  which  by  unlikely  MF  to  discharge  on  i n the dentate  symmetrical  Since  some  of  those  appear on the P2 component are  evoked  but  stimulation  represent  always  neurones d i s c h a r g i n g anywhere  ( F i g . 6-12).  antidromically  activated  P2 i s not  are  synaptically  ( F i g , 6-12),  G-cells.  The  they  neurones  are that  the P2 component are f r e q u e n t l y recorded h i l u s and  may  represent  interneurones  that were a c t i v a t e d by G - c e l l axon c o l l a t e r a l s . In t h i s regard,  Lomo  (1 968)  has  suggested  s i g n i f i e s the s t a r t o f IPSP's on  that P2 component  granule  cells  which  are i n i t i a t e d by i n h i b i t o r y i n t e r n e u r o n e s . On t h e b a s i s of the above data i t may be suqqested part  the  t h a t P2 may be i n  r e f l e c t i o n o f d e n d r i t i c EPSP and i n part the  s t a r t of i n h i b i t o r y mechanisms. The l a t e n e q a t i v e component identified.  It  (N3) has not y e t  i s recorded i n the r e g i o n o f the c e l l  body l a y e r and i s maximal i n the r e g i o n o f the hilus  at  Stimulating production  been  approximately intensities  2.0 mm below  from  the  threshold  dentate midline.  for  the  o f a p o p u l a t i o n s p i k e produce a r e l i a b l e S3  component and a s the s t i m u l a t i n g i n t e n s i f y i s i n c r e a s e d  212  Fig  A  6-JJi  IntidromiG  And  Orthodromic A c t i v a t i o n  Of  Dentate Granule C e l l s , Aj. depth  profiles  between  the  PP  indicating population  a  relationship  spike  ( l e f t ) and  a  s i m i l a r n e g a t i v e response evoked by mossy f i b r e (MF)  stimulation  (right) .  B i the e f f e c t s of r e p e t i t i v e Hz)  on the  MF  (top trace)  stimulation  and PP (bottom  evoked responses recorded at the G - c e l l Note MF  that  the  layer.  thus  may  antidromic.  C: a n t i d r o m i c  a c t i v a t i o n of G - c e l l f o l l o w i n g  stimulation.  The  r e l a t i o n s h i p between cell  (obligue  trace indicates 200  Hz  DJJ.  MF  characteristic sec),  trace  that  and  both  MF  indicates  antidromically  arrow)  s t i m u l a t i o n of evoked  top  activated  field.  resonses  Bottom followed  MF.,  response  i n d i c a t i n g the c o n s i s t e n t  1.0  trace)  amplitude o f response evoked by  s t i m u l a t i o n i s not attenuated and  be  (100  at  fast  sweep speed  l a t e n c y and  of antidromic  responses  amplitude CIS I  =  2\3  214  the amplitude of N3 a l s o i n c r e a s e s . The amplitude of 133 was  dependent  electrode  on  the  spike  the  stimulating  without the N3 component.,  evoked discharges  superimposed on the cases  of  but no s t i m u l a t i n g p o s i t i o n s were found t h a t  evoked a p o p u l a t i o n The  position  N3  of neurones were not u s u a l l y  component,  s m a l l s p i k e s were recorded  l a t e negative  wave  spikes  The  latency  to  longer  than t h a t f o r the monosynaptic p o p u l a t i o n  individual  spikes  neurones that activated  difficult were  are  by  the  9-15 msec and was always  to  assess  spike.  whether  these  r e l a t e d to P2 or N3. The same  evoked  mossy  seme  near the peak of t h i s  of  i t is  was  in  onset  However,  these  ( F i g . 6-12).  although  near  fibre  N3  are  synaptically  stimulation  ( F i g . 6-12)  suggesting  t h a t they are not G - c e l l s .  Furthermore  the  amplitude  of  reduced  low  N3  was  freguency s t i m u l a t i o n population  spike  significantly (<20 Hz)  response  which  and  by  potentiated  o f t e n r e s u l t e d i n the  complete disappearance of N3 and the appearance of negative  spikes  resembling  the  t h e N2 component  new  (Fig. 6-  12D). The long have  latency  that  r e s u l t e d from s t i m u l a t i n g commissural  coursing  i t  may  projections  through the a n g u l a r bundle to terminate i n the  e n t o r h i n a l cortex. the  of the N3 suggests  commissural  10-20 days before  However, a complete  transection  of  p r o j e c t i o n s i n 6 r a t s (see chapter 7) the  recording  experiments  d i d not  215  FIG  t  6-12.1  Identification  Componen t  1N3L  Following Ai  Stimulation  population  spike  component  (N3).  Bz_  a  (N2)  Negative  In  The  Denote  volley  and  Perforant  is  more  Path.  the  latency  the  later  population  variable  than  the  s i n g l e u n i t evoked i n the v i c i n i t y of  evoked  of  discharge  PP.  This  unit  MF  synaptically  (2.5  N3 was  the experiment.  of a neurone recorded  the dentate h i l u s f o l l o w i n g s t i m u l a t i o n and  the  (N1).,  f i r i n g spontaneously during  (2 V)  of  negative  Note a l s o t h a t the  following stimulation  Cz  Late  Of The  between  amplitude  presynaptic  The  Recorded  relationship  spike  Of  of  in PP  V) . Note that t h i s neurone i s  activated  by  MF  stimulation  i n d i c a t i n g that i t i s not a G - c e l l . Pi e f f e c t s of frequency s t i m u l a t i o n the  PP-evoked  f r a c t i o n a t i o n of l a t e enhancement response. The  of  responses negative the  (10 Hz)  indicating component  population  numbers of pulses g i v i n g  and spike  rise  the corresponding response are i n d i c a t e d on left.  on  to the  217  e l i m i n a t e the N3 component. On that  the  N3  basis  of  represents  the above data, i t i s proposed  the  neurones i n the dentate had  a  maximal  polysynaptic  h i l u s . The  longer l a t e n c y than the in  the  region  of  activation  observations  of  that i t  population s p i k e and  the  hilus  support  is  this  suggestion. The  least  recorded  a t the  negative  conspicuous G-cell  component  component o f the response  body  (N1  layer  in  is  F i g . 6-4).  the  earliest  Dnlike a l l the  components d e s c r i b e d above, N1 i s not always When present,the before  the  stimulation  H1 component was  onset  of  frequencies  P1  recorded  component  greater  observed.  0.4-0.8 msec and  than  200  followed Hz  which  blocked the monosynaptic a c t i v a t i o n of G - c e l l s (Fig. 610D).  It  is  likely  that  N1  component  e x t r a c e l l u l a r r e f l e c t i o n of the p e r f o r a n t recorded  in  the  region  i n t e r p r e t a t i o n i s i n accord Lomo (1971a) and The dentate in  of  the with  Steward e t a l  extracellular  path  G-cell the  (1976).  the  volley  layer. This  terminology  of  s  f i e l d responses recorded  f o l l o w i n g s t i m u l a t i o n of the PP are  F i g . 6-2.  is  i n the  summarized  S t i m u l a t i o n of the angular bundle produces  a PP f i b r e v o l l e y i n the p r e s y n a p t i c t e r m i n a l s . T h i s i s followed  by  the  depolarization  of  which i s r e f l e c t e d by a l a r g e negative to  as  the  population  EPSP.  The  G - c e l l dendrites field  referred  depolarization  218  £IG*.  6-13i Discharge P a t t e r n Of Ai  interval  oscilloscope discharge cell  fientate  histogram sweep  and  x  bursting  p a t t e r n of a u n i t recorded i n the  G-  layer. discharge  pattern  a dentate c e l l and slow e l e c t r i c a l  activity  recorded  in  the  m i c r o e l e c t r o d e . The BSA  Cells  corresponding  indicating  I i r e l a t i o n s h i p between the of  Granule  (top  vicinity  of  the  same c e l l i s recorded d u r i n g  sweeps) and i r r e g u l a r  activity(lower  sweeps). , C i a non-bursting dentate u n i t recorded sensory s t i m u l a t i o n (between the two  during  arrows).  2/9  > E  IT)  b  —  d  220  discharges a proportion the  negative  of t h e  population  d i s c h a r g e s neurones i n the by  of  the  causing  Following  d e n t a t e h i l u s are  PP-evoked  p r o j e c t v i a MF  on  Qa. S i n g l e  Discharge  Unit  Dentate urethane either  a tail  G-cell activated  90  or  Hz.  simultaneously  the  firing in a  from the  consists  response  (Fig.  6-14).  follow high vary  of  freguency  approximately  s t i m u l i at t h r e s h o l d monosynaptically  slow  at  and  in in  rates  evoked  discharge  the  (>100  recorded  microelectrode  o v e r l y i n g CA1  region  3).  of  firing  the  latency Hz)  G-cells  intensity  of  perforant  between (ISI=1.0  and  3-  path  activation did  stimulation  0.5-1.0 msec  activated  a  pattern  a c t i v a t i o n at a latency  short  as  (approx.20%)  activity  of  i n the  stimulation This  rate  spontaneously  of s i n g l e s p i k e  msec f o l l o w i n g  recorded  proportion  vicinity  hippocampus (chapter  The  CA3.  pattern  bursting  rhythmical  from b i p o l a r e l e c t r o d e s  of the  G-cells  spontaneously  bursting  ( F i g . .6-13). T h i s to  fire  late  Somatosensory s t i m u l a t i o n such  increased  related  The  (G-cells)  rats  discharge pattern  G-cells  or  cells  irregular  pinch  bursting  was  granule  2 and  response.  to pyramidal c e l l s of  anaesthetized an  between  7  spike.  cells  mossy f i b r e axon c o l l a t e r a l s g i v i n g r i s e t o t h e  components  of  granule  not  could  consecutive sec).  These  n e u r o n e s were i d e n t i f i e d  as  221  fISi  Szliii  The  Response  Granule C e l l  A:  top  sequence  An  Identified  To S t i m u l a t i o n  trace  and bottom  Of  Of  The  Dentate Perforant  i n d i c a t e s spontaneous discharge  trace  shows  activation-inhibition  following s i n g l e pulse stimulation of  PP. B  A  fast  sweep  speed  showing  single  spike  a c t i v a t i o n which preceded the i n h i b i t i o n . C:. unit  corresponding following  PST  stimulation  different intensities stimulus  histograms of the above  presentations  of  PP  at  two  ( b i n width = 5.0 msec; 50 i n each case).,  222  223  IiSi.  6 z l 5 ^ I dent i f .icat i on Of Dentate Ne u r o n e s Aj. schematic arrangement in  of r e c o r d i n g  A  electrode  the G - c e l l l a y e r and s t i m u l a t i n g  electrodes  i n PP and G - c e l l axons (MF). E i response o f a dentate c e l l t o s t i m u l a t i o n of the PP  ( l e f t ) and MF  response  to  indicating there  is  stimulation  an  (right).  PP  had  interposed  minimal  a  Note  that  variable synapse,  latency  in  the  evoked  latency whereas,  shift following  i n d i c a t i n g that  i t is  MF  antidromic. ,  Each record c o n s i s t s of 5 superimposed Cj_ the l e f t  the  sweeps.  photo shows a dentate c e l l recorded  same experiment which was s y n a p t i c a l l y  by MF s t i m u l a t i o n i n d i c a t i n g  particular  unit  is  photo shows a G - c e l l stimulation  not which  a  that  this  G - c e l l . The r i g h t is  evoked  by  MF  on the a n t i d r o m i c f i e l d and f o l l o w s  high freguency (200 Hz) s t i m u l a t i o n .  224  PP  •  L MF  L MF  IMF  l m s e c  225  G-cells since layer,  2)  1)  they  they  were  discharged  recorded  in  s p i k e and 3) they were o f t e n  activated  by  stimulation  were not evoked near synaptically  the  by  MF  t e n t a t i v e l y i d e n t i f i e d as h i l a r The  short l a t e n c y  cells  was  lasting which  followed  50-300 msec  could by  perforant  path  be  occur  neurones  were  { F i g . 6-16). G-  by a period of i n h i b i t i o n Individual  a l l cases  lengthened  suprathreshold  G-cells  of  considerably stimulation  the  (up to of  the  by i n h i b i t i o n having a s i m i l a r  The i n h i b i t i o n of G - c e l l s  as  duration  ( F i g . 6-14), Antidromic a c t i v a t i o n of G-  was a l s o f o l l o w e d  duration.  were  not a c t i v a t e d by low i n t e n s i t y s t i m u l a t i o n  700 msec)  cells  and  stimulation  {Fig..6-14).  were s t i l l i n h i b i t e d . In inhibition  spike  a c t i v a t i o n of spontaneously f i r i n g  always  were  antidromically  {Fig, 6-15). C e l l s which  population  activated  G-cell  a t the same l a t e n c y as t h e  population  MF  the  a  result  i n h i b i t o r y interneurones  of  is  collateral  (Gloor,  postulated  to  activation  of  196 3; Andersen et a l ,  1964) . Multiple  discharge  to PP s t i m u l a t i o n  o f s i n g l e G - c e l l s i n response  was r a r e l y encountered.  However, i n 3  of 94 experiments the same granule c e l l s were  observed  to f i r e twice on the p o s i t i v e f i e l d . , I n these cases low intensity  (1-3 V) s t i m u l a t i o n evoked a s i n g l e s p i k e a t  3-7 msec l a t e n c y whereas higher resulted  in  intensity  stimulation  the appearance of a second spike  f o l l o w i n g the f i r s t s p i k e .  The occurrence of  2-3 msec a  second  226  FIG^  6-J6_i  Response  Stimulation  Of  Hilar  Neurones  Of The Perforant  Following  Path And The Mossy  Fibres^ Ai s t i m u l a t i o n  o f e i t h e r PP o r MF  synaptically  a c t i v a t e t h e same neurone recorded i n the h i l a r region.  The 4 superimposed o s c i l l o s c o p e sweeps  i n each case i n d i c a t e t h a t after  the  variable Bj. a  primary  hilar  neurone  <N2)  evoked  and shows a  speed  spontaneous  which  is  evoked  by  PP  and appears on the P2 component of  p o s i t i v e wave.  sweep  response  is  latency.  stimulation the  the u n i t  The  lower  indicates discharge  a c t i v a t i o n response.  trace  inhibition  following  the  at of  slow the  initial  2Z  7  228  IISA  6-J7:  Paired  Pulse  Potentiation  Of  The  (open c i r c l e s ) and  rate  E x t r a c e l l u l a r EPSP Aj. the peak amplitudes of  r i s e of the t e s t response measured 1.0 msec  a f t e r i t s onset a  percentage  (filled circles) of  control  are p l o t t e d a s  responses  at  the  i n d i c a t e d C-T i n t e r v a l s . Bz  the negative EPSP recorded i n the d e n d r i t i c  layer following conditioning test  (top  arrow)  (lower arrow)  and  s t i m u l a t i o n o f t h e PP a t an  i n t e r v a l of 35 msec. C:  superimposed  condition  (first  oscilloscope deflection)  sweeps and  EPSP*s at i n t e r v a l s of 10-100 msec.  of  the  the test  230  spike  was dependent on the p o s i t i o n o f the  e l e c t r o d e i n t h e angular bundle. M u l t i p l e G-cells  discharge  may thus be a r e s u l t of a c t i v a t i o n  afferents  stimulating of  of separate  from the medial and l a t e r a l e n t o r h i n a l  cortex  (McNaughton and Barnes, 1977).  Potent r a t i o n o f Dentate E x t r a c e l l u l a r fie§fiSQ§§§  P2ES2§tipn EPSP F i g . 6-17 shows t h e e f f e c t s of a volley  on  the  amplitude  and  rate  conditioning of  rise  p o p u l a t i o n EPSP produced by a subsequent t e s t  PP  of the stimulus  to the same pathway. Measurements of the EPSP were made 1.0 msec  after  i t s onset  a s s o c i a t e d with G - c e l l response elicited  to  a  discharges  single  by a c o n d i t i o n i n g Potentiation  observed at  C-T  obtained a t intervals  intervals  increase  (less  pulse at the of  the  of  than  of  due  5.0  to refractoriness  It i s interesting intervals  the  test  t o note  test  indicated response  20-200 msec  with  150% of c o n t r o l  30-50 msec.  The  At  short  was the was C-T  This attenuation  may  of the p o s t s y n a p t i c element. that  presynaptic  at  the  volley  shortest is  C-T  actually  enhanced at a time when the t e s t EPSP i s depressed. enhanced p r e s y n a p t i c v o l l e y  C-T  msec) the s i z e of the t e s t  EPSP was much lower than c o n t r o l . be  (see chapter 2).  of approximately  intervals  contamination  t e s t pulse was compared to t h a t  intervals.  maximum  to eliminate  An  at these s h o r t i n t e r v a l s i s  231  FIG_.  6-_18i S t a t i s t i c a l A n a l y s i s Of EPSP A i d i s t r i b u t i o n of EPSP conditioning Note  that  amplitude  and there of  Potentiation^  amplitudes  evoked  t e s t p e r f o r a n t path  volleys.  is  in  less  the t e s t  variance  EPSP and that  Bz_  joint  perforant  amplitude evoked  by  test  density  plot  conditioning  path v o l l e y s . , N o t e that  responses i n the f i r s t EPSP  was  of  EPSP  and  test  t h e r e a r e no  guadrant i n d i c a t i n g always  larger  than  c o n t r o l EPSP.See Chapter 2 f o r d e s c r i p t i o n the  analysis.  the  EPS P.  amplitudes  the  the  the modal  amplitude of the t e s t EPSP i s g r e a t e r than control  by  that the of  5 0 -t  JITest  O  c 3  CT  CD  Condition  Ii  o-J 5.0  4.0  Amp. (mV)  6.0  7.0  High  1L CL  E <  IV  Low '—Low  Amp.  High  233  most  likely  due  t o temporal summation o f s t i m u l a t i n g  currents., As shown i n F i g . 6-18, a t a given conditioning  and t e s t EPSP e x h i b i t e d  distributions.  The  C-T i n t e r v a l the unique  amplitude  f a c t t h a t a t optimal C-T i n t e r v a l s  (35 msec i n F i g . 6-18) the t e s t EPSP i s r e l i a b l y than the c o n d i t i o n joint  amplitude  EPSP i s f u r t h e r demonstrated density  shown i n F i g . 6-188. number  of  trials  p l o t (described  The  4th  guadrant  contains  separate  EPSP  and  were no o c c a s i o n s i n which  in  latencies  of  EPSP*s  variance  observed i n the amplitude  conditioning  greater  and  the  volleys  the  test  the  PP  which  c o n d i t i o n and was  the f i r s t a  was l a r g e r than a t e s t EPSP. I n two  experiments  amplitudes  the  (76 out o f 84) on which a t e s t EPSP  shows t h a t there  conditioning  i n the  i n Chapter 2)  was l a r g e r than a c o n d i t i o n EPSP. In c o n t r a s t guadrant  larger  volleys. latency  The  were  modal  variance evoked  measured,  500 more  and l a t e n c y o f amplitude  of EPSP was s h o r t e r  0.5 msec) f o l l o w i n g the t e s t v o l l e y .  by  of  was  (by 0.3-  233a  Leaves 234-235 do not exist .  236  Bj_ Population  Spike  F i g , 6-19  shows the time course of p o t e n t i a t i o n of  the EPSP recorded  by one b a r r e l of an  is  the s y n a p t i c l a y e r and the p o p u l a t i o n  situated  spike  simultaneously  located (0-20 is  in  in  G-cell  recorded  by  electrode  a  which  second  body l a y e r . At short C-T  barrel intervals  msec) the amplitude of the t e s t population depressed  whereas  at  longer  intervals  spike it  p o t e n t i a t e d 2-3 times c o n t r o l v a l u e . I t i s important  was to  note that the amplitude of the t e s t spike was depressed at s h o r t i n t e r v a l s potentiated.  In  (10-20 msec) when the t e s t  most experiments the p o p u l a t i o n  was p o t e n t i a t e d f o r much 400 msec)  while  the  d i f f e r e n t at these  longer  test  C-T  intervals  the  (200-  periods.  PP  potentiation  of  v o l l e y . P a i r e d pulse s t i m u l a t i o n  with low i n t e n s i t y d i d not give of  spike  spike were dependent on the i n t e n s i t y of  conditioning  period  is  EPSP was not s i g n i f i c a n t l y  The magnitudes o f depression and the p o p u l a t i o n  EPSP  depression  rise  to  the  initial  but produced marked p o t e n t i a t i o n  ( F i g . 6-20). I n some cases c o n d i t i o n i n g s t i m u l a t i o n d i d not evoke a p o p u l a t i o n s p i k e response volley  of  population  the  same  intensity  resulted  was  population  in  a  test  a large  spike.  The magnitude of p o t e n t i a t i o n spike  whereas  up  to  4  times  of  greater  EPSP. T h i s d i f f e r e n c e i n  the  population  than t h a t of the the  magnitude  of  237  6^19:  Paired-pulse  The Population  P o t e n t i a t i o n Of The EPSP And  Spike Rj.spqnse.__  ft: the p o p u l a t i o n s p i k e response conditioning test  (first  (second  depression short  C-T  response)  circles) circles)  PP  pulses.  of of the t e s t population intervals  amplitude of and  the rate  by  a  response i n each sweep) and  p o t e n t i a t i o n a t longer Bz  evoked  (<  20  Note  spike msec)  at and  intervals. test of  pop rise  p l o t t e d as f u n c t i o n o f  Each point i s the average of 20  spike of C-T  (filled  EPSP  (open  interval.  trials.  239  FIG.  6-2OL  Effects  Of  S t i m u l u s I n t e n s i t y On  p.ulse P o t e n t i a t i o n Of The  PojguJLation  Sjgijse,.  Amplitude of the t e s t p o p u l a t i o n plotted interval.  as  Paired-  spike  a f u n c t i o n of c o n d i t i o n - t e s t The  c o n d i t i o n i n g and  intensity t e s t pulse  of was  both increased.  is (C-T) the  °i—i -20  1 0  1 +&0  1  1  1  160  C-T Interval  1 240  (msec)  1  1 3 20  1  241  potentiation amplitude  was  since  not  due  t o reaching a maximal EPSP  reducing  the  intensity  of  the  conditioning  and t e s t PP v o l l e y s a l s o d i d not r e s u l t i n  potentiation  o f t h e EPSP t o the same degree as that of  the  population  that  evoked  spike. by  Furthermore, a l a r g e r  the  test  pulse  could  EPSP  be evoked by  i n c r e a s i n g the i n t e n s i t y of the t e s t v o l l e y . it  is  Therefore  u n l i k e l y that the l e s s e r degree o f p o t e n t i a t i o n  of the EPSP r e l a t i v e to the population  spike  maximal a c t i v a t i o n o f the p o s t s y n a p t i c  elements.  £t sLAaale Unit  perforant  single  spike  either  as  elicited  middle  path  also  discharge.  an  of  trace  increase  individual of  pulse s t i m u l a t i o n of  This in  potentiation  the a  number  F i g . 6-21,  of  reduced  neurones.  As  occurred neurones  latency shown  spontaneously  low i n t e n s i t y appear on t h e p o s i t i v e f i e l d  by the t e s t As spike spike was  to  i n the firing  neurones which were not evoked by a c o n d i t i o n i n g of  to  r e s u l t e d i n p o t e n t i a t i o n of  by the t e s t v o l l e y or  discharge  i s due  Discharge  As shown i n F i g , 6-21, p a i r e d the  than  volley  produced  pulse.  F i g . 6-21  shows  potentiation  of  individual  d i s c h a r g e occurred a t a time when the p o p u l a t i o n was a l s o potentiated not  evoked  on  evoked c o i n c i d e n t l y  the with  inasmuch as  a  G-cell  that  c o n t r o l population  spike  the  population  potentiated  was  242  P o t e n t i a t i o n Of G - c e l l JiscJaj§£ge---By.-Pai£S^--  kz2.ll  Pulse S t i m u l a t i o n A. j_  Of The P e r f o r a n t  spontaneously  inhibited  but  firing  not  Path  G-cell  excited  A  which  by  is  a  single  to  double  c o n d i t i o n i n g PP v o l l e y . Bz response o f pulse  the  above  neurone  s t i m u l a t i o n i n d i c a t i n g that i t i s evoked  by the t e s t and not the c o n d i t i o n i n g Cj;  correlation  population (arrow) .  spike The  conditioning  and  unit  test  potentiation single  was  population  appears on t h e sweep).  between  volley.  not  unit  of  discharge  evoked  spike  population  the  on  the  (top sweep) but spike  (lower  £ 4 J  50 msec.  J|_Jo.2mV 10 msec.  Control  Test  T 2.0 mV •  10 msec.  244  spike.  As i n t h e c a s e o f t h e p o p u l a t i o n s p i k e  response,  s t r o n g c o n d i t i o n i n g v o l l e y s which evoked a s i n g l e s p i k e resulted 20  in  i n h i b i t i o n of the  msec) C-T  intervals  i n t e r v a l s . I t i s noteworthy  longer  than  spike discharge occurs discharge the  test spike at short  of the  20 at  that  a t i m e when  the  overcome  the  of  However a t s h o r t C-T  i s not  sufficient  6 g_ 4  G-cell  simultaneously  cells.  C-T  spontaneous  same G - c e l l i s c o m p l e t e l y  potentiation  at  msec p o t e n t i a t i o n o f s i n g l e  inhibited  conditioning v o l l e y . , T h i s suggests that  underlying  (5-  by  mechanisms  discharge  can  o c c u r r i n g i n h i b i t i o n of  i n t e r v a l s the  t o overcome t h e potent  G-  potentiation inhibition.  Discussion  Field  Analysis  Of  The  Perforant  Path  Input  To  that  has  Th.e  Dentate Gyrus Studying simple  field  laminar  anatomically  p o t e n t i a l s i n an a r e a  o r g a n i z a t i o n a l l o w s a c o m p a r i s o n between verified  terminal  e l e c t r o p h y s i o l o g i c a l responses. of is  PP  Electrical  r e s u l t s i n an e x t r a c e l l u l a r  maximal i n t h e m i d d l e m o l e c u l a r  c o n t a i n s the densest entorhinal 1956)  and  lesions electron  investigations field  a  terminal as  negative  areas  stimulation field  l a y e r . The  (Nafstad,  in light 1967)  following (Blackstad, microscopic  i n the r a t . This e x t r a c e l l u l a r  {shown i n F i g . 6-22)  may  represent  which  same z o n e  degeneration  observed  and  the  negative summed  245  EPSP's r e s u l t i n g from the d i r e c t a c t i o n o f PP on  the  dendrites  presynaptic synaptic  of  G - c e l l s s i n c e 1) i t f o l l o w s the  v o l l e y by 0.4-0.8 msec which i s w i t h i n  delay,  2)  it  freguency s t i m u l a t i o n simultaneously G-cells  f o l l o w s moderate but not  and  3}  it  drawing  current  area of the  cell  body.  interpreted  the  negative  molecular  layer  as  the  region  PP  studies  response  have  recorded  current  also  in  the  reflecting  the G-  of  the  synchronously  granule  cell  body  image of the  extracellular  and i n c r e a s e d s t i m u l a t i n g c u r r e n t  discharges  a  large  number  of G - c e l l s  spike which i s r e f e r r e d  as the p o p u l a t i o n spike response.  The  observations  the u n i t s g i v i n g r i s e t o the p o p u l a t i o n s p i k e identified  histological  by  is  conclusions  antidromic  localization  supports the suggestion 6-4  the are  EPSP  I n d i v i d u a l G - c a l l s are evoked  g i v i n g r i s e to a l a r g e negative  G-cells  PP  evokes a p o s i t i v e waveform which, i n p a r t ,  the p o s i t i v e f i e l d  Fig.  be  to the l e v e l of the  Previous  which i t i s a source.  that  may  from passive sources i n the  synaptic  appears as the mirror  to  recorded  (Lomo, 1971a; Steward et a l , 1 976).  stimulation  on  high  a c t i o n of PP t r a n s m i t t e r on the d e n d r i t e s of  In  for  been  (Lomo, 1971a). T h i s e x t r a c e l l u l a r EPSP  synapses  cells  has  one  with i n t r a c e l l u l a r EPSP's of i n d i v i d u a l  due t o an a c t i v e sink r e s t r i c t e d  direct  terminals  of  activation  supported  spike by  and  the r e c o r d i n g e l e c t r o d e  t h a t the N2 component shown  population  are  in  of G - c e l l s . These  previously  published  246  experiments  in  rabbits  and  cats  (Gloor et a l ,  1964;  Lomo, 1971a), In a d d i t i o n to the cells,  polysynaptic  monosynaptic a c t i v a t i o n  activation  of  interneurones  axon c o l l a t e r a l s of  G-cells  components  field  recorded  The  observation  cell  of  the  body l a y e r  (N3).  components are recorded fibres  or  give  of  rise  to  the  Gvia late  i n the area of  the  that s i m i l a r l a t e  following activation  of  mossy  s t i m u l a t i o n Of the commissural pathway  (see  chapter 7 ) , suggests that the l a t e components are not unigue f e a t u r e of the PP input reflect  the  activity  dentate h i l u s . T h i s may stimulating associated late  G-cells  but  neurones i n t h e area  explain  s i t e s in the  the  failure  of  to  may the find  angular bundle which were not  with l a t e responses and  negative  abolished  of  onto  a  component  (N3  in  the  fact  that  the  F i g . 6-4)  was  not  by l e s i o n i n g commissural pathways.  Response Of Spontaneously F i r i n g . G-cells,,The  spontaneous  discharge  consists  of  both  patterns.  The  b u r s t i n g discharge  slow  rhythmical  dentate pulse  irregular  and  electrical  (See chapter 3, stimulation  of  pattern  et  al,  the  G-cells discharge  may  recorded 1976).,  underly i n the Single  PP r e s u l t s i n s i n g l e spike  a c t i v a t i o n of G - c e l l s at short l a t e n c y corresponds to  of  bursting  activity  Bland the  pattern  population  spike  (3-7  msec) which  response,  This  247  6-22: Th§  I n t e r p r e t a t i o n Of The  Stimulation, r  Dentate F o l l o w i n g PP A  stimulating  Responses Recorded In  electrode  a c t i v a t e s axons o r i g i n a t i n g i n cortex  (EC) and i n the  stimulus  propogates t o PP  a  PP  transmitter  dentate  at  time  causes  and  the  associated  r e s u l t s i n a negative (T=2)  a p o s i t i v e p o t e n t i a l at profile).  G-cells  (bottom  negative  The  results  r e l e a s e of on  G-cell  inward c u r r e n t potential  l a y e r (top p r o f i l e ) the  cell  body  layer  subseguent discharge  schematic)  and  results  in  of a  p o p u l a t i o n spike . (T=3) ... A c t i v a t i o n of  interneurones inhibits  The  artifact  (T)=0.  extracellular  i n the molecular  (middle  EPSP's  PP  entorhinal  t e r m i n a l s and  s m a l l f i b r e v o l l e y (T=1). The  dendrites  (T=4)  the  r i s e t o the field  the  the  r e s u l t s i n a stimulus  recorded  in  in  by G - c e l l axon  discharge long  responses  latency  (T=5).  of  collaterals  G - c e l l s and components  of  gives the  249  activation may  is  be  followed  caused  interneurones  by p r o l o n g e d i n h i b i t i o n  by  recruitment  located  immediately  layer  ( A n d e r s e n e t a l , 1 9 6 4 ) . The  cells  which  inhibited  are not  activated  studies  granule c e l l s make  in  which  with  histograms activation  of  discharge  of  The  observed  to  G-cells  few  fire  the  in  be  second  and  1973) .  long  which 0-5  msec  which  axons  mm  in  prevent  separate  shown  s p i k e may  by  still  interneurones  is  up t o 1.0  bundle.  middle  which  t h e most d i s t a l after  This  are  away  (Cajal,  following the  the  multiple  to a p e r f o r a n t path the  same  cell  molecular l a y e r ,  be  Barnes  from  2-3  respectively,  seconds  after  be t h e r e s u l t o f EPSP* s g e n e r a t e d  d e n d r i t e s and w o u l d  the  project  angular bundle s t i m u l a t i o n .  occurred  a  coursing  and  afferents  was  may  afferents  McNaughton  that  which  post-stimulus  the m e d i a l e n t o r h i n a l c o r t e x which  activated spike  initial  PP  t w i c e on t h e p o s i t i v e f i e l d  angular  t o t h e o u t e r and may  the  i n response  cases  (1977) h a v e r e c e n t l y lateral  by  the  may  r e s u l t o f a c t i v a t i n g two through  o b s e r v a t i o n t h a t some  the f u s i f o r m c e l l s below  from  G-cells  G-cell  by  G-cells  appears  the  supported  This potent i n h i b i t i o n  volley.  below  were o b s e r v e d t o h a v e  contact  1911).  inhibitory  suggests that these i n h i b i t o r y  project t o neighbouring c e l l s . Golgi  of  which  The the on  t h u s r e a c h t h e soma  mere p r o x i m a l s y n a p t i c c u r r e n t s ( B a l l and  Rinzel,  250  Discharge of  The  The  Neurones Other  Than  G-cells  d i s c h a r g e of neurones o t h e r than  G-cells  h a v e been r e c o r d e d i n t h e a r e a o f t h e G - c e l l body and a d j a c e n t h i l a r  zone.  may layer  U n f o r t u n a t e l y , r e c o r d i n g s were  h a r d t o o b t a i n from t h e s e n e i g h b o u r i n g neurones because they  generate  obscured cases  mossy  amplitude  spikes  and  by t h e G - c e l l p o p u l a t i o n r e s p o n s e s .  when  neurones,  small  In  fibres  excitatory  inputs  from  by  G-cell  Those n e u r o n e s may  axon  collaterals.  s t u d i e s r e v e a l a heterogeneous  produce  synchronous  those generated is  MF  described bodies.  Since  schematically  Goigi types  unlikely to  by t h e u n i f o r m d i s c h a r g e o f G - c e l l s .  It  fusiform  interneurones  be  spikes similar  which  were a c t i v a t e d  s t i m u l a t i o n correspond  These  and  G-cells  p o p u l a t i o n of c e l l  population  p o s s i b l e t h a t the c e l l s  PP and  those  thus  i n t h e r e g i o n o f t h e h i l u s t h e s e neurones are to  few  PP  at l a t e n c i e s l o n g e r t h a n t h o s e of  were r e a d i l y d e m o n s t r a t e d .  be  a  s t a b l e r e c o r d i n g s were o b t a i n e d f r o m  converging  activated  may  cells  cells  which  would  postulated shown i n F i g ,  thus  to  the  the  G-cell  inhibitory  by A n d e r s e n e t a l (1966) 6-22.  both  anatomically  project to the be  by  and  251  P o t e n t i a t i o n 9_f The The  above d i s c u s s i o n has  the f i r s t  1-1.5  reflects  the  presented  msec o f the negative synaptic  p e r f o r a n t path. of  E x t r a c e 11 u l a r EPSP  An  evidence  d e n d r i t i c response  current  generated  i n c r e a s e i n the amplitude  by and  the rate  r i s e of t h i s response occurs 5-200 asec f o l l o w i n g a  conditioning  pulse  to  potentiation  could  occur  the  same  either  pathway.  as  a  i n c r e a s e i n the s i z e of the a f f e r e n t t e s t to  that  an i n c r e a s e i n e f f i c i e n c y of  between The  the  perforant  first  volley  is  which  potentiated 1971b).  path and  mentioned  involvement  synaptic  Such  r e s u l t of an v o l l e y or  transmission  the G - c e l l d e n d r i t e s .  possibility  of  presynaptic  u n l i k e l y since the amplitude of the  reflects in  this  However,  presynaptic and  this  due  current  was  previous experiments  argument  is  based  PP not  (Lomo,  on  the  assumption t h a t the amplitude of the p r e s y n a p t i c v o l l e y reflects  the  c o n t r o l and Fig,  6-4  activity  shows  that  the  an  this  amplitude  and are  than those  data  the in  terminals  in  presented  in  case  in  stimulus  control intensity  of the p r e s y n a p t i c v o l l e y and potentiated  state  terminals  which are a c t i v a t e d i n c o n t r o l s t a t e s  which do not give r i s e to activated.  is  increase  the EPSP, Perhaps i n the other  presynaptic  p o t e n t i a t e d s t a t e s . The  s i t u a t i o n s since enhances  of  On  cannot e l i m i n a t e t h i s  the  the  presynaptic  b a s i s of the present  possibility.  volley data  one  252  An  increase  between of  the  perforant  G - c e l l s may  transmitter which  i n the  of  path t e r m i n a l s  and  be m e d i a t e d by  an  by  the  increase  same  the  release  of  element  synaptic  current  of  transmitter.  could  extracellular  synaptic  current  without  involving  transmitter  release  include  enhanced  in  sensitivity  of  morphological their  the  postsynaptic  generating  must be s p e c i f i c t o t h e since conditioning terminate  the  perforant  See  also Chapter  Population of  the  activated  path.  by t h e  synapses does  Double  the  PP  that  of  7).  present  the  population  number o f i n d i v i d u a l  following pulse i n the  d a t a and  stimulation  Such  of  s t i m u l a t i o n of  PP  amplitude of the  PP  e v o k e d by t h e t e s t v o l l e y r e l a t i v e t o t h a t conditioning stimulus.  not  Spike  a m p l i t u d e of  r e s u l t s i n a marked i n c r e a s e spike  elements  of a t e s t EPSP e v o k e d by  i s r e l a t e d to the  G - c e l l s which are the  t o t h e PP  to  1970).  afferents  basis  response  affect  s t i m u l a t i o n of commissural  A n d e r s e n e t a l (1971) t h e spike  postsynaptic  area adjacent  adjacent  Of The  which  and  synapses  ( S t e w a r d e t a l , 1977;  On  membrane  in  PP  r a t e of r i s e  Potentiation  increase  characteristics (Ball,  However, t h e a b o v e c h a n g e s i n t h e  a l t e r the  an  changes i n d e n d r i t i c spines  current  which  to  The  mechanisms t h a t  changes  rise  dendrites  postsynaptic  the  amount  give  transmission  augmented  and/or changes i n the  substantially  generated  effectiveness  potentiation  evoked could  253  occur  either  as  a  result  c u r r e n t thus producing  o f an i n c r e a s e i n s y n a p t i c  a greater depolarization  c e l l s o r by an e n h a n c e d p r o b a b i l i t y is  evoked  by t h e t e s t v o l l e y .  to a lowering action  The l a t t e r c o u l d be due  of the threshold f o r the generation  in  the  effectiveness  d e p o l a r i z a t i o n s reaching As d i s c u s s e d increase  of  to  an  dendritic  i n the previous  s e c t i o n , there  is  an  i n t h e s y n a p t i c c u r r e n t g e n e r a t e d by t h e t e s t  the  population  spike  response.  m a g n i t u d e o f p o t e n t i a t i o n o f t h e EPSP usually  animals  response  potentiation However,  (less than  the 150%)  much l e s s t h a t t h e d e g r e e o f p o t e n t i a t i o n  of the population some  o f an  t h e soma.  PP v o l l e y w h i c h c o u l d i n p a r t a c c o u n t f o r  was  G-  that a given G - c e l l  p o t e n t i a l by a n i n d i v i d u a l G - c e l l o r due  increase  of  of  was  spike  (up t o  700%).  potentiation  of  observed  the  in  changes i n t h e r a t e of r i s e  the  Furthermore population  absence  of  in  spike  apparent  o f t h e EPSP (See a l s o Lomo,  1971b). A  comparison  potentiation of ( F i g , 6-19)  the  between EPSP  reveals  that  the  and  time  the the  population amplitude  population  s p i k e i s g r e a t e r than c o n t r o l  intervals  (over  200 msec)  d i f f e r e n t from c o n t r o l . short test  C-T  intervals  when  course  at  of  spike  of  test  long  C-T  t h e t e s t EPSP i s n o t  I t i s a l s o noteworthy  that  ( 0 - 2 0 msec) t h e a m p l i t u d e  PP s p i k e i s d e p r e s s e d a t a t i m e when t h e  at  of the  EPSP  is  254  potentiated.,  Depression  of  the  population  amplitude at s h o r t C-T i n t e r v a l may be recurrent volley  inhibition  (Lomo,  197 1b;  potentiation intervals  initiated  of  is  Steward  the  due  by  et  population  to  the  due  the  to  action  at  of  potent  conditioning  a l , 1 976). spike  spike  Perhaps long  C-T  polysynaptic  mechanisms on G - c e l l s . The r e l a t i o n s h i p between p a i r e d - p u l s e p o t e n t i a t i o n discussed from  above and l o n g - l a s t i n g p o t e n t i a t i o n r e s u l t i n g  t e t a n i c s t i m u l a t i o n of the PP i s not c l e a r .  and Lomo  (1973) have shown that the r a t e of r i s e o f the  EPSP and amplitude o f the potentiated hours  population  spike  could  a  (100 Hz)  brief  train  (3-4  stimulation. Bliss,  sec)  of  high  Gardner-Medwin  (1973) r e p o r t e d t h a t l o n g - l a s t i n g p o t e n t i a t i o n was produced  be  f o r p e r i o d s ranging from 30 minutes to 10  following  frequency  Bliss  on  not  a l l occasions  when there was p a i r e d pulse  stimulation.  Furthermore,  these  Lomo,  Bliss  1973;  studies  and Gardner-Medwin,  (Bliss  and  1973) observed  i n c r e a s e s i n the amplitude of the p o p u l a t i o n s p i k e  with  no change i n t h e s y n a p t i c c u r r e n t . T h i s o b s e r v a t i o n and the  fact  that  potentiation  the  magnitude  and  time  course  o f t h e p o p u l a t i o n s p i k e d i f f e r from  of the EPSP suggest t h a t a t l e a s t a component o f lasting  potentiation  may  be  of those long-  due to changes i n t o n i c  i n f l u e n c e s a c t i n g on the G - c e l l s . The above suggestions  imply  that  potentiation  of  255  the  population  in transmitter activity  of  spike could r e l e a s e and  the  occur i n absence of changes may  postsynaptic  examine t h i s p o s s i b i l i t y , the extrinsic  afferents  responses w i l l  to  be s t u d i e d  the  be  dependent  elements. effects  In order  of  dentate  i n the remaining  on  the to  stimulating on  PP-evoked  chapters.  256  CHAPTER 7..  NEURONAL I S I E S M I S S T O N  IN THE DE N TA TE -  GIBUS: ROLE OF THE COSHISSURAL INPUT  Z*JL XlLtrgduct ion  The  previous  responses recorded of  chapter  characterized  (PP), Homosynaptic p o t e n t i a t i o n  of t h i s c o r t i c a l i n p u t i n v o l v e d current  field  i n the dentate f o l l o w i n g s t i m u l a t i o n  t h e p e r f o r a n t path  synaptic  the  both  an  increase  and amplitude of t h e population  response. I t was suggested that the i n c r e a s e d  in  spike  efficacy  of the PP input may c o u l d be a r e s u l t o f changes i n the postsynaptic occur  cell  i n a d d i t i o n t o those p o s t u l a t e d t o  i n the p r e s y n a p t i c  elements o f t h i s pathway.  S i n c e the t e r m i n a t i o n input  to  extending below  the dentate  of the commissural  gyrus  i s r e s t r i c t e d t o a zone  50-100 um above the G - c e l l  the PP  Cowan, 1 9 7 3 ) ,  (COMM)  synapses (Blackstad,  layer  and  just  1956; G o t t l i e b and  a c t i v a t i o n o f the COMM i n p u t may generate  s y n a p t i c c u r r e n t at s i t e s adjacent  t o PP synapses.  arrangement a l l o w s an examination  of the p o s s i b i l i t y  that  conditioning  COMM  stimulation  potentiates  This  PP-  evoked responses. The  aim o f t h e present  the laminar  chapter  p r o f i l e of s y n a p t i c  i s t o : 1) determine  currents  recorded  in  the dentate f o l l o w i n g s t i m u l a t i o n o f t h e COMM i n p u t . 2) examine  whether  conditioning  input a l t e r s t h e f i e l d  s t i m u l a t i o n o f the COMM  responses evoked by  a  test  PP  257  volley.  Zi.2 2x2erimental Procedures. E x t r a c e l l u l a r r e c o r d i n g s were performed on a t o t a l of  15  urethane a n a e s t h e t i z e d r a t s . C o n c e n t r i c b i p o l a r  e l e c t r o d e s were p o s i t i o n e d i n activate CA3-CA4  the  perforant  area  of  commissural  an in  hippocampus at  additional the  psalterium  bregma;  lateral;  were  Single unit  recorded  from  previous c h a p t e r s . presentations  the  the  o r i g i n . , In  some  electrode  was  pathway as i t courses (1.5 mm  and  posterior  dentate  responses  field  to  potentials  as d e s c r i b e d i n the to  20-30  stimulus  (ISI 2.5-4.0 seconds) were averaged and  p l o t t e d a t predetermined depths to allow between the f i e l d and COM  to  3.0 mm below the c o r t i c a l  activity  The  bundle  activate  bipolar  through the v e n t r a l  s u r f ace),  to  its  commissural  0.5-2.0 mm  angular  path and i n the c o n t r a l a t e r a l  projection  experiments positioned  the  the  pathways.  responses evoked  a  comparison  by s t i m u l a t i o n of PP  258  7__3 Results Fig.,7-1  shows the e x t r a c e l l u l a r f i e l d  recorded a t i n d i c a t e d stimulation in  depths i n the dentate  latency  chapter, PP s t i m u l a t i o n  superimposed  (4-7 When  results i n a  negative wave which i s maximal 175-225 um  above the G - c e l l l a y e r  layer.  and  population  COMM s t i m u l a t i o n  the recording  a  positive  spike  wave  recorded  at c e l l  electrode  positive  i s situated  wave  wave a t the l e v e l of the PP maximum  negativity  the r e c o r d i n g  100 um  electrode  body  latency  i n the most waveform i s  r e v e r s e s to a negative  synapse  and reaches  a  above the G - c e l l l a y e r . As  i s advanced f u r t h e r  G - c e l l l a y e r the e x t r a c e l l u l a r n e g a t i v i t y p o s i t i v e wave a t approximately bodies.  a  response i n t h e dentate.  d i s t a l d e n d r i t e s a low amplitude p o s i t i v e This  with  a l s o r e s u l t s i n a short  msec a t i t s peak) f i e l d  recorded.  following  (5 V) o f the PP and Comm pathways. As shown  the previous  short  potentials  25 um  towards t h e  r e v e r s e s to a  above  the  cell  259  :  l l Lamin ax  J22&e4 la  P r o f i l e s Of The F i e l d P o t e n t i a l s  The Dentate  By.  Stimulation  P e r f o r a n t Path A_n d Cgmmissural Field  potentials  COHM ( r i g h t ) blade  of  indicated  DG  volleys along  by PP  recorded  in  vertical  depths  below  record  is  the  The  Pathway,  evoked  a  Of  ( l e f t ) an the  upper  t r a c k at the  surface  of  the  cortex. Each  the average o f 20  and the arrows i n d i c a t e the stimulus  trials  artifacts.  2GO  Depth (JUM)  , - J  2  5 msec  M  V  t_COMM  5 V  261  Identification  Aj_ M o l e c u l a r Fig. the  Of T h e D e n t a t e R e s p o n s e s  Layer  7-1 shows t h a t t h e most p r o m i n e n t r e s p o n s e i n  molecular  layer  maximal i n t h e i n n e r 75-125uM field  above  occurs  i s a  the G-cell 3-5 msec  activation  of  t h e COMM  psalterium  (1.5 mm  or  i n  were  rarely  response  followed  Hz) f r e g u e n c y  the  the midline).,  latency  of  In  this  the  direct ventral t h e same negative  s h i f t s greater  encountered.  moderate  of  of  following  and p e a k l a t e n c i e s  0.5 msec  distance  stimulation  pathway  and  which i s  The o n s e t o f t h i s  2-4 msec  from  are consistent  (>200  layer.  after  CA3  animal the onset  field  molecular layer a t a  contralateral  wave  negative  This  (1-75 Hz)  than  negative  but n o t  high  stimulation.  Since t h i s negative  wave i s m a x i m a l i n t h e  inner  m o l e c u l a r l a y e r a t t h e same l e v e l a s t h e t e r m i n a t i o n the  COMM  pathway  Simonsen  and  (Gottlieb  Laurberg,  extracellular  a n d Cowan, 1973;  1978) ,  reflection  i t  of  a  Hjorthbe  monosynaptic  EPSP  the depolarization  dendrites.  Although i n t r a c e l l u l a r data i s l a c k i n g , t h e  similarity  between  produced  by  negative  t h e PP { d e s c r i b e d  dipole  oriented  and  that  i n c h a p t e r 6) s u p p o r t s  t h i s suggestion.  S i n c e t h e maximal  125 um  the G-cell  above  apically  the  reflecting  this  of  may  of  layer,  negativity the  i s 75-  depolarizing  262  synaptic  current  dendrites  of  previously  proposed  the  generated  A  similiar  by Deadwyler  that  structures  neurones  be  G-cells,  possibility  other  may  as  the proximal  i n t e r p r e t a t i o n was  e t a l (1975).  these currents  such  by  However,  a r e generated  the distal  whose c e l l b o d i e s a r e b e l o w t h e  dendrites G-cell  by of  layer  can n o t e l i m i n a t e d .  Long. L a t e n c y As  Responses  shown  i n F i g , ,7-2,  r e s p o n s e s were s o m e t i m e s secondary  responses  and 20 mSec, greater  Since  shift  do n o t f o l l o w  may  be e v o k e d  the  late  the late  these  late  responses  than the e a r l i e r  20-50 Hz s t i m u l a t i o n  component  PP-evoked  was  profile were  display  ( F i g . 7-3B) t h e y  not s i m i l a r  ( F i g . 7-2B). never  a  components  The l a m i n a r p r o f i l e  b y COMM s t i m u l a t i o n  components  by  h a v i n g o n s e t l a t e n c i e s b e t w e e n 15  polysynaptically.  r e s p o n s e s evoked  latency  (6 o f 15 a n i m a l s ) f o l l o w e d  i n latency  and  t h e above s h o r t  t o the  of  earlier  b u t was r e l a t e d t o However,  observed  similar followinq  s t i m u l a t i o n o f t h e PP i t s e l f . The a  l a t e c o m p o n e n t s were c o m p l e t e l y e l i m i n a t e d  transection  o f t h e i p s i l a t e r a l perforant  shown i n F i g . 7-3C, the  entorhinal  electrode, the  PP  i f the knife cut  cortex  t h e l a t e COMM  (EC) a n d response  by  p a t h . As  i s made  between  t h e PP s t i m u l a t i n g disappears  response i s normal. Hjorth-Simonsen  whereas  (1973) h a s  262a  Leaf 262 continued on 271 •  263  FIG*.  ~Lz 2l Laminar Ii§14  P r o f i l e s Of Primary  Potentials  Recorded  And  Secondary  I n The Dgntat-e-  loilowiaa S t i m u l a t i o n Of The COMM Pathway..; depth p r o f i l e s  recorded  at the i n d i c a t e d  d i s t a n c e above t h e granule c e l l l a y e r stimulation sweeps)  and COMM  psalterium the  in  oscilloscope the  oscilloscope  f o l l o w i n g COMM  profile  (COMM1) measured PP  (upper  pathway  (lower  1  evoked  comparison.,  (obligue  stimulation.  of t h e amplitude  and l a t e  ventral  sweeps).,Note  appearance o f secondary responses  arrows) B:,  o f t h e PP  following  (COMM 2)  o f the e a r l y  evoked  potentials  msec a f t e r t h e i r onset. P r o f i l e o f potentials Note  is  included  for  that the l a t e COMM2 response  p a r a l l e l s the PP p r o f i l e .  264  265  FIG..  7- 3: C h a r a c t e r i s t i c s Of Responses  Hecgrded  Stimulation hi  Of The  effects  of  amplitude  of  Early.  In  The  at  the  Late  Dentate  field  Foilowing  Commissural Pathway.  stimulus  intensity  responses  oh  recorded  molecular l a y e r . Each r e c o r d sweeps  And  indicated  is 5  the  in  the  superimposed  stimulus i n t e n s i t y .  Note that the l a t e components are only  produced  at higher v o l t a g e s . , JBj. e f f e c t of freguency s t i m u l a t i o n on the and  l a t e responses i n d i c a t i n g the  nature follow  of  the  Cz_  (40-80  elimination  suggesting  polysynaptically cortex.  Hz)  stimulus  ;  of  the l a t e component but  the e a r l y response f o l l o w i n g PP  polysynaptic  l a t e response s i n c e i t does not  moderate  frequencies.  early  that  the  relayed  t r a n s e c t i o n of  late via  response the  not the is  entorhinal  1\) (Ts  266a  Leaves 267-270 do not exist.  271  provided anatomical evidence f o r from PP.  CA3  to the  Thus  the  activation  i p s i l a t e r a l EC late  of  the  depolarization  a  in  that  responses  could  entorhinal  cortex  of G - c e l l d e n d r i t e s .  stimulation  EC which  1,5  msec.  precede Although no  EC  also  subsequent  Deadwyler  et  al  discharges  responses  fay  responses which precede  the  of 1 animal. Although  activated  from  s i n g l e EC u n i t s were recorded i n  dentate l a t e component by 5-7  the  and  dentate  the  that  the  result  evokes u n i t  late  the present i n v e s t i g a t i o n f i e l d  suggest  r i s e to  This p o s s i b i l i t y i s  of  of CA3  the  projection  which g i v e s  strengthened by the o b s e r v a t i o n s (1975)  direct  msec were recorded i n  Deadwyler  ipsilateral  et  al  entorhinal  (1975)  cortex  was  d i r e c t l y by c o n t r a l a t e r a l hippocampus, i t  possible  collaterals  of  that  antidromic  the  ipsilateral  activation  of  the  EC  on  possibility  i s more l i k e l y  the since  activation CA3  of  is  axon  results  in  same s i d e . The  latter  there  direct  anatomical evidence f o r a c o n t a l a t e r a l  is  no  projection.  ]3. G - c e l l Layer Fig. evoked by cell  body  7-4  shows the  COMM and  PP  layer.  extracellular field  stimulation  An  early  recorded at the same l a t e n c y which 0.8  was  msec  discharge  observed before or  in  the  compound  recorded  negative as the  the  onset  and  potentials in  deflection  presynaptic  spikes  the  earliest  (indicated  by  is  volley  molecular l a y e r and of  the  0.5cell  oblique  272  FIG  t  7- 41 F i e l d P o t e n t i a l s Recorded Cell  Layer  Following  In  The Granule  Stiffiulatisn  Of The  PjISfor&St P a t h And, £ogfflissu£a3, Pafeh»ay§ 4 i comparison between the responses PP  and COMM  stimulation  v o l t a g e s . I n each case  a  A  evoked  by  at t h e i n d i c a t e d negative  population  spike i s i n d i c a t e d by the arrow, Bi  interaction  between  PP  and COMM  responses a t the i n d i c a t e d C-T i n t e r v a l s .  evoked Note  depression o f the n e g a t i v e s p i k e a t the s h o r t e r C-T  i n t e r v a l s u g g e s t i n g convergence of the two  inputs  on  response.  (  the units  giving  rise  to  this  275  274  arrows  i n F i g . 7-4).  I t may  thus  represent  the  p r e s y n a p t i c v o l l e y o f t h e COMM pathway. The reason it  that  i s more prominent than the PP f i b r e v o l l e y recorded  from the same s i t e may be r e l a t e d t o the  observations  t h a t COMM f i b r e s pass through the G - c e l l l a y e r en route to  t h e inner  prominent  molecular  spike  (2.5 msec)  as  was  layer.  recorded  the f i b r e  In 2 o f 15 animals a  a t the same  latency  v o l l e y . T h i s s p i k e was l e s s  than 0.2 msec i n d u r a t i o n and may thus be caused  by a  s i n g l e axon. Following  t h e f i b r e v o l l e y a l a r g e compound spike  (oblique arrow) i s sometimes recorded  (in 4  of  15  animals)  i n response t o COMM s t i m u l a t i o n . However, the  stimulating voltages reguired s p i k e was 3 times higher prominent  dendritic  t o produce  than those  potential.  a  compound  r e g u i r e d t o evoke a  The amplitude o f the  compound spike was maximal a t the same depth as the PPevoked p o p u l a t i o n evoked  spike  s p i k e i n the G - c e l l l a y e r . The COMfl-  was markedly depressed when preceded (1-  20 mSec) by a PP-evoked p o p u l a t i o n spike. On the hand,  i f a COMM v o l l e y precedes PP s t i m u l a t i o n the PP-  evoked population spikes  other  recored  spike following  i s depressed. , The compound commissural s t i m u l a t i o n may  r e f l e c t the synchronous d i s c h a r g e  of a  dentate  be r e f e r r e d t o a s the  neurones and w i l l thereby  COMM-evoked  population  of  p o p u l a t i o n spike. I t i s noteworthy t h a t t h e  COMM evoked p o p u l a t i o n s p i k e always occurs e a r l y on the descending  limb  of the p o s i t i v e wave, whereas, the PP  Leaf 274 continued on  277.  Leaves 275-276 do not e x i s t .  277  evoked  population  descending due  limb  to a  distal  on  may  occur  o r on t h e a s c e n d i n g  shorter  synapses  spike  conducting  proximal  late  limb. This  distance  dendrites  on  may be  between  than  the  COMM  PP s y n a p s e s on  dendrites.  The  last  identified  negative  but i t s  following  PP  component  similarity  stimulation  h a s n o t y e t been t o t h e N3 component  suggests  that  i t  also  represents  t h e p o l y s y n a p t i c a c t i v a t i o n o f neurones i n  the dentate  hilus.  Cj_ S i n g l e U n i t The cells and  Discharge  r e s p o n s e o f 60  spontaneously  firing  was s t u d i e d f o l l o w i n g s t i m u l a t i o n o f b o t h t h e PP  COMM pathway. Of t h o s e ,  11 (18%)  msec f o l l o w i n g s t i m u l a t i o n o f  were a c t i v a t e d 4-8  t h e COMM  10 V) a n d 21 (35%)  were a c t i v a t e d by t h e  (3-5 V ) .  The  was  intensity  i norder  even  dentate  i n a  PP  always  t o avoid  filtered  pathway  (5-  perforant  path  stimulated population  with  lower  spikes  which  record obscured the discharge of  i n d i v i d u a l n e u r o n e s . A s shown i n F i g . 7-5, c o n v e r g e n c e o f COMM a n d PP i n p u t s o n 9 n e u r o n e s was d e m o n s t r a t e d b y pairing  t h e two  inputs  i n t e n s i t i e s a n d a range Two  subthreshold  resulted  i n a  ( F i g . 7.5B,  a t s u b and  suprathreshcld  of c o n d i t i o n - t e s t  stimuli  intervals.  p a i r e d a t 1-5 msec  spike  following  bottom  trace)  the  intervals  second  pulse  suggesting  that  277a  Leaf 277 continued on 282.  278  7-  5_i. Response  Qf Spontaneously F i r  Neurones Following  Stimulation  Dentate  Of The P e r f o r a n t  Path And Commissura1 Inputs ii  top:  spike  fast  sweep  speed  indicating  a c t i v a t i o n o f the same neurone  stimulation  at slow  indicating i n h i b i t i o n following that  following  o f PP ( l e f t arrows) and COMM ( r i g h t  arrows).bottom: same c e l l  Note  single  COMM  stimulation  sweep  speed  the a c t i v a t i o n . produced  longer  inhibition. B: i n t e r a c t i o n between PP and COMM indicating  possible  convergence  i n p u t s on the same neurone that  both  pulses  shown  stimulation of  the two  i n A. ,, Note  at s u p r a t h r e s h o l d  intensity  e l i c i t a spike  (top) but when the C-T i n t e r v a l  is  t h e response t o the second  shortened  i s occluded (middle) . I n c o n t r a s t , a only  elicited  subthreshold  following  pulses  t h e second  (bottom) .  spike  pulse is  o f two  17 7  PP ,  ,.  COMM >«**w  " J o . 2 mV 5 msec  ESSE  •Jo.2 mV 50 msec  B. PP-COMM  ( l.5xT)  PP-COMM  (1.5 xT)  PP-COMM  (0.5 xT)  5 msec  LEAVES 280 AND 281 OMITTED IN PAGE NUMBERING.  282  temporal/spatial pairing  summation  two suprathreshold  had  occurred.  pulses a t the same c r i t i c a l  i n t e r v a l resulted i n a spike following not  t h e second  either  pulse  refractoriness  firing  short  latency  neurones e l i c i t e d  followed  t h e f i r s t but  ( F i g . 7-5; middle trace) o f t h e neurone  i n h i b i t i o n which i s d e s c r i b e d The  However,  or  due t o  recurrent  below.  activation  of  spontaneously  by COMM s t i m u l a t i o n was always  by a prolonged p e r i o d  of i n h i b i t i o n  lasting  50-800 msec. Spontaneous u n i t s (49 out of 60) t h a t were not by  a c t i v a t e d by COMM s t i m u l a t i o n were s t i l l low i n t e n s i t y  stimulation  (1-3  V)  of t h e COMM  pathway. The length of i n h i b i t i o n f o l l o w i n g of  t h e COMM  pathway  at  1.5T  inhibited  stimulation  i n t e n s i t y reguired t o  a c t i v a t e a neurone was u s u a l l y 2-3  times  elicited  by s t i m u l a t i o n o f the PP a t the  intensity  (1.5 X t h r e s h o l d ) .  longer  that  same r e l a t i v e  O r i g i n Of The Commissural Pathway, Histologically responses  verified  described  sites  above were l o c a t e d i n the CA3-CA4  subfield of the c o n t r a l a t e r a l Responses  having  amplitude were  the s h o r t e s t  obtained  electrode  dorsal latency  following  which were nomotopic t o the stimulating  f o r evoking the  was  recording  hippocampus and maximum  stimulation  sites  electrode.  I f the  moved 0.5-1.0 mm from  this  o p t i m a l s i t e a p o s i t i v e - g o i n g wave was recorded i n the  Leaf 282 continued on 287. Leaves 283-286 do not e x i s t .  287  dentate  independent  of  e l e c t r o d e . .Placements  t h e depth  w h i c h were  of  2.5-3.0  m i d l i n e were more e f f e c t i v e t h a n t e m p o r a l the  region o f the fimbria. Electrode  ventral  psalterium  dentate  field  the recording mm  from  the  placements i n  placements  were  more  effective  responses  than  those  i n the  i n evoking  situated i n the  hippocampus proper.  ill§£ts  Of  Commissural  Stimulation  On  P£r§I§K5^  Responses Fig,  7-6  shows  t h e e f f e c t s o f low i n t e n s i t y ( 3 -  5 V) c o n d i t i o n i n g COMM v o l l e y on t h e a m p l i t u d e population a  test  s p i k e and r a t e o f r i s e  o f t h e EPSP e v o k e d by  PP v o l l e y . Whereas t h e a m p l i t u d e a n d r i s e  o f t h e t e s t EPSP were n o t a l t e r e d , t h e t e s t spike  of the  was  markedly  time  population  p o t e n t i a t e d a t l o n g C-T i n t e r v a l s  (20-400 msec) a n d d e p r e s s e d a t  shorter  i n t e r v a l s (5-  20 m s e c ) , As shown i n t a b l e I I , maximum p o t e n t i a t i o n o f the  PP-evoked  population  spike  (290±33%) was o b s e r v e d  50-70 msec a f t e r c o n d i t i o n i n g s t i m u l a t i o n o f pathway. population long a  spike  that  potentiation of the  was o b s e r v e d i n e v e r y a n i m a l  as t h e amplitude o f t h e p o p u l a t i o n  control  stimulated spike  I t i s noteworthy  PP  t h e COMM  volley  with high  was  was n o t m a r k e d l y  s p i k e e v o k e d by  submaximal.  intensity  (n=9) as  I f t h e PP was  (20-30 V) t h e p o p u l a t i o n  potentiated  ( i . e. L e s s t h a n 125%  o f c o n t r o l ) b y a p r e c e d i n g COMM p u l s e .  The c o n d i t i o n i n g  stimulus  critical  intensity  was  not  as  since  287a  L e a f 287  c o n t i n u e d on  294.  288  ElSt,  lz  6.1  Effects  Of  Dentate  field  Perforant  Path  Ai  Cpjmmissjar^l  Responses  Jyoked  rise  of  EPSP  evoked  p r e c e d e d by c o n d i t i o n i n g pathway  (lower  spike  Ji  population  by  (arrows)  spike  alone  commissural  of  stimulation  population  and  spike  following  conditioning  responses path  conditioning path i t s e l f o r  alone  #1) a t t h e same Cthat  o f r i s e o f t h e EPSP i s a l t e r e d o n l y  PP-PP).  (trace  stimulation of  (35 msec) as i n B s h o w i n g  double pulse s t i m u l a t i o n (i.e.  (upper  pathway.  PP ( t r a c e #3) o r COMM ( t r a c e  rate  COMM  t h e perforant  t h e perforant  and f o l l o w i n g  T interval  of  potentiation of  C: EPSP e v o k e d by s t i m u l a t i n g PP #2)  rate  b u t n o t t h e EPSP.  stimulating  stimulation  Test  and  g r a p h ) o r t h e PP i t s e l f  a v e r a g e s o f 20  evoked  A  by a t e s t PP v o l l e y  graph). Note the h e t e r o s y n a p t i c the  By  On  Volley^  amplitude of the population  of  Stimulatioa  of the perforant  the after path  A.  B. PP-PP  300 i  J  " l  -40  1 1 0 +40  1  1 120  1  1 200  1  1 280  1  2 msec  C-T Interval (msec.) 00  2?o TABLE I I EFFECTS OF CONDITIONING  STIMULATION OF THE  COMMISSURAL PATHWAY ON PP-EVOKED POPULATION SPIKES  EXPT.  NO.  amplitude o f population spike* (percent o f c o n t r o l )  duration (mSec)  SC-74  275  260  SC-75  135  120  SC-76  240  160  SC-77  260  180  SC-92  500  300  SC-115  350  320  SC-116  250  280  SC-133  280  300  SC-137  325  400  TOTAL  =  9  MEAN  *Each value r e p r e s e n t s condition-test  = 290±33  MEAN  = 258+29  the average o f 20 t r i a l s a t a  i n t e r v a l o f 35 mSec.  290a  Leaves 291-293 do not exist.  294  p o t e n t i a t i o n o f PP-evoked p o p u l a t i o n s p i k e was observed f o l l o w i n g a wide range  (3-40 V) of commissural  stimuli.  However c o n d i t i o n i n g v o l l e y s at i n t e n s i t i e s higher than 10 7  caused  a s m a l l but s i g n i f i c a n t  (110% of c o n t r o l ,  p<0.05) i n c r e a s e i n the amplitude of the PP-evoked EPSP recorded i n 2 animals and prolonged  both  period of d e p r e s s i o n and subseguent PP-evoked  population  spike  the i n i t i a l  potentiation o f the  i n a l l cases.  I n the 2  animals i n which a s m a l l i n c r e a s e i n EPSP amplitude was observed  the conditioning  prominent  late  COMM  responses.  stimulation Thus  evoked  the  observed  p o t e n t i a t i o n of the EPSP i n those two cases may be due to p o l y s y n a p t i c a c t i v a t i o n o f the t e s t PP pathway.  Evidence  That P o t e n t i a t i o n O f T h e P o p u l a t i o n Spike Was  JSfit Due To Changes In The Test Pathway. An i n c r e a s e i n t h e amplitude population  spike  entorhinal  commissural  volley.  cortex  This  responses.  Although  p o t e n t i a t i o n o f the PP-evoked possibility,  further  s e c t i o n i n g the outflow o f animals. stimulating recording  The  by  prior  would r e s u l t i n homosynaptic  this  the  potentiation  of  the f a i l u r e EPSP  does  precaution the EC  experimental  conditioning  a c t i v a t i o n o f the EC the PP-  to  observe  not support was  taken  v i a the PP  paradigm  EC, t h e PP i t s e l f and COMM from  the PP-evoked  could be caused by a c t i v a t i o n o f t h e  ipsilateral  evoked  of  in 2  consisted pathways  by  of while  the dentate. When the e l e c t r o d e s were  Leaf 294 continued on 298. Leaves 295-297 do not e x i s t .  298  positioned volley  so t h a t  stimulation  of  EC  i n t h e PP and a p o p u l a t i o n  a stereotaxic Following evoked  evoked  spike  the knife c u t s t i m u l a t i o n  i nthe dentate  of  EC  Commissural  in a  prominent  conditioning t h e PP-evoked  volleys  population  spike  7_j_4  Discussion  A)  Of The C o n i s s u r a l  Molecular  pathway  results  negative  field  layer:  in a  latency  l a y e r . The l a m i n a r p r o f i l e s u g g e s t s t h a t negative  above  the G-cell  anatomically pathway  fields  (Blackstad,  region  potentiation.  of  of  extracellular  and  corresponds  terminal  1956; G o t t l i e b  t h e molecular  PP s y n a p s e s on t h e d i s t a l  dendrites  molecular  t h e zone  areas and layer,  of  dendrites  structures, this layer  the  t h e COMM  which  1973). contains  i s below  of G-eells. I n contains  and axons o f c e l l s i n t h e p o l y m o r p h i c  Unlike  from  to  Cowan,  p r i n c i p a l l y the d e n d r i t i c shafts of G - c e l l s ,  a d d i t i o n t o these  t h e COMM  were r e c o r d e d e x t e n d s 50-100 urn  layer  verified  to  suggesting  which i s maximal i n t h e i n n e r  which  spike.  I n g u t T o The- D e n t a t e  Stimulation  short  proximal  continued  t h e EC d i d n o t m e d i a t e t h e o b s e r v e d  Field Analysis  longer  population  that  the  no  a d e n t a t e r e s p o n s e , b u t PP s t i m u l a t i o n  potentiate  fibre  k n i f e c u t was made b e t w e e n t h e EC a n d PP.  to the c u t r e s u l t e d  This  a  the  layer.  t h e n e g a t i v e d e n d r i t i c wave w h i c h i s e v o k e d  299  by PP s t i m u l a t i o n , the COMM n e g a t i v i t y has not related  to  individual  in t r a c e l l u l a r l y  G-cells  (Lomo,  recorded  1971a).  t o determine  precisely  which  elements  are mediating  t h e COMM  evoked  However,  the laminar p r o f i l e s recorded  and  previous  suggest  experiments  that  the s h o r t  (Deadwyler latency  EPSP^  of  makes  i t  This  difficult  postsynaptic responses.  i n the  dentate  the COMM negative  produced  1)  monosynaptically  1975)  (4-7 msec) responses  of  since  present  et a l ,  r e s u l t from a d i r e c t a c t i o n G-cells  yet been  the COMM  and i s  pathway  on  field i s  preceded  by  a  presynaptic  v o l l e y , 2) as i n the case of the PP i n p u t ,  the negative  d i p o l e produced  by  COMM  stimulation  accompanied by a p o s i t i v e wave recorded which at  may r e f l e c t a passive  the COMM synapses  B)  Responses  i n G - c e l l layer  source f o r the a c t i v e s i n k  and 3)  sometimes evoked on the  is  individual  positive c e l l  recorded  G-cells are  layer  i n G-cell  field.  l a y e r : In t h e  region of G - c e l l body l a y e r COMM s t i m u l a t i o n produces a p o s i t i v e waveform superimposed. 2-20  reguired  individual  the s i z e of t h i s  i t was  positive f i e l d .  which  I n c r e a s i n g the s t i m u l a t i n g  V) i n c r e a s e d  although  were  upon  always  High  smaller  t o evoke  a  voltage  positive than  stimulating  spikes  with  waveform,  (15-20 V)  an amplitude  comparable to t h a t e l e c i t e d by PP s t i m u l a t i o n In  (from  the PP evoked  voltages  field  are  (3-5 V ) .  4 of 15 experiments a compound spike s i m i l a r to the  PP-evoked p o p u l a t i o n  spike  was  superimposed  on t h e  300  p o s i t i v e w a v e f o r m . D e a d w y l e r e t a l (1975) were n o t a b l e to  elicit  population  stimulation  fine  t o the f a c t that  monopolar e l e c t r o d e s  o f o r i g i n o f t h e COMM effective bipolar  PP  as  units  which  firing  activated  the c e l l s  n o t be as  directly  with  i n the G-cell  have  low p r o p o r t i o n  are activated,  G-cells  over  are inhibited  than of  90% o f following  i n d e p e n d e n t o f w h e t h e r t h e same  units  o r n o t . T h i s i n h i b i t i o n may be m e d i a t e d  long  basket-type  interneurones  a x o n s p r o j e c t i n g t o w a r d s G - c e l l body  ( C a j a l , 1 9 1 1 ; A n d e r s e n e t a l , 1964) . Since the i n h i b i t i o n  2-3  times  longer  p r o d u c e d by COMM  than  f o l l o w i n g PP s t i m u l a t i o n (1.5  evoked  t o the  c o l l a t e r a l a c t i v a t i o n of  is  may  t h e pathway  In contrast  COMM s t i m u l a t i o n ,  layer  t o stimulate  (1975)  was a l w a y s l o w e r f o l l o w i n g COMM s t i m u l a t i o n  spontaneously  which  differences  Deadwyler e t a l  which  number o f s i n g l e u n i t s  dentate  by  pathway  activating  stimulation.  were  a l l following  electrodes.  The layer  at  o f t h e c o n t r a l a t e r a l CA3. T h e s e  may be r e l a t e d used  spikes  stimulation  the inhibition  a t t h e same r e l a t i v e i n t e n s i t y  X T) i t becomes n e c e s s a r y t o p o s t u l a t e  inhibitory  interneurones  stimulation.  These  observed  are activated  interneurones  may  that  more  f o l l o w i n g COMM be  the  hilar  neurones having d e n d r i t i c a r b o r i z a t i o n extending t o the inner  molecular  terminals  layer  i n the region  ( G o t t l i e b a n d Cowan,  of  t h e COMM  1973; H j o r t h - S i m o n s e n  301  and  Laurberg,  1978).  The  observations  that  s u b s t a n t i a l p r o p o r t i o n o f COMM t e r m i n a l s are the  hilar  region  (Gottlieb  Simonsen and Laurberg, 1978) that in  and Cowan, 1973; supports  postulated  t o that  postulated  feed-forward  f i b r e s would  explain  concomitant  activation  following  COMM  inhibitory  Hjorth-  on  interneurones  G-cells.  This  i n h i b i t i o n o f G - c e l l s by COMM  the potent  inhibition  observed  stimulation.  in  Since  without  most  the  cases  axons  of  i n t e r n e u r o n e s ramify e x t e n s i v e l y w i t h i n the  G - c e l l l a y e r only a few d i r e c t connections neurones  in  t h e suggestion  the COMM i n p u t may be on i n h i b i t o r y addition  found  a  are  reguired  i n h i b i t i o n observed  to  i n this  produce and  with  those  the prolonged  Deadwyler  et al»s  (1975) study.  Comparison With The Termination Of The P e r f o r a n t Path As  d e s c r i b e d i n t h i s and the p r e v i o u s chapter, PP  and COMM f i b r e s terminate molecular  layers  upon  the outer  o f t h e dentate,  and inner  r e s p e c t i v e l y . The  d e l i n e a t i o n between the t e r m i n a l areas of PP pathways zones  i s c l e a r with minimal  (Lynch and Cotman,  a l s o apparent The  o v e r l a p between the two  1975).  This  from the present f i e l d  functional  and COMM  significance  delineation i s  analysis. of  these  t e r m i n a l f i e l d s i s not yet  clear,  underlie  i n the amplitudes of f i e l d  the differences  however,  adjacent they  may  302  responses  and  number  of G - c e l l s  e x t r a c e l l u l a r negative f i e l d smaller  evoked. , The COMM  has a slower r i s e time and  amplitude than t h a t evoked by the PP. This may  be due to e i t h e r d i f f e r e n c e s i n the e f f e c t i v e n e s s o f PP and a  COMM t e r m i n a l s greater  to generate s y n a p t i c c u r r e n t s  number of PP synapses i n the outer molecular  l a y e r . The l a t t e r molecular synapses  layer with  i s more has a  likely  large  dendritic  dendritic  spines  would  concentrated synaptic  be  current  main d e n d r i t i c s h a f t s . These arrangement  G-cells.  which  Perhaps  degenerate  expected to generate more than COHM synapses on the differences  G-cells  in  synaptic  effectiveness  and  producing  t h e p h y s i o l o g i c a l r o l e of  the COMM system i s t o a l t e r the distal  of en passage  may a l s o u n d e r l i e t h e g r e a t e r  spikes.  t h e outer  1967) . These synapses on  of the PP input i n d i s c h a r g i n g population  since  number  spines  f o l l o w i n g PP l e s i o n s (Nafstad,  more  or t o  effectiveness  of the  PP i n p u t r a t h e r than t o d i r e c t l y  activate  303  Effect  Of  Commissural  Stimulation  On  PP  Evoked-  Responses Single in  a marked i n c r e a s e  population of in  pulse stimulation  spike  resulted  i n t h e a m p l i t u d e o f t h e PP-evoked  without a l t e r i n g the amplitude or r a t e  r i s e o f t h e e x t r a c e l l u l a r EPSP, I n t h e same a n i m a l s which c o n d i t i o n i n g  the  size  paired  of  COMM s t i m u l a t i o n  t h e EPSP  o f t h e PP i t s e l f  of  this  observation  i s i n agreement  Steward  a l  et  potentiation conditioning additional paired  (1978) of  the  pulse stimulation  the f i n d i n g s  also  failed  of  Steward  of  either  latter  to  EPSP  of find  following  afferent.  The  e t a l (1978)  that  t h e P P , COMM  or  homosynaptic  o f a t e s t EPSP s u g g e s t s t h a t  potentiation  current  al  reached (1978)  of  result  can only  the test  was  stimulation  The  in  stimulation of  et  with  PP-evoked  pathways  synaptic  conclusion  alter  resulted i n a  response.  o f t h e COMM  observation  potentiation  Lynch  who  stimulation  associational  d i d not  p r o d u c e d by a t e s t PP v o l l e y ,  pulse s t i m u l a t i o n  reliable potentiation  of  o f COMM p a t h w a y  pathway by  who  an a f f e r e n t  CA1 p y r a m i d a l c e l l  produced by p r i o r  itself.  A  similar  A n d e r s e n e t a l (1978) and observed  that  tetanic  t o one d e n d r i t i c zone o f a  r e s u l t s i n long  o f t h e same a f f e r e n t b u t n o t  be  lasting  afferents  potentiation  projecting  to  adjacent d e n d r i t i c layers.  In  contrast  t o t h e EPSP, t h e a m p l i t u d e o f t h e PP-  304  evoked p o p u l a t i o n  spike  was  markedly  c o n d i t i o n i n g COMM s t i m u l a t i o n . of  the  EPSP  restricted  that to  of  the  Thus  enhanced unlike  population  conditioning  potentiation  spike  stimulation  The o b s e r v e d  spike  is  d e p e n d e n t on the COMM pathway s i n c e  seen  following  psalterium,  population by  acute  spike  surgical  or  chronic  Furthermore,  transection  in  of  origin  some  animals  population a  COMM  of  any the  of  EPSP  p o t e n t i a t e d argues heterosynaptic events  leading  the against  was n o t  was  not  of  the  of  eliminated  that  the  PP-evoked  10 msec  following  restricts  extrahippocampal in  population the  cortex  The o b s e r v a t i o n of  changes  the  the  severely  potentiation is to  it  of  within  volley  polysynaptic  when  test  population  the involvement  was o b s e r v e d  case t h e absence of  the  between the e n t o r h i n a l  t h e PP i n p u t .  conditioning  not  potentiation  potentiation  spike  involvement In  of  the  is  transection  by COMM s t i m u l a t i o n  and t h e PP t h e r e b y e l i m i n a t i n g cells  of  of  pathway.  ventral  potentiation  following  the  rate  spike  is  possibility m e d i a t e d by  i n c r e a s e d PP t r a n s m i t t e r  the  systems. of  rise  markedly that  the  presynaptic release.  305  7__5 Summary I n summary t h e demonstrate  that  r e s u l t s i n short  results  of  stimulation  latency  field  the present of  chapter  t h e COMM  pathway  responses i n the dentate  g y r u s . The l a m i n a r p r o f i l e and i t s r e l a t i o n s h i p t o t h e depth p r o f i l e f o l l o w i n g s t i m u l a t i o n t h e COMM i n p u t of  G-cells  than  o f PP s u g g e s t s  t o the dentate depolarizes  the  the d i s t a l l y  located  G-cells  inhibition  stimulation potentiation altering  of  f o l l o w i n g CO MM  stimulation few  cases  i n t h e remainder. S i n g l e  pulse  t h e COMM  pathway  results  o f t h e PP-evoked p o p u l a t i o n  i n marked  spike  without  t h e EPSP p r o d u c e d b y a t e s t PP v o l l e y .  On t h e  basis o f these data, heterosynaptic population  body  PP s y n a p s e s . T h e r e s p o n s e o f  causes a c t i v a t i o n - i n h i b i t i o n seguences i n a pure  dendrites  a t a p o s i t i o n more p r o x i m a l t o t h e c e l l  spontaneously f i r i n g  and  that  spike  may  neuronal transmission  be  an  potentiation  additional  through t h e dentate  of the  feature gyrus.  of  306  CHAPIH  8: THE HAPHE^SEBOTONIN TRANSMISSION  AND NEURONAL  IN THE DENTATE GYROS  8 j_1 I n t r o d u c t i o n The  previous  two chapters  p r o f i l e of t h e p e r f o r a n t path and  the  feasability  e x t r a c e l l u l a r EPSP  described  the  laminar  (PP) i n p u t to the dentate  o f using the r a t e of r i s e of the  and  amplitude  of  the  population  s p i k e as i n d i c a t o r s o f s y n a p t i c c u r r e n t and synchronous neuronal in  d i s c h a r g e s , r e s p e c t i v e l y . The o b s e r v a t i o n made  Chapter  7  that  conditioning  commissural pathway population  spike  increases without  the EPSP prompted an  stimulation  the  amplitude  of the of the  a l t e r i n g t h e r a t e of r i s e of  examination  of  the  effects  of  s t i m u l a t i n g known monoamine p r o j e c t i o n s t o the dentate. Unlike  the  commissural i n p u t the monoamine systems do  not s u b s t a n t i a l l y i n n e r v a t e t h e molecular dentate  and a r e thus u n l i k e l y t o a f f e c t the PP synapses  on the d i s t a l d e n d r i t e s o f granule The  present  chapter  cells.  examines  s t i m u l a t i n g t h e median raphe nucleus origin  l a y e r of the  of  hippocampal  evoked i n the dentate possible  the  serotonin by  test  PP  the  effects  of  (MR), the s i t e  of  on f i e l d p o t e n t i a l s volleys.  response of s i n g l e dentata  units i s also  examined i n order t o r e l a t e observed changes potentials recorded  to  the  activity  from the same s i t e .  of  Whenever  individual  in  field  neurones  307  8.2 Experimental  Procedures  The methods used were s i m i l a r to in  chapter  7,  Bipolar  stimulating  s t e r e o t a x i c a l l y positioned i n activate  the  those  described  electrodes  angular  bundle  L = +3.5 mm;  V =-3.5  to a c t i v a t e g r a n u l e c e l l s a n t i d r o m i c a l l y . ,An stimulating  electrode  raphe nucleus - 6 , 5 mm).  was  (AP = -8.0 mm;  The 5  rats  Immediately experiments,  L = 0.0 mm;  V = -6.0 mm t o  pretreated  the median  on 15 normal with  the  animals  (5  i . p.). ,  electrophysiological normals  and  treated) were d e c a p i t a t e d and t h e hippocampal both  sides  removed  d e s c r i b e d i n chapter 2.  para-  400 mg/kg;  following some  additinal  in  experiments were performed  and  mm)  positioned  c h l o r o p h e n y l a l a n i n e (p-CPA,  on  to  the p e r f o r a n t path and i n the mossy f i b r e s or  i p s i l a t e r a l CA3 (AP = -3.0 mm;  rats  were  for  subseguent  5 p-CPAformation  5-HT  assay  308  8JJ_3  Results  E f f e c t s Of MR S t i m u l a t i o n The  response  was s t u d i e d median on  of  On G - c e l l s  66 spontaneously f i r i n g  f o l l o w i n g s t i m u l a t i o n i n the r e g i o n  raphe  responses  of  the  nucleus. Dentate G - c e l l s were i d e n t i f i e d  the b a s i s o f t h e i r response  stimulation  G-cells  and  patterns  following  PP  t h e i r r e l a t i o n s h i p t o PP-evoked f i e l d  (Fig, 8-1). In some cases  (n=15)  cells  were  f u r t h e r i d e n t i f i e d by a n t i d r o m i c a l l y a c t i v a t i n g them by mossy f i b r e As  stimulation.  shown  in  F i g , 8-1D, s i n g l e pulse  (10-20V) of the MR i n h i b i t e d a t o t a l cells  56  (85%)  G-  at l a t e n c i e s ranging between 10-25 msec (See a l s o  F i g , 8-2), periods of  of  stimulation  The  duration  o f 25-175 msec  i n h i b i t o n could  with higher pulses  of  inhibition  (mode=43.0  lasted  msec)... The  be lengthened by s t i m u l a t i n g  intensity  or  increasing  the  for  duration the MR  number  of  ( F i g . 8-2).  H i s t o l o g i c a l v e r i f i c a t i o n of e f f e c t i v e stimulating electrode  placements  indicated  a direct relationship  between t h e l e n g t h of i n h i b i t i o n and proximity electrode sites the  t o the MR  1.0-2.0 mm  ( F i g . 8-3). In a d d i t i o n posterior  of  the  stimulating  t o the MB d i d not produce  observed i n h i b i t i o n i n d i c a t i n g a s p e c i f i c a c t i o n of  t h i s p a r t i c u l a r nucleus on G - c e l l s .  309  IISx  8-  Xl  E f f e c t s •• O f  MR  Stimulation  On  Dentate  G r a n u l e C,gll§» A i arrangement o f r e c o r d i n g level  of  electrodes  the  (closed  entorhinal  nucleus  body  i n excitatory  inhibitory the  cell  (open  {EC)  PP  the  stimulating and  afferents  from  median  raphe  r e s p e c t i v e l y . C o l l a t e r a l of t h e (MF), a c t i v a t e s an  interneuron.  Bx o s c i l l o s c o p e by  at  triangles)  and  G - c e l l a x o n , t h e mossy f i b r e inhibitory  and  triangles)  cortex  (MR),  electrode  traces  stimulation  i n d i c a t i n g that  o f t h e waveforms  evoked a t v a r i o u s  recordings  evoked  intensity  were from t h e G - c e l l  layer. C^p: p o s t s t i m u l u s msec)  of  a  histograms (bin width  G-cell discharge following  pulse stimulation Inserts  show  o f t h e PP 25  (C)  superimposed  sweeps. A r r o w s i n d i c a t e s t i m u l u s calibrations  are  and  5  msec/. 1 mV i n C and D.  msec/1.0  =  5  single  MR  (0).  oscilloscope artifacts  mV  and  i n B and 50  B 5 V  10 V  - -'—F=»—«'  I -Neurone  D  c. 50  50  n  •j  t  a.  ,  . *  !  .  I _ „ .  .  I  i  I  '  I  '  I  ' 750  . I ' 0  I ' A  I '  1 '  I '  — r  I  1  I  1  I  1  I '  I ' I 1  0  0  0  311  FIG,  8- 2j_ • I n h i b i t i o n Of Spgntaneously F i r i n g  Dentate  C e l l s By MB S^jfulatipnjs. A i e f f e c t s of i n c r e a s i n g t h e s t i m u l u s i n t e n s i t y on  the l e n g t h of i n h i b i t i o n observed  MB s t i m u l a t i o n ,  (10  superimposed  following  oscilloscope  sweeps) , .• B_j,  effects  d e l i v e r e d to observed two  of i n c r e a s i n g the number of p u l s e s the  MB  inhibition.  pulses  superimposed  were  on  the  length  of  the  In the lower records the  repeated  by  10  msec.  (20  o s c i l l o s c o p e sweeps).  Cj, PST histogram of the response of a G - c e l l t o MB  stimulation  with s i n g l e or r e p e t i t i v e (300  Hz) pulses. B i n width i s egual to 10 t r i a l s i n each case.  msec;  50  B.  313  E f f e c t s Of MR The  Stimulation  response of 12  which were e x c i t e d  pulse  spontaneously  by the  following stimulation single  On Pg-§voked Responses  perforant  of the MR.  stimulation  of  As MR,  firing  G-cells  path were examined shown i n F i g .  8-4,  which i n h i b i t e d the  spontaneous d i s c h a r g e of a l l 12 c e l l s , a l s o blocked s i n g l e spike a c t i v a t i o n stimulation  of  8  cells  of the PP a t t h r e s h o l d  stimulation of activation  the  produced  at 2 X T. When  the  MR  did  not  (6 6%)  was  following  i n t e n s i t y . However, reliably  by s t i m u l a t i n g the PP  block  the  perforant  path  stimulated  with  3  i n t e n s i t y , thereby evoking a number of G - c e l l s 4C) ,  MR  stimulation  discharge of G - c a l l s  resulted which  in  resembled  the  volley  s i n c e they may  In  order  PP-evoked population  single  increase spike  8-  population to determine  at  s p i k e was  volley  i n the amplitude o f the critical  intervals  r i s e time of the PP-evoked pulses  test  spikes  8-4C.  of the MR.  conditioning  conditioning  by the  to overcome t h i s problem, the  and a f t e r s t i m u l a t i o n a  (Fig.  be masked by compound  such as that shown in F i g .  of the  T  i n d i v i d u a l c e l l s which were evoked i n response  to c o n t r o l PP s t i m u l a t i o n were a l s o evoked PP  x  a more synchronous  spike response. Thus, i t became impossible whether  the  EPSP  amplitude  measured  before  As shown i n F i g . to  MR  r e s u l t e d i n an  PP-evoked  population  between 20-70 msec. was  that potentiated  8-5,  not  altered  The by  the amplitude of  314  DLGA,  8-  Belatignship. Between I n h i b i t i o n 0£  3z  C e l l s And P o s i t i o n Of The S t i m u l a t i n g In The Region Of  hE  Dentate Electrode  x  A i schematic of a c o r o n a l  section  brain  (A160) i n d i c a t i n g t h e  a t the l e v e l of MR  of  p o s i t i o n of the s t i m u l a t i n g e l e c t r o d e  the r a t  along  a  v e r t i c a l t r a c k which produced t h e corresponding responses shown i n B. Bi  the  dentate region  response unit of  of  a  following  spontaneously stimulation  MR a t the i n d i c a t e d  firing in  the  positions.  Each  r e c o r d c o n s i s t s of 10 superimposed  oscilloscope  sweeps.Abbreviations as on page 130.  3\5  316  FIG..  8- j4z_ E f f e c t s Of  MR  Stimulation  A c t i v a t i o n Of Dentate Ai  spontaneously  On  PP  Cellsj,  firing  dentate  were i n h i b i t e d by s i n g l e pulse  u n i t s which  stimulation  MR  (top) and a c t i v a t e d by PP (bottom).,  B-  i n d i c a t e s that t h e PP-evoked s p i k e  eliminated  by  a  (bottom) .  PP  stimulus  and  C-T  preceding  interval  activation  of  is  the  Evoked  pulse  of  (top)  to  the  is MR  i n t e n s i t y at threshold 30 mSec., S i n g l e above  spike  u n i t . , Note  the  e l i m i n a t i o n o f the PP evoked s p i k e i n t h e lower sweep. . C i same experiment as i n B stimulated number compound  except  the  PP  is  with s u f f i c i e n t i n t e n s i t y t o evoke a  of  neurones.  spike  Note the appearance o f a  following  MR  s t i m u l a t i o n i n the lower sweep. ,  conditioning  {_ [ 0.2 mV 2 msec  PP MR-PP  • T 0.2 mV t  5 msec  PP MR-PP  T 0.2 mV 5 msec  318  8-  5:,  Effects  Of MS C o n d i t i o n i n a Pulses OB  F i e l d Responses Evoked By The  Perforant  kz_ graphs of the amplitude of p o p u l a t i o n and  rate  of  volley  (7.5 V)  pulse  (15  (lower  graph).  rise  to  C: o s c i l l o s c o p e population conditioning right)  pulses.  PP  spike  traces  (top  conditioning  (top graph) or to the  of  MB  control  PP-evoked  and  following  spikes(left) PP  A  of the EPSP evoked by a PP  when preceded by a  V)  Path  The  right)  and  MR  (lower  320  the population Potentiation every  of  animal  ranging  was  with  the  related  same  animals.  maximum  potentiation  t o t h e d i s t a n c e between t h e  and  stimulation  not r e s u l t  the  center  of  i n t h e DR and a d j a c e n t  i s noteworthy t h a t a t the s t i m u l u s (10-20V)  that  the  MR, areas  i n reliable potentiation.  MR  stimulation  s i g n i f i c a n t depression to  the  p o p u l a t i o n s p i k e was o b s e r v e d i n  electrode  Conditioning  used  the  in  b e t w e e n 1 1 0 % a n d 170% o f c o n t r o l . The d e g r e e o f  stimulating  It  recorded  tested  potentiation  did  spike  which  d i d not  of the population  initially  intensities result  spike  follows  in  similar  conditioning  s t i m u l a t i o n o f t h e PP i t s e l f .  ISlationship Eopjulatign  Between  Spike  Effects  Of  And I n h i b i t i g n  MR  S t i m u l a t i o n - - On-  Of S i n g l e U n i t s . .  :  As i l l u s t r a t e d i n F i g . 8-6, t h e t i m e c o u r s e o f t h e facilitation  evoked  by  the  with the  recorded  at  vicinity.  When t h e d u r a t i o n o f t h e i n h i b i t o r y  same  of  conditioning  coincided  the  period  MR  inhibition  position  or  of  pulses G-cells  i n t h e immediate component  was a l t e r e d by c h a n g i n g i n t e n s i t i e s o f s t i m u l a t i o n , t h e period of f a c i l i t a t i o n  of  altered  direction.  in  the  same  relationship i s further amplitude  the  population  illustrated  In  spike  F i g . 8-7,  by  of a representative population  plotting  was this the  s p i k e and t h e  p r o b a b i l i t y that a given G - c e l l i s i n h i b i t e d at various  321  |IG  i ;  8;  6:  Facilitation  Response  Following  Of  The  Population  PP  And  MS  Spike  Conditioning  Pulses The  time  potentiation and MR the  of  (upper graphs)  popoulation following  (A)  (B) c o n d i t i o n i n g p u l s e s i s compared  with  response of a spontaneously  recorded  (PST histograms, in  spike..Note related  e l i c i t e d by case.  spike PP  neurone  is  course  the  vicinity  the  the  dentate  b i n width = 5 mSec) of  t h a t the d u r a t i o n to  firing  length  the p o p u l a t i o n of  potentiation  of the  conditioning  )  pulse  inhibition in  each  323  times f o l l o w i n g MB computed  by  stimulation.  counting  the  were i n h i b i t e d during 5,0 MS  stimulation.  is  probability  number of c e l l s msec sample  was  (n=66) which  bins  following  I t i s noteworthy t h a t the time period  when the majority stimulation  The  of the  G-cells  were  optimal C-T  f o r maximal f a c i l i t a t i o n  inhibited  interval  of the population  by  MR  (30-35 msec) spike.  E f f e c t s o f P_;CPA On Bespones Ivoked JEjy. S t i m u l a t i o n  Of  MR As shown i n t a b l e 3, in  a  significant  p-CPA pretreatment  d e p l e t i o n (69%)  resulted  of hippocampal  5-HT  measured by the s p e c t r o f l u o r o m e t r i c assay d e s c r i b e d chapter  2.  significant single  The  pretreatment  attenuation  G-cells  and  of  also  resulted  MR-evoked  enhancement  in  inhibition  of the PP  the  inhibition  enhancement (80%) hippocampal  5-HT.  (61%)  were s i m i l i a r  and to  population the  a of  population  spike response. Moreover, the degree of a t t e n u a t i o n both  in  of  spike  depletion  of  324  ZLQ.*. 8~  ll And  R e l a t i o n s h i p Between Inhibi£ion Of G - c g l l s Amplitu.de Of The P o p u l a t i o n The  probability  inhibited/  cells  of  tested  Spijcej.-  inhibition X  (  cells  100) shown i n the  histogram and t h e amplitude of a r e p r e s e n t a t i v e population right  (dashed l i n e ) are the l e f t and  ordinates,  stimulated represents (n=66)  spike  The  MB  the  abscissa  5 msec sampling periods of  neuronal  at  respectively. time  discharges.,  zero  and  was  8.0  / \ h-6.0  o 100-  0^  c o  80-  15 1c c  60-  r  obabi lity  o  Q_  Q.  CO  -  h-4.0  m  h2.0  40-  Q.  O 0_  •a CL  £ <  20-  0-  > £  L-0.0  | 0  i i—i—|—i—•— —| 1  20  40  •  ^ T" 60  Time after MR Stimulation (msec)  "1  80  3ZG  TABLE I I I EFFECTS OF p-CPA ON HIPPOCAMPAL 5-HT  AND  RESPONSES TO STIMULATION OF THE MEDIAN RAPHE  pp-evoked population spike (% increase) Control p-CPA percent difference  inhibition of G - c e l l s (no. i n h i b i t e d no. tested)  5-HT concentration (ng/g wet tissue)  40±5 (n=15)  55 (83%) 66  545±29 (n=5)  8±3 (n=4)  8 (32%) 25  166±18 (n=4)  -80*  p-CPA (400 mg/Kg, i . p .) was  -61*  -69**  administered 3 days  before r e c o r d i n g experiments.  5-HT l e v e l s were  assayed i n both s i d e s of the hippocampal formation u s i n g s p e c t r o f l u o r e m e t r i c techniques chapter  2 (*p<0.01; **p<0.001).  described i n  327  8 .J.  Discussion  Effects  Of  MR S t i m u l a t i o n O n S p o n t a n e o u s D i s c h a r g e .  Of  G-cells Single pulse  stimulation i n the region of  r e s u l t s i n short latency majority  of  between  proximity  of  suggests  that  particular not  the  from  length  and the  of  to  i s mediated  not t h e adjacent present  data  direct  inhibition  electrode  inhibition  nucleus  possible  the  f i r i n g G-cells..The  stimulating  the  MB  (10-25 msec) i n h i b i t i o n o f t h e  spontaneously  relationship  the  and  the by  areas.  MB  this I t i s  to distinguish  between  mono- a n d p o l y s y n a p t i c MR e v o k e d i n h i b i t i o n o f  G-cells.  The o b s e r v a t i o n  that  inhibition  occurred  at  s h o r t l a t e n c i e s a n d i n some c a s e s i m m e d i a t e l y a f t e r t h e stimulus  supports  a  than  indirect  action  an  systems.  Within  d i r e c t i n p u t onto G - c e l l s r a t h e r  the  involving  dentate the d i s t r i b u t i o n  terminals.is primarily to the hilus.  extrahippocampal  Histofluorescence  region  of  o f 5-HT  the  dentate  and a u t o r a d i o g r a p h i c  studies  ( H a l a r i s e t a l , 1976, s e e a l s o s e c t i o n 1.1.1) r e v e a l clear  infragranular  band  e i t h e r onto interneurones some  of  the  stimulation  serotonergic  terminals  or the G - c e l l  w h i c h may be bodies.  Since  i n h i b i t e d n e u r o n e s were i d e n t i f i e d a s G-  c e l l s by a n t i d r o m i c a l l y fibre  of  a  firing  them  following  mossy  t h e s e n e u r o n e s may r e c e i v e a d i r e c t  i n p u t o r i g i n a t i n g i n MR.  328  E f f e c t s Of  MS  Stimulation  S i n g l e pulse activation  of  that  at  s t i m u l a t i o n of  G-cells  suprathreshold  On PP;ey ok ed Responses  evoked  s t i m u l a t i o n of  higher  PP  when  the  by  PP  the  path  population  was  population  spike  was  fact  response  stimulation. Since was  In  the  blocked  was  at  intensities amplitude  the  to to  spike.  Since  commissural  observed f o l l o w i n g  increase  an  increase  conditioning  pathway  the  in  Miller,  2) and  to  region  population of  the  the mossy f i b r e s  unpublished  results)  spike without a l t e r i n g  EPSP e x t r i n s i c a f f e r e n t s t o the dentate may  T h i s point w i l l  the  transmitter  stimulation  (Chapter  population  dentate t r a n s m i s s i o n  in  or the  MR  spike  not due  account f o r p o t e n t i a t i o n of the  {Lomo, 1971b; Assaf and potentiate  the  d i s t a l d e n d r i t e s . Thus i t i s not  postulate  release  of  p o t e n t i a t i o n of the p o p u l a t i o n  PP synapse on  necessary  perforant  enhancement  r a t e of r i s e or amplitude o f the EPSP i t was  of  can  G-cells.  the  on the e n t o r h i n a l c o r t e x  not  suggests  onto  spike,  not accompanied by a concomitant  the a c t i o n of MR  but  This  not reduced by an  the  activation  stimulated  spike  stimulation.  PP.  inhibition  s u f f i c i e n t to evoke a p o p u l a t i o n of  MR  threshold  the  intensities  overcome the raphe mediated Thus  the  alter  without changing s y n a p t i c  be developed f u r t h e r i n chapter  the PP-  current. 10.,  329  BglgtionshJE  Between  IfiMMtion  Of  Shells  And  P o t e n t i a t i o n Of The Population. Spike The  present  relationship and  data  between  demonstrate  MR  a  temporal  evoked i n h i b i t i o n of G - c e l l s  p o t e n t i a t i o n o f t h e p o p u l a t i o n s p i k e response  that  the  onset  of  inhibition  c r i t i c a l C-T i n t e r v a l s at which amplitude  i s increased.  i n t e r v a l f o r producing largest  proportion  coincides the  such  with  population  the spike  Furthermore, t h e optimum C-T  maximum p o t e n t i a t i o n i s when the  of  G-cells  is  inhibited  by  MR  s t i m u l a t i o n . T h i s r e l a t i o n s h i p between i n h i b i t i o n o f Gcell  discharge and p o t e n t i a t i o n of the p o p u l a t i o n spike  was  also  of  the  demonstrated during p a i r e d pulse s t i m u l a t i o n PP  mechanisms,  itself. in  This  part,  suggests may  that  mediate  potentiation of the population spike  inhibitory the  without  observed altering  synaptic current.  S o l e For S e r o t o n i n : The i n h i b i t i o n o f spontaneously enhancement  firing  G - c e l l s and  o f t h e PP-evoked p o p u l a t i o n s p i k e  observed  f o l l o w i n g MR s t i m u l a t i o n were s u b s t a n t i a l l y reduced p-CPA  pretreatment  which decreased  5-HT c o n c e n t r a t i o n  i n the hippocampal formation. Taken together relationship  between  the  inhibition  of  with  these  data  support  the  proposal  the  G - c e l l s and  p o s i t i o n o f t h e s t i m u l a t i n g e l e c t r o d e i n the 8-3),  by  MR ( F i g .  that  these  330  responses were mediated by The MR  observation  enhances  spike  was  personal  the  a raphe-serotonin  t h a t s i n g l e pulse  stimulation  amplitude of the PP-evoked  recently  confirmed  communication).  He  by  Winson  also  evoked by PP  between 20 the  and  effects  of  anaesthetized spike  70  s t i m u l a t i o n a t C-T  MR  was  (Winson,  On  may  be  neuronal  MR  population ranging  (1978) examined  the  the  not basis  in  the  population  transmission  behaviour-specific.  in  alert  state  of these data,  ainson  (1978) suggested that the e f f e c t s of a on  that  observed i n slow wave s l e e p and  s t a t e but  system  and  s t i m u l a t i o n i n awake as w e l l as i n  the anaesthetized 1978).  (1978  intervals  msec. However, Hinson  animals. Augmentation of  response  the  of  population  observed  s t i m u l a t i o n i n c r e a s e s the amplitude of spike  system.  i n the  raphe-serotonin dentate gyrus  331  8^5 Summary In summary, s i n g l e pulse results firinq  in  short  G-cells  population  EPSP. There i s period  potentiation  without a l t e r i n g  a  temporal  of  the  the  MR  PP  evoked  the r i s e time o f the  relationship  between  o f i n h i b i t i o n of u n i t a c t i v i t y and c r i t i c a l  i n t e r v a l s f o r p o t e n t i a t i o n . Depletion  of  hippocampal  the  respones  of  l a t e n c y i n h i b i t i o n of spontaneously  and  spike  stimulation  formation  suggesting  serotonin-containing  attenuates  that system.  they  are  5-HT  the C-T  i n the  MR-elicited  mediated  by  a  332  CHAPTER 9j. THE LOCUS COERULEUS AND NEURONAL TRANSMISSION IN THE- DENTATE GJRUS  Iatrgduction Conditioning pathway  (Chapter  (Chapter path  8)  7)  increase  (PP)-evoked  innervation  stimulation  but  of  the  that  dense  median  in  Like the s e r o t o n i n noradrenaline  originate  the e f f e c t s  of  the  b u t may a l t e r  a t some o t h e r s i t e .  in  the  dentate  the  individual  neurones.  synapses This  discharge  of  G-  The p r e s e n t c h a p t e r e x a m i n e s  stimulating  changes i n f i e l d  locus  PP s y n a p s e s o r  LC  on  field  potentials  s i n g l e d e n t a t e c e l l s i s a l s o e x a m i n e d i n an  to r e l a t e  (NA)-  hilus.  e v o k e d i n t h e d e n t a t e by a t e s t PP v o l l e y . The of  nucleus  amplitude of the p e r f o r a n t  dentate, which  commissural  raphe  LC i s u n l i k e l y t o a f f e c t  t h e EPSP d i r e c t l y cells  the  the  ( L C ) , a r e s p a r s e i n t h e zone o f PP  relatively  suggests  the  population spike.  containing terminals, coeruleus  and  of  potentials  to  response attempt  activity  of  333  3i2  E x p e r i m e n t a l Procedures The  methods  used were s i m i l a r t o those  i n c h a p t e r s 7 and 8. In a d d i t i o n t o a l l placements  provided  coeruleus  ear bars; 6.5 mm  the  was  positioned  the  midline;  V  =  which  had  5.5  previously  to  (15-20  a b i l a t e r a l i n j e c t i o n o f 6-OHDA (4 ug i n  2 u l of 0. 15M s a l i n e with 0.2 mg/ml a s c o r b i c the  i n the  s u r f a c e o f c e r e b e l l a r cortex) of 15  normal r a t s and 10 r a t s days) r e c i e v e d  electrode  (AP = 1.5 mm p o s t e r i o r to s t e r e o t a x i c  L = 1.1 mm from  below  the  i n chapter 8 (PP, DG,CA3, MR), a  bipolar stimulating electrode locus  described  dorsal  NA  bundle.  electrophysiological  acid)  Following  experiments  the  into the  hippocampal  formation was removed and t i s s u e samples assayed f o r NA as d e s c r i b e d  9 _3 f  i n Chapter 2.  Results  E f f e c t s Of LC S t i m u l a t i o n The  responses  On Dentate C e l l s  o f 63 spontaneously f i r i n g  neurones were examined  following  pulse  the  stimulation  of  single  locus coeruleus.  c e l l s , 56 were i d e n t i f i e d as G - c e l l s on thier  response  to  or  stimulation  of  the  PP  dentate multiple  Of the 63 basis  of  as w e l l as by  h i s t o l o g i c a l l o c a l i z a t i o n o f the recording  electrode i n  the dentate c e l l body l a y e r . I n a d d i t i o n  12 of  G-cells  by mossy f i b r e  were  activated  antidromically  the 56  334  2z  l L Effects Neurones Aj  Of  LC  Stimulation  spontaneously f i r i n g layer  the  response  f o l l o w i n g s i n g l e pulse  same  s i n g l e and m u l t i p l e  to  Response  300 Hz) s t i m u l a t i o n o f LC i s  the  lower r a s t e r .  BJL  o s c i l l o s c o p e records  evoked  stimulation. Single  pulse  by  inhibition.  pulse shown  the (4 by  mossy  stimulation, fibre  (MP)  s t i m u l a t i o n of LC was  without e f f e c t while m u l t i p l e in  of  showing a G - c e l l which  was monosynaptically evoked by PP antidromically  a  stimulation  (bottom),  neurone  of  neurone recorded i n t h e G-  of LC (top) and MS  pulses,  Dentate  t  r a s t e r d i s p l a y showing  cell  On.  pulses  resulted  l_Jo.l mV pp  5 msec  • To.l  mV  2 msec  nimjmiiimiiiiiUttiHiij^. ^. LC I Pulse  50 msec  M  tie 4 Pulses  m V  0.2 mV  50 msec  336  stimulation. cells  7 neurones c o u l d  since  t h e y were s y n a p t i c a l l y a c t i v a t e d  fibre stimulation layer. as  and were r e c o r d e d  The l a t t e r  hilar  n o t be i d e n t i f i e d  below  intrinsic  to  G-  by mossy  the  n e u r o n e s were t e n t a t i v e l y  neurones, p o s s i b l y  as  G-cell  identified  the  dentate  gyrus. The (88%) the  discharge  pattern  of the m a j o r i t y  was n o t a l t e r e d by s i n g l e LC  at  Inhibition observed  pulse  i n t e n s i t i e s r a n g i n g from  at short in  4  latencies  G-cells  stimulation 0-25V  (less than  of  ( F i g . 9-1).  25 msec)  (7%) u n i t s and s i n g l e s p i k e  was o b s e r v e d i n 3 (5%) G - c e l l s .  of  was  activation  O n l y 1 o f 7 non  G-cells  was i n h i b i t e d . During stimulating  stable electrode  plane t o insure observed  recordings  at  that  a  G-cells  the  was moved i n t h e d o r s a l - v e n t r a l the  different  response  stimulating  1.0-1.5 mm b e l o w t h e l e v e l were  from  o f t h e LC  of  the  cell  was  depths. At depths facial  movements  e v o k e d by t h e s t i m u l a t i o n , t h e s e movements c a u s e d  large  artifact  field and  immediately may  be  following  related  to  the  stimulus  activation  o f the  nucleus o f the f i f t h c r a n i a l nerve. Electrodes animals 21  were p l a c e d i n both  allowing  neurones  and  MB  in  4  a c o m p a r i s o n between t h e r e s p o n s e s o f  following  Fig.  9-1, t o p ) s i n g l e  the  discharge  of  LC  16  MB  and  LC  stimulation  (e.g.  p u l s e s t i m u l a t i o n o f MB i n h i b i t e d neurones  whereas  that  of  LC  337  inhibited  only  following  MR  2  of  neurones.  The  inhibition  s t i m u l a t i o n was s i m i l a r i n l a t e n c y  than 25.0 msec) and described  the  duration  (mode-45 msec)  (less  to  that  i n the p r e v i o u s c h a p t e r .  The e f f e c t s o f r e p e t i t i v e s t i m u l a t i o n of the LC (25  p u l s e s , 300 Hz) were examined on 15 G - c e l l s recorded  i n 5 animals. stimulation reliable  As shown by the lower r a s t e r i n F i g . 9-1, of  the  inhibition  LC  with  4  pulses  resulted  in  8 (55%) neurones while  single  pulses had no e f f e c t . The onset of i n h i b i t i o n was than  in  less  30 msec f o l l o w i n g the l a s t pulse of the t r a i n and  continued  f o r 50-100  rate  the  of  higher periods.  mSec.  neurone  during  background  discharge  was o f t e n (4 o f t h e 6 neurones)  stimulus  Slight  The  presentations  than  f a c i a l movements were observed  control during  s t i m u l a t i o n , t h e r e f o r e the increased d i s c h a r g e r a t e  of  the  of  neurone  may  be  related  to  sensory-motor n u c l e i adjacent t o LC,  the  activation  338  UJect  Of  The  LC S t i m u l a t i o n e f f e c t s of  repetitive  EPSP  was  pulses,  in  r e p e t i t i v e but  of  reliably  300  Eg§B9M§§Sji.  single  hZ.)  and  pulses  on  r i s e time of  the  control  rats.  As shown i n  single  pulse  stimulation  not  potentiated  response i n a l l 6 r a t s but  with  spike and  6  F i g . 9-2,  LC  15V,  population  examined  LC  PPz§.I2l£t<l JLi&l&  stimulating  (2-5  amplitude of the  On  the  population  spike  did not a l t e r the r i s e  time  of the EPSP i n the same animals. The  c r i t i c a l C-T  population the  last  spike pulse  (150-175% of  i n t e r v a l s f o r p o t e n t i a t i o n of  ranged  was  i n t e r v a l s between 35 and F i g . 9-3 is  related  between 20-80 msec f o l l o w i n g  of the b r i e f t r a i n . control)  observed  2-4  at  optimal  C-T  50 msec. potentiation  the number of s t i m u l a t i n g p u l s e s  s i n g l e pulse d i d not r e l i a b l y whereas  Maximum p o t e n t i a t i o n  i n d i c a t e s t h a t the degree of to  result  in  since  potentiation  p u l s e s produced r e l i a b l e p o t e n t i a t i o n .  response f o l l o w i n g a stimulus  t r a i n of 5 pulses  was  s u b s t a n t i a l l y d i f f e r e n t than that observed f o l l o w i n g or  more  adopted  pulses, as  the  thus  the  a 4-5  test  pulse stimulus  stimulus  for  train  The not 6 was  inter-animal  comparisons. As  shown  in  F i g . 9-4,  there  was  r e l a t i o n s h i p between depth of the s t i m u l a t i n g tip  and  the  degree  of  potentiation.  a  direct  electrode Placements  339  0<LJ_  2.L E f f e c t s  2Z  Of  Dentate Population  LC  Stimulation  EesponseSj.  A i the e f f e c t s of c o n d i t i o n i n g (15V,5  pulses  population Bz  at  arrow)  300 Hz.)  sweeps  stimulation on  showing  PP-evoked  PP-evoked  s t i m u l a t i o n o f LC  the  population  p o t e n t i a t i o n of t h i s response preceding  LC  spike and EPSP.  oscilloscope  (lower  On Pgreygked  (top  control  spike and arrow)  ( C-T = 35 mSec).  by  Test Responses (96of Control) ZZ  O O  O  O  PO O  w O  * O  o —h m Tl  >  341  9-  3z_ R e l a t i o n s h i p Pulses And  Between  The  Number  Amplitude Of The P o p u l a t i o n  Of LC  Spike*  Each p o i n t i s the average o f 20 t r i a l s a  constant  condition-test interval  Freguency o f the p u l s e t r a i n was 300  at  (35 msec) . Hz. ,  342.1  FIG.  9- 4_L H i s t o l o g i c a l L o c a l i z a t i o n  Of.  Stimulation  E l e c t r o d e In LC ,i:  The  photomicrograph  l e v e l of LC placement  shows  the  (arrow).  corresponding relationship  taken at the r o s t r a l stimulating  The  lower  profiles between  electrode  schematic indicate  proximity  the of  s t i m u l a t i n g e l e c t r o d e t o LC and enhancement the  PP-evoked p o p u l a t i o n  the average o f 30  the of  s p i k e . Each r e c o r d i s  trials.  Abbrevi atignSji. CEE  and  cerebellum  DTN  d o r s a l tegmental nucleus  LC  locus  IVV  fourth cerebral v e n t r i c l e  coeruleus  542-2  343  localized  to  r o s t r a l pole,  t h e locus  coeruleus,  e s p e c i a l l y the  produced s i g n i f i c a n t l y more  potentiation  than e x t r a LC placements.  Effects  Of  6-OHDA L e s j o n s Of-The Dorsal No|adreneraic  Pathway Bilateral saline)  into  injection  of  6-OHDA  the d o r s a l NA  substantial depletions  (4 ug  bundle  (mean=91%) o f hippocampal NA. As  s p i k e response. In t h e same  stimulation  of  significant potentiation for  LC  i n 6-  t r e a t e d r a t s d i d not s i g n i f i c a n t l y p o t e n t i a t e the  population pulse  2 ul  resulted i n  shown i n F i g . 9-5 e l e c t r i c a l s t i m u l a t i o n of OHDA  in  PP  continued  animals to  produce  i n d i c a t i n g that the  i n c r e a s e i n amplitude was not e l i m i n a t e d  paired a  capacity by 6-OHDA  l e s i o n s . I t i s noteworthy that t h e only l e s i o n e d animal i n which a low degree  ( 120- 125%)  of  potentiation  was  observed had t h e l e a s t e f f e c t i v e d e p l e t i o n o f NA (30%).  344  ££<LL. 2Z §i I l f e c t s Of 6-OHDA On  The Besnonse  To LC  Stimulation^ _A:  amplitude  of  the test  p l o t t e d as a f u n c t i o n o f interval.  The  population  spike  condition-test  (C-T)  v e r t i c a l bars i n d i c a t e standard  e r r o r s of t h e mean. Bjj. o s c i l l o s c o p e t r a c e s o f c o n t r o l (LC-PP) population amplitude stimulation not  spikes  i s increased of  LC  (PP) and t e s t  i n d i c a t i n g that following  in control  spike  electrical  (top photo) but  i n 6-OHDA l e s i o n e d r a t (lower photo) .  LC-PP  PP LC-PP C - T (msec)  346  94 X  Discussion  E f f e c t s Of LC In  S t i m u l a t i o n On G - c e l l  contrast  to the i n h i b i t i o n observed  single pulse stimulation delivered  to  Discharge  the  LC  of  the  did  MB,  single  not r e l i a b l y  were  much  more  i n h i b i t i o n o f 55% o f t h e consistently  less  train.  However,  trains  usually  increase i n neurone.  than  30  resulted  studies  neurones  { P h i l l i s and  s t u d i e s do n o t twitches.  and  LC  firing  is  whether  Phillis  reveal  a higher background  being  recordad.  fin  and  latencies  the onset  of  the  to and  cortical these  observed  facial  ( S e g a l and  Blocm,  Kostopoulos, discharge  that  inhibit  1976) . However  they  an  recorded  indicated  1974)  of  repetitive  movements and  Nevertheless, their records  F i g . 2;  in  reguired  Bloom,  1974b  resulting at  also  Kostopoulos,  report  of  with  facial  have  r e p e t i t i v e s t i m u l a t i o n o f LC (Segal  of  in  background  Previous  cells  Trains  msec f o l l o w i n g  stimulation  the  hippocampal  effective  dentate  volleys  i n f l u e n c e the  discharge of the m a j o r i t y of dentate c e l l s . stimuli  following  of  1976  F i g . 1)  the  neurone  i n c r e a s e i n d i s c h a r g e r a t e may  be  r e l a t e d t o a c t i v a t i o n of a d j a c e n t sensory-motor r e g i o n s due  to current spread  stimulation  (Bagshaw  resulting and  reasons  high  frequency  E v a n s , 1976). T h i s i n c r e a s e d  r a t e of discharge could obscure  The  from  LC-evoked  t h a t s t i m u l a t i o n o f LC  inhibition.  with  repetitive  347  s t i m u l i a t low i n t e n s i t i e s i s more single  effective  a  strong v o l l e y may be due t o the o r g a n i z a t i o n of  the LC and i t s mode of t e r m i n a t i o n cells.  than  Anatomical  upon  the  recorded  i n v e s t i g a t i o n s have r e v e a l e d t h a t a  r e l a t i v e l y s m a l l p o p u l a t i o n of LC c e l l  bodies  (estimate  range between 1400-2000) g i v e r i s e t o t h i n unmyelinated axons which b i f u r c a t e c o n s i d e r a b l y t o terminate  i n wide  r e g i o n s o f t h e f o r e b r a i n (Fuxe, 1965; Ongerstedt, 1971; Swanson Perhaps  and  Hartman,  repetitive  1975 ;  stimulation  p r o b a b i l i t y o f conduction number  of  axon  Jones  overcomes  1977 ) . the  f a i l u r e inherent i n a  bifurcations  absence of acceptable  et a l ,  (Hall,  high large  1974).  In t h e  r e p o r t s on t h e discharge  patterns  of i d e n t i f i e d LC neurones no comparisons can be made a t t h i s time between optimal the LC was  spontaneous  stimulation  parameters  or p h y s i o l o g i c a l discharge  pattern of  neurones. I n the present study the number of kept minimal  (3-5 pulses)  whereas i n other  (Segal and Bloom, 1974b) very long seconds)  and  trains  pulses reports  (up  to  10  were used. Such d i f f e r e n c e s make i t d i f f i c u l t  to compare the l a t e n c i e s ,  potencies  and  duration  of  evoked responses between s t u d i e s . In  light  of  the  diffuse  distribution  t e r m i n a l s i n the dentate,  special  care  was  i d e n t i f y the c e l l s that were r e c o r d e d . , T h i s the  inclusion  the purposes  of only 15 c e l l s recorded of  monosynaptically  data  analysis.  of  taken  NA to  resulted i n  in 8 ratsfor  A l l 15  cells  were  a c t i v a t e d by PP s t i m u l a t i o n , i n h i b i t e d  348  by  MR  and  were l o c a l i z e d  to the  v i c i n i t y of the  G-cell  l a y e r . These c r i t e r i a suggest that these c e l l s were fact  G - c e l l s , however, i t i s not p o s s i b l e t o determine  whether pulse  the LC  input  inhibition  stimulation  observed was  Conditioning increase spike  in  On  PP-evoked Bespouses of  LC  the amplitude of the  without a l t e r i n g the PP-evoked EPSP. The  control)  pulses  was  pulse  amplitude or  e f f e c t i v e C-T  maximum  observed  stimulating  supports  a  was  time  conditioning  observed The  to  of  (150-175%  following  observation  r e l a t e d to the  electrode  an  i n t e r v a l s ranged  potentiation  of LC.  in  population  rise  f o l l o w i n g 3-5  stimulation  the degree of p o t e n t i a t i o n of the  resulted  PP-evoked  whereas no p o t e n t i a t i o n was  single  on  multiple  mediated by a monosynaptic  stimulation  between 20-80 msec and of  following  d i r e c t l y onto G - c e l l s .  E f f e c t Of LC S t i m u l a t i o n  the  in  LC  that  proximity  proper  further  s p e c i f i c a c t i o n of t h i s p a r t i c u l a r nucleus  PP-evoked  observation  population that  hippocampal  NA  6-OHDA  block  spike.  The  injections  the  additional  which  potentiation,  deplete strongly  suggests involvement of a noradranergic system. Since amplitude increase  potentiation was in  not the  l i k e l y t o be due  of  accompanied rate  of  the by  population a  spike  concomittant  r i s e o f the EPSP i t i s not  to the a c t i o n of LC on the  entorhinal  349  cortex  or  the  r e g i o n o f the PP synapse on the d i s t a l  d e n d r i t e s of G - c e l l s . In t h i s r e s p e c t the a c t i o n s o f LC s t i m u l a t i o n on PP-evoked responses may those  be  similar  observed f o l l o w i n g s t i m u l a t i o n of other  to  extrinsic  a f f e r e n t s i n c l u d i n g t h e commissural input and the MB.  9.J5  Summary E l e c t r i c a l s t i m u l a t i o n o f LC caused an i n c r e a s e i n  the  amplitude of the dentate  evoked by a  test  stimulation  did  of  rise  of  mechanisms  PP  p o u l a t i o n s p i k e which was  volley.  The  same  not r e s u l t i n an i n c r e a s e i n the r a t e  the  could  EPSP not  suggesting account  that  dorsal  NA  bundle  presynaptic  f o r enhancement of the  p o p u l a t i o n s p i k e response. I n j e c t i o n s the  conditioning  resulted  of in  depletion  and  abolished  stimulation  on  the  population spike response. On t h e  these  noradrenergic the dentate  data,  i t  was  proposed  system modifies neuronal gyrus.  of  of  NA  of  effects  into  hippocampal  basis  the  6-OHDA  that  LC  a  transmission i n  350  CHAFER I P i GEJERAI DISCUSSIQSJThe thesis  r e s u l t s o f t h e experiments d e s c r i b e d have  demonstrated  noradrenergic  systems  respectively,  originating  modulate  response of G - c e l l s t o path and  (PP)  input.  previous  presented  that  RSA  this  serotonergic  and  in  and/or  stimulation  MS  and  the  of  the  LC,  population perforant  D e t a i l e d d i s c u s s i o n s of the present  data which support  at  in  t h e end  of  this  conclusion  each chapter.  p h y s i o l o g i c a l i m p l i c a t i o n s of the present  were  However, the data and  how  they r e l a t e to e x i s t i n g concepts of the f u n c t i o n a l r o l e of the hippocampal formation Previous  have not been  electrophysiological  discussed.  and  behavioural  s t u d i e s have emphasized that RSA may r e f l e c t or p r e d i c t 1)  a c t i v i t y of other b r a i n areas such as the  and  t h e s e p t a l area  al,  (Green and A r d u i n i , 1954; Petsche e t  1962) 2) overt behaviour (Vanderwolf, 1 969;  1975)  and 3) i n f e r r e d mental processes  and RSA  neocortex  0'Keefe, 1974) . However,  Ranck,  (Gray, 1970; Hadel  t h e mechanisms  underlying  and the involvement of s p e c i f i c neuronal systems i n  this  response  have  recieved  little  c o n t r a s t , hippocampal p o p u l a t i o n well  characterized  (Gloor  Lomo, 1966; Lomo, 1971a) their  magnitude  investigated Andersen  et  and  attention.  responses  have  In been  a l , 1964 ; Andersen and  mechanisms  which  alter  were, and continue t o be, e x t e n s i v e l y  (Lomo,  1971b  Bliss  and  Lomo,  1973;  e t a l , 1977; Lynch e t a l , 1977; Dunwiddie and  351  Lynch, 1978). More r e c e n t l y , s t u d i e s which examine  the  r e l a t i o n s h i p between hippocampal p o p u l a t i o n responses , behaviour Miller  (Winson  and  Abzuq, 1978)  and RSA  {Assaf  i n p r e p a r a t i o n ) have been i n i t i a t e d . ,  The which  present  could  distinct  the DG  t h e s i s has  1)  delineated  u n d e r l i e the e f f e c t s of  neuronal  activity  and  systems  on  hippocampal  such as the commissural i n p u t  amplitude  projection  of  Furthermore,  the the  (Chapters  PP-evoked  observation  mechanisms  pharmacologically  2) i n d i c a t e d t h a t e x t r i n s i c  monoaminergic  electrical a f f e r e n t s to  {Chapter  spike,  also  produced  population that  hippocampal  suggests that the magnitude response  may  be  related  of to  the  neuronal  systems,  brainstem,  electrical  T o r i i , 1961;  studies  the  did  population  population  activity.  Activity that  originating  characteristic activity  (Green  distinct in  patterns and  elucidate  the of  Arduini,  d i s t i n c t neuronal  anatomically  or  systems t h a t could  serve as a model f o r s t u d y i n g the mechanisms  J  spike  Macadar et a l , 1974). However, these  not  pharmacologically  spike.  desynchronization  postulated  probably  mediate  hippocampal  had  the  a raphe s e r o t o n i n  lQ.x.1 P a t t e r n s Of Hippocampal E l e c t r i c a l studies  and  or dependent on ongoing  p a t t e r n s of hippocampal e l e c t r i c a l  Previous  7)  8 and 9) a l t e r  system, wich i n c r e a s e d the amplitude of the  1954;  and  mediating  352  the  d i f f e r e n t patterns.  serotonin-containing has  facilitated  within  the  response.  present  system produced  area  postulated  inhibition  of  subseguent  disruption  that  irregularly  1962)  1969)  of  could  underlie  firing  present other  in  I-neurones  and  the b u r s t i n g of B-neurones, anatomical  (Tombol  and  and e l e c t r o p h y s i o l o g i c a l {Petsche et a l ,  the  medial  data d i d not  population  s e p t a l nucleus.  eliminate  the  of  Althouqh  possibility  the that  i n t r a - a n d e x t r a s e p t a l mechanisms can u n d e r l i e  desynchronization,  they provide  r e a d i l y t e s t e d . The  a d d i t i o n a l observations  neurones  may  discharge  patterns  2)  this  which i n c l u d e d  s t u d i e s i n d i c a t i n g a heterogenous  neurones  that a  desynchronization  mechanisms,  were c o n s i s t e n t with previous Petsche,  observation  the d e l i n e a t i o n of neuronal mechanisms  septal The  The  kainate  be  a model which could  bodies  intra-  and  1974),  simulation  specifically. response  and  without  Miller,  1978d)  e x t r a s e p t a l mechanisms i n the generation  The  could  desynchronization  of  acitivty.  the b a s i s of previous LC  MS  f a c i l i t a t e f u t u r e s t u d i e s on the r o l e of  hippocampal e l e c t r i c a l  On  be  their  or t h e i r hippocampal p r o j e c t i o n s  l e s i o n s , which destroy c e l l  RSA,  t h a t 1)  d i f f e r e n t i a t e d on the b a s i s of  i n f l u e n c i n g f i b e r s of passage (Assaf and eliminate  the  was  neuronal  reports expected  (Macadar to  mechanisms  then reulting  be  al,  produce  BSA  mediating  compared from  et  MR  with  this the  stimulation.  However, the r e s u l t s of chapter 5 i n d i c a t e d that 6-OHDA  353  injections RSA  which  depleted  f o r e b r a i n NA  d i d not b l o c k  e l i c i t e d by s t i m u l a t i o n i n the region  additional  observation that e l e c t r o l y t i c  d i d not a b o l i s h RSA system  of  may  not  that  The  l e s i o n s of LC  examination  of t h i s  be s u i t a b l e f o r d e l i n e a t i n g mechanisms  which mediate RSA. confirmed  suggested  LC,  These f i n d i n g s , which were  by Robinson  recently  (1978) i n the f r e e l y moving r a t ,  do not e n t i r e l y e l i m i n a t e noradrenergic involvement the  generation  of  RSA  since:  d i f f u s e region i n the v i c i n i t y RSA,  thus  the  noradrenergic  effects component  1) of  stimulation LC  of  6-OHDA  may  be  also  nuclei  masked  3)  and may  multiple  (reviewed  in  generation  or  NA-containing  section  of  RSA  and  response.  1. 3)  are  implicated  threshold initiated  be c r i t i c a l f o r the generation  may  for a particular  as  Gray  result  neuronal activity  reflected  from  the  freguency  lower  (7.7 Hz) of  by the output  interaction  the  a  manner  physiological states.  of of  between  appropriate  the  which i s septal  of B-neurones,  systems which modulate hippocampal in  the  and h i s c o l l e a g u e s  by the s e p t a l a r e a . A c t i v i t y  perhaps  in  none of them, with exception  Perhaps,  of  postulated transmitters  (1975) have proposed, noradrenergic systems  area,  a  even  be i n v o l v e d i n the generation  pathways and  the s e p t a l area, may this  on  l o c a t e d caudal to LC p r o j e c t t o the s e p t a l area  (Moore, 1978) RSA  in a  initiates  injections  compensated f o r by these other systems 2)  in  to  various electrical ongoing  354  10 «_,2  The  Significance  Of  HifiEocamgal  Population  Responses, Previous s t u d i e s  (Gloor  taken together with the the  interpretaion  the  direct  following  amplitude  of  Steward  et  studied  either  Hz)  al,  support  PP s t i m u l a t i o n  e n t o r h i n a l cortex  reflect  on  dentate  the  population  1976).  extracellular  EPSP  Gardner-Hedwin,  This  1973)  period  ( u s u a l l y 1-3  long-term and  spike  of  or  has  been  of r e p e t i t i v e  seconds a t 50-100  potentiation  population  spike  following  of  (Bliss a  the  and  the  ( l e s s than 1 second) period  of time (Lomo, 1971b; Steward e t a l , 1976). Since  in  the  single  v o l l e y which produced p o t e n t i a t i o n of  same parameters f o r a short  s h o r t and  PP  (Lomo, 1971b;  potentiation  following a brief  which r e s u l t e d i n  stimulation  i n the rate of r i s e of the EPSP  stimulation  conditioning  6,  p o t e n t i a l s recorded  that p a i r e d - p u l s e  r e s u l t e d i n an i n c r e a s e  conditioning  Lomo, 1971a),  I n t e r e s t i n these responses stemmed from  the o b s e r v a t i o n s  and  the f i e l d  a c t i o n of the  granule c e l l s .  1964;  r  r e s u l t s of chapter  that  e x t r a c e l l u l a r l y i n DG  et a l  both  long-term p o t e n t i a t i o n have been demonstrated PP-dentate p r o j e c t i o n and  there  i s no  evidence  to i n d i c a t e t h a t d i f f e r e n t fundamental  mechanisms  are  involved,  purpose  the  we  will  assume,  for  the  of  present d i s c u s s i o n , t h a t they share common mechanisms.  Initially transmitter  it  release  was  proposed  underlies  the  that greater  auqmented synaptic  355  c u r r e n t and cells  subsequent i n c r e a s e i n  evoked  by  the  test  PP  the  number  pulse  of  (Lomo, 1971b),  P r e v i o u s s p e c u l a t i o n s that an i n c r e a s e d q u a n t a l of t r a n s m i t t e r accounts f o r of  neuromuscular  Liley,  1956)  post-tetanic  transmission  provided  However, i n the i n i t i a l s t u d i e s Lomo, 1973)  release  potentiation  ( E c c l e s and B a l l ,  impetus  for  this  (Lomo, 1971b; B l i s s  in  the  Lomo(1973) and B l i s s mechanisms  current  could  postsynaptic  suggestion LC  than the  responsiveness  of  spike  to  the  f o r the  the  amplitude  without same  of  altering  animals,  PP i t s e l f  the  latter  the  transmission  PP-evoked PP  synaptic  conditioning  potentiated  pulses  both the EPSP imply  that  from the e n t o r h i n a l c o r t e x to DG  could be modulated by e i t h e r 1) p r e s y n a p t i c  2)  the  c o n d i t i o n i n g s t i m u l a t i o n of Comm, MR  and the p o p u l a t i o n s p i k e . These o b s e r v a t i o n  which  proposed  augmentation of s y n a p t i c  t h e s i s provides support  p o t e n t i a l . In the  neuronal  and  calls.  increases  delivered  absence  For t h i s reason. B l i s s  (personal communication)  enhance  since  population  EPSP.  other  The present  and  and  i n c r e a s e s i n the amplitude of the PP-evoked  changes  that  1951;  proposal.  p o p u l a t i o n spike were sometimes observed i n the of  G-  mechanisms  i n c r e a s e the e f f i c i e n c y of the a f f e r e n t i n p u t postsynaptic  responsiveness mechanisms. potentiation  of Both  mechanisms the  enhance  the  r e c e i v i n g c e l l or i t s e f f e c t o r  mechanisms  observed  which  or  during  could  account  for  the  paired-pulse stimulation  356  of  the  PP  account  but  only  f o r the  following  postsynaptic  increase  mechanisms  i n population  conditioning pulses  to  spike  could  amplitude  extrinsic  afferents  which d i d not a l t e r the EPSP. The the PP  e f f e c t s of stimulating e x t r i n s i c a f f e r e n t s  cn  evoked responses have not been s t u d i e d i n d e t a i l  p r e v i o u s to the present work. However, Lomo (1971b) shown t h a t c o n d i t i o n i n g  s t i m u l a t i o n of the mossy  has  fibre  system, which a n t i d r o m i c a l l y a c t i v a t e s G - c e l l s , r e s u l t s in  an  increase  population  in  spike  the  Alvarez  and  of  chapters  the  rate of  evoked  rise  s t i m u l a t i o n of  7-9,  number  constant PP  synaptic  mechanisms  can  suggest than  of  the  These data, taken together with  s t i m u l a t i o n of s i t e s other increase  the PP  Gardner-Medwin (1976)  a s i m i l a r e f f e c t following  medial s e p t a l area. results  of  without changing the  EPSPs. More r e c e n t l y , reported  amplitude  that  the  PP  the  conditioning can  somehow  of G - c e l l s which are evoked by a current.  not  Therefore  account  for  presynaptic  the  observred  potentiation. Postsynaptic  mechanisms t h a t could account f o r  increase  in  the  include  1)  activation  which p a r t i a l l y al,  1967)  the PP  and  amplitude  of  of  depolarize  the  population  excitatory  interneurones  2) removal of f a c t o r s normally  interneurones  spike  the G - c e l l soma (Andersen et  from evoking a given G - c e l l . The  excitatory  the  is  unlikely  preventing  contribution since  in  of the  357  present  study  p o t e n t i a t i o n i s observed i n the  of any e x c i t a t i o n . Moreover, t h e r e i s no the  existence  of  excitatory  immediate v i c i n i t y o f feature  of  all  potentation  of  inhibition of MS,  of  evidence  interneurones  G-cells.  In  absence  fact,  for  in  the  the  common  the i n p u t s p r e s e n t l y shown to produce the  population  spike  response,  is  G - c e l l s e i t h e r d i r e c t l y , as i n the case  or subsequent to an a c t i v a t i o n as i n the case cf  the PP and commissural i n p u t s . The  r e l a t i o n s h i p between i n h i b i t i o n of G - c e l l s and  p o t e n t a t i o n of the p o p u l a t i o n most  detail  following  p a r t i c u l a r nucleus was  not  stimulation  produced a potent  preceded  by  activation.  i n h i b i t i o n of G - c e l l s was degree  of  spike  related  potentiation.  was of  MB  The the  in  since t h i s  inhibition  to  Several  examined  which  duration  cf  length  and  mechanisms  could  account f o r t h i s apparent paradox between depression  of  spontaneous G - c e l l d i s c h a r g e and  f a c i l i t a t i o n of the  PP  evoked  the  population  spike.  At  simplest  i n h i b i t i o n of a l a r g e number of G - c e l l s may random  activity  discharge the  thereby  allowing  of  the  population  reset their  a more synchronous  i n response to a prepotent  amplitude  level  PP  volley.  Since  spike r e f l e c t s , in  p a r t , the synchronous discharge of a l a r g e number of cells,  it  mechanism  will may  be also  septal-hippocampal (1975)  enhanced., be  operative  activity.  had suggested e a r l i e r ,  This  synchronizing  during  Perhaps,  G-  as  rhythmical Vinogrova  information a r r i v i n g via  358  the PP i s modulated by the b u r s t i n g  discharge  pattern  of s e p t a l or hippocampal neurones.  lQ.i.3  Mctivitj  BfeltliliSSl  And  Neuronal  Transmission  I:Q_t h e_Den tat e_ Gyrus The  d i s c u s s i o n t o t h i s point has  mechanisms increase  w i t h i n the dentate  the  amplitude  the  An  population  s p i k e response as the output  the  output  mossy  fibre  approach  system  is  onto  to  spike  regard  o f the  CA3.  Perhaps t h i s ongoing  p h y s i o l o g i c a l s t a t e s by a d j u s t i n g the responsiveness G-cells.  As  indicated  i n F i g . 10-1,  r e g i o n would play a  pivotal  role  almost  dentate  output  the  entire  connections  with  the  connections mossy  through the  fibre  since and has  septal as  A  the  of CA3  receives  both d i r e c t  and  area.  in  the  via  systems  output,  it  dentate  associational/commissural  the  dentate  i s r e g u l a t e d i n a manner a p p r o p r i a t e to  dentate  to  which could  population  response.  via  limited  gyrus i t s e l f  of  additional  been  the indirect  decrease  case  of  in  G-cell  i n h i b i t i o n , would i n i t i a t e mechanisms t h a t enhance  the  population  The  spike  response  d i r e c t feedback may  be  a  mediated  d e p o l a r i z a t i o n of proximal enhancing  to  given by  PP input.  changes  in  d e n d r i t e s of G - c e l l s  thereby  or shunting PP s y n a p t i c c u r r e n t generated  the d i s t a l d e n d r i t e s . attenuate  the  input  discharge  pattern  of  The  indirect by  septal  septal  initiating neurones  the  the  loop  on may  bursting  (McLennan  and  359  fTGj. 10- 1: grpgosed E x t r i n s i c I n f l u e n c e s Transmission The may  Neuronal  In The Dentate Gyrus.  s o l i d l i n e s i n d i c a t e that information  be t r a n s m i t t e d from t h e  {EC)  On  to  the  p e r f o r a n t path  dentate  entorhinal  gyrus  via  the  (PP). The output from DG i s  via  the  mossy f i b r e system  (MF)  the  hippocampus.  dotted  The  (DG)  cortex  onto CA3 r e g i o n o f lines  indicate  p o s s i b l e feedback c o n t r o l of EC-DG t r a n s m i s s i o n by  CA3  system,  via the  brainstem NA  the  medial  associational/commissural septal  area  (MS)  and 5-HT-containing systems.  and  3 £ 0  1  I  ro  <  (J o o co co  o o  >  ~ n i i i i i i i  I  Q  em -HI  «  \  c CO lO CO  Q_  L _  O Ld  <  361  Miller,1976)  which may then 'gate*  (Vinogradova,  1975 ) .  by the i n d i r e c t s e p t a l output the  to  ongoing  the incoming PP i n p u t  The a d d i t i o n a l f e a t u r e o f f e r e d loop  would  be  to  match  CA3  p h y s i o l o g i c a l states which produce  characteristic  discharge  patterns  of  septal  neurones (chapter 3). The  recent  findings  of  behaviourally  specific  m o d i f i c a t i o n o f the PP evoked population s p i k e the  above  suggestions  (Winson  Moreover, p r e l i m i n a r y experiments 1978e)  show  that  the  and  Abzug,  (Assaf  amplitude  of  support 1978).  and  the  Miller,  PP  evoked  p o p u l a t i o n s p i k e i s dependent on the ongoing p a t t e r n of hippocampal discharge.  electrical If  activity  and  septal  unit  t h e PP i s s t i m u l a t e d during BSA or when  B-neurones are b u r s t i n g the amplitude of the p o p u l a t i o n spike i s r e l i a b l y PP  s m a l l e r than t h a t evoked by the  volley  delivered  desynchronization.  It  Winson  (1978)  and  Abzug  is  during interesting report  that  same  hippocampal to  note  that  the PP evoked  population s p i k e i s s m a l l e s t when the f r e e l y moving r a t i s i n an a l e r t or aroused s t a t e and l a r g s s t during slow wave s l e e p . Previous  s t u d i e s have shown t h a t BSA  during a l e r t s t a t e s  and  desynchronized  hippocampal a c t i v i t y i s recorded  or  occurs  irregular  during slow wave s l e e p  (Vanderwolf, 1972; Robinson, 1978). Taken dentate  together  these  studies  suggest  t r a n s m i s s i o n may be enhanced d u r i n g  t h a t PP-  hippocampal  362  d e s y n c h r o n i z a t i o n and noteworthy neocortex in  that  attenuated  when  electrical  c o n s i s t s of desynchronized  arousal  prominent  states,  in  Arduini,  the  of  compensatory  septal-hippocampal  axis  cortico-hippocampal-thalamic implication  long-term  of  potentiation  slow  activity  is  (Green  and  formation  reciprocity i s a within  maintain  this  constancy  extrinsic  relay  PP-dentate  inputs  this  and  Likewise,  whether  transmission  understanding to  information  septal  c o n t a i n i n g n u c l e i modify t h i s  area  overall nature  2) where does the and  3)  to the hippocampal formation  those o r i g i n a t i n g i n the  of  i s an i n t e g r a l component of i t  the i n f o r m a t i o n r e l a y e d by the PP,  hippocampus  the  constancy  b r a i n f u n c t i o n depends on knowing 1) what i s the of  the  transmission.  must await f u r t h e r experiments. the relevance of  of  is  as  mechanisms  which  It  fast activity,  rhythmical  hippocampal  RSA.  activity  1954). 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