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Physiological and pharmacological studies of the feline thalamus Marshall, Kenneth Christie 1971

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PHYSIOLOGICAL AND  PHARMACOLOGICAL  STUDIES OF THE FELINE  THALAMUS  by  KENNETH CHRISTIE MARSHALL B.Sc,  University  o f T o r o n t o , 1961  M.Sc,  University  o f Toronto,  1967  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS  FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY  In  t h e Department of PHYSIOLOGY  We a c c e p t t h i s required  thesis  as c o n f o r m i n g  to the  standard.  THE UNIVERSITY OF BRITISH COLUMBIA F e b r u a r y , 1971  In p r e s e n t i n g t h i s  thesis  an advanced degree at the L i b r a r y s h a l l I  f u r t h e r agree  in p a r t i a l  fulfilment of  the U n i v e r s i t y of  B r i t i s h Columbia,  make i t f r e e l y a v a i l a b l e  that permission  the requirements f o r  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 g r a n t e d by the Head o f my Department o r by h i s of  this  written  representatives; thesis  for  It  financial  i s understood that copying o r p u b l i c a t i o n gain s h a l l  permission.  Department of  s/,o t o <*• y  The U n i v e r s i t y o f B r i t i s h Vancouver 8, Canada  Columbia  not be allowed without my  PHYSIOLOGICAL.AND  PHARMACOLOGICAL  STUDIES  OF THE F E L I N E THALAMUS  ABSTRACT  The ventralis  drug  sensitivity  lateralis  o f neurones o f the Nucleus  (VL) o f t h e t h a l a m u s , and t h e i r  a c t i v a t i o n by e l e c t r i c a l  stimulation  (BC),  and e n t o p e n d u n c u l a r n u c l e u s ,  has  precruciate  been s t u d i e d  Cells  evoked w i t h  particularly applied with did  short  latency  and i n d e c e r e b r a t e  (EN)  cats.  by BC s t i m u l a t i o n were  (ACh) and L - g l u t a m a t e  o f more d o r s a l  thalamic n u c l e i . sensitivity  and N - m e t h y l a s p a r t i c a c i d .  glutamic acid  (LG) when  compared  The VL n e u r o n e s t o DL-homocysteic  The a - m e t h y l  derivative  (a-MG) was f o u n d i n many c a s e s t o d e p r e s s  t h e e x c i t a t i o n o f t h a l a m i c n e u r o n e s by LG, b u t had  e f f e c t on ACh e x c i t a t i o n .  effects  conjunctivum  s e n s i t i v e t o e x c i t a t i o n by i o n t o p h o r e t i c a l l y  acetylcholine  cells  or b l o c k no  i n anesthetized  n o t e x h i b i t s u c h an e n h a n c e d  acid of  cortex  of brachium  synaptic  of other e x c i t a t o r y  a MG  sometimes d e p r e s s e d t h e  amino a c i d s ,  but to a l e s s e r  d e g r e e t h a n t h o s e p r o d u c e d by LG.  Short  latency  r e s p o n s e s evoked  s i n g l e a c t i o n p o t e n t i a l and l a t e  i n VL by BC o r c o r t i c a l  stimulation  burst  have  been r e p o r t e d study.  by  anesthetized  in  VL  and  shorter  the  EN  latency  amino a c i d s  stimuli  could  alter  reverse  Intravenous t h e s e ACh evoked  could  their the  synaptic  blocked  synaptic  ACh  but  response  i n VL  motor c o r t e x  mediated, but  o f EN  part  of  VL  and  cortex the  N.  rise  I t was t o VL  the  to  of  cortical  evoked  atropine  and  cells  and the  may  responses. blocked  field  BC  response  concluded t h a t the  be  but  atropine  0.5-1.0 mgm/kgm a l s o  are  and  responses  e x c i t a t i o n o f VL  o f EN  neurones..  to c o l l a t e r a l  cell  medial parts  a c t i v a t i o n by  pathways  u n l i k e l y t o be c h o l i n e r g i the  a-chloralose  centrum-medianum.  evoked  early  iontophoretically applied  synaptic  cerebello-thalamic  and  e x c i t a t i o n i n VL give  converted  w i t h o u t a f f e c t i n g the  t h a t ACh  Pentobarbital o f ACh  be  only  response  i n a d d i t i o n markedly reduced the  f r o m EN  at l e a s t  BC  Both the  a c t i v a t i o n , although  i n doses of  stimulation.  for  could  ACh  depression  to c o r t i c a l  cally  by  msec.  Iontophoretically applied  effects,  and  4-22  e i t h e r e x c i t e or depress the  atropine  field  and  ACh.  stimulation.  not  this  s t i m u l a t i o n evoked b u r s t  single spikes  dihydro-3-erythroidine did  EN  l a t e n c i e s of  facilitated but  in  r e s p o n s e s w h i c h were o b s e r v e d  evoked r e s p o n s e s  and  ACh  t o EN  animals.  neurones with  were c o n f i r m e d  found t h a t both c o r t i c a l  evoked e a r l y b u r s t  in  BC  w o r k e r s and  However, i t was  stimulus  burst  other  transmitter  pathway.  were p o t e n t  I t was  blockers  shown t h a t  neurones  axon b r a n c h e s w h i c h p r o j e c t Stimulation responses  of  i n the  to  sensori-motor lateral,  centrum medianum-Parafascicular  but  not  comple  TABLE OF CONTENTS Page Introduction Anatomy - Nucleus  Ventralis Lateralis  - Nucleus  C e n t r u m Medianum  1 14  Electrophysiology - Nucleus  Ventralis Lateralis  17  R o l e s o f VL and CM Iontophoresis thalamic  37  and t h e p h a r m a c o l o g y neurones  *  of  ......  Parkinson's Disease  40  ;  48  Cholinesterase  52  Methods Preparation  o f animals  Stereotaxic  procedure  55 w  ?.  i  59  Electrodes......  61  Equipment  i i  Histology  ^  66 70  Results Nucleus  Ventralis  Lateralis  - Electrophysiology  75  -.Effect  85  Nucleus  o f drugs  C e n t r u m Medianum  118  Entopeduncular Nucleus Discussion.  122 i  Summary and C o n c l u s i o n s . Bibliography  126 *  * ......  ...... . ;  144 147  L I S T OF  TABLES Page  I.  Drug S o l u t i o n s  II.  E f f e c t s of Cholinergic Blocking EN-Evoked C e l l s  Used  for Iontophoresis Agents  65 on 109  ii. L I S T OF  FIGURES  Figure  Page  1.  Spontaneous  2.  Model  3.  Decerebrating  4.  Concentric  5.  Five-barrelled iontophoresis  6.  Block diagram f o r iontophoresis ing  bursting  f o r thalamic  of thalamic  bursting  neurones  activity...  20 20  electrodes  61a  bipolar stimulating  electrode  electrode and  61a 68  record--  equipment  68  7.  Spot marking  t i p of steel  recording  8.  Spot marking  t i p of glass  electrode  71  9.  Photograph of frozen b r a i n  section  73  10.  Spontaneous  11.  BC-evoked  12.  BC-induced b u r s t i n g  13.  Cortically-evoked  14.  Cortical-induced  15.  Antidromically  16.  EN-evoked p r e s y n a p t i c  17.  EN-evoked s p i k e  18.  Mean l a t e n c i e s o f E N - e v o k e d VL n e u r o n e s .  86  19.  ACh  e x c i t a t i o n o f VL n e u r o n e s  86  20.  ACh  depression  21.  BC  stimulus  depression  o f ACh-induced  firing...  89  22.  EN  stimulus  depression  of ACh-induced  firing...  89  23.  ACh  bursting  electrode..  o f VL n e u r o n e s  78  r e s p o n s e s i n VL  78  i n VL  80  r e s p o n s e s i n VL bursting  80  i n VL  82  a c t i v a t e d VL n e u r o n e field  82  r e s p o n s e i n VL  r e s p o n s e s i n VL  of b u r s t i n g  facilitation  71  thalamic  o f BC-evoked  firing  84 84  neurones...  88  91  iii. Figure 24. 25.  26. 27. 28.  Page ACh c o n v e r s i o n o f c o r t i c a l l y - e v o k e d b u r s t to s i n g l e spike response  91  ACh c o n v e r s i o n o f E N - e v o k e d b u r s t spike response  93  E f f e c t o f ACh response  and  DLH  on  to  EN-evoked  spike 93  S e n s i t i v i t y of thalamic amino a c i d s  n e u r o n e s t o ACh n e u r o n e s by  29.  Excitation  n e u r o n e s by  30.  E f f e c t o f i o n t o p h o r e t i c a t r o p i n e and ACh-induced f i r i n g ;  32.  of thalamic  ACh ,  99 LG...  DH£E  99  on 100  E f f e c t o f i o n t o p h o r e t i c a t r o p i n e on c o r t i c a l l y - e v o k e d neurone  BC-  and 10 3  o f i o n t o p h o r e t i c DH$E on  33.  Effect  of  34.  E f f e c t o f I.V. a t r o p i n e on evoked r e s p o n s e .  BC-  E f f e c t o f I.V. d i s c h a r g e •.  EN-evoked  36.  and  DG. and  Effect spike  35.  and 97  E x c i t a t i o n of thalamic amino a c i d s  31.  single  BC-evoked 105  I.V.  atropine  atropine  on  on  BC-evoked r e s p o n s e ! . and  neurone 107  37.  Effect  o f a-MG  and  38.  Effect  o f a-MG  on d r u g - i n d u c e d  39.  Effect  of strychnine  of  cortically105a  E f f e c t of i o n t o p h o r e t i c atropine EN-evoked neurone d i s c h a r g e  of drug-induced  105  NMG  on  on  and  DHftE  on 108  LG-induced  firing.... I l l  firing  BC-evoked  I l l  depression  firing  40.  Effect  a - c h l o r a l o s e on  41.  E f f e c t o f p e n t o b a r b i t a l on firing.  113 drug-induced drug-induced .  firing..  113'  114  iv. Figure  Page  42.  E f f e c t o f t h i o p e n t a l on drug-induced  43.  E f f e c t o f t h i o p e n t a l on l a t e n c y induced f i r i n g . .  of  firing....  116  drug117  44.  Effect of pentobarbital  on BC-evoked c e l l s  117  45.  Cortically-evoked  field  responses  120  46.  Cortically-evoked  cell  47.  C o l l i s i o n o f VL- and CM-evoked a n t i d r o m i c a c t i v a t i o n o f EN n e u r o n e e  response  i n CM...  i n CM  123  123  L I S T OF  ACh AL BC CL CM CNS DA DG DH(3E DLH EN EPSP GABA HC1. 5HT IPSP I.V. kg L. L-dopa LG L-Glut. LGN LP LSD M MA MD mg min ml mm MRF msec mV MS N NA nA NMA NMG NR N.retic P PAE Pf PSP RF sec  ABBREVIATIONS  acetylcholine ansa l e n t i c u l a r i s brachium conjunctivum Nucleus c e n t r a l i s l a t e r a l i s N u c l e u s c e n t r u m medianum c e n t r a l nervous system dopamine D-glutamic a c i d dihydro-3-erythroidine D,L h o m o c y s t e i c a c i d entopeduncular nucleus excitatory postsynaptic potential y-amino b u t y r i c a c i d hydrochloric acid 5-hydroxy-tryptamine inhibitory postsynaptic potential intravenous kilogram litre L-dihydroxy-phenylalanine L-glutamate o r L-glutamic a c i d L - g l u t a m a t e ( i n f i g u r e s 27,28, 29, l a t e r a l geniculate nucleus Nucleus l a t e r a l i s p o s t e r i o r lysergic acid diethylamide metre milliampere Nucleus m e d i a l i s d o r s a l i s milligram minute millilitre millimetre mesencephalic r e t i c u l a r formation millisecond millivolt megohm nucleus n o r a d r e n a l i n e _^ nanoampere (10 ampere) N-methyl-D,L-aspartic acid N-methyl-D,L-glutamic a c i d red nucleus Nucleus r e t i c u l a r i s thalami probability post-anodal exaltation Nucleus p a r a f a s c i c u l a r i s postsynaptic potential r e t i c u l a r formation second  vi. SN V VA VBC VL VM VPL aMG u yA  substantia nigra volt Nucleus v e n t r a l i s a n t e r i o r v e n t r o b a s a l complex Nucleus v e n t r a l i s l a t e r a l i s Nucleus v e n t r a l i s m e d i a l i s Nucleus v e n t r a l i s p o s t e r o - l a t e r a l i s a-methyl-D,L-glutamic a c i d m i c r o n (10~6 m e t r e ) m i c r o a m p e r e (10~6 ampere)  vii. ACKNOWLEDGMENTS The  w r i t e r wishes t o acknowledge t h e h e l p  p e r s o n s who a s s i s t e d h i m d u r i n g and  preparation of this  Mr.  R. W a l k e r , Mr. R. A s s i n n a ,  Forsyth a l l provided and  thesis.  advice  Garrett,  valuable assistance.  by t h e c a n d i d a t e ' s  D r . R. K e e l e r ,  Sanders i s very  much a p p r e c i a t e d .  beneficial. author's  of data  sincerely  sharing of s c i -  c o m m i t t e e , D r . F.D. and D r . H.B.  The a s s i s t a n c e and e n -  i n a l l p h a s e s o f t h i s work was  The c o n t r i b u t i o n s o f D r . Hugh McLennan t o  education  and concepts  valuable  Mr. P. G r a y s t o n e  The s o u n d a n d c o n s t r u c t i v e  D r . C.N. L o e s e r  couragement o f I l o n a M a r s h a l l  the  Mr. K. Henze a n d M r s . A.M.  and t e c h n i c a l knowledge. provided  work f o r  M r s . Y. Heap, M i s s E . P e t r a l i ,  D r . R.D. H u f f m a n were g e n e r o u s i n t h e i r  entific  very  the experimental  o f many  and l a s t i n g  i n research  of neural  techniques,  f u n c t i o n have p r o v i d e d  benefits of this  appreciated.  interpretation the. most  e n d e a v o u r and a r e  CHAPTER I INTRODUCTION  ANATOMY  Nucleus V e n t r a l i s L a t e r a l i s Definition The continue  nuclei  t o p o s e many p r o b l e m s o f d i f f e r e n t i a t i o n and  nomenclature. earlier  no  criterion  gave r i s e  cytoarchitectural differentiation  t o s e p a r a t i o n o f r e g i o n s w h i c h have  d i f f e r e n c e s i n function or i n f i b r e  conversely  been f o u n d  used o n l y  to differ  i n fibre  connections  i n different  animals  and f u n c t i o n . Organization, t o whole  Nucleus v e n t r a l i s  lateralis  :  has been exposed  thalamic  since  sometimes gave r i s e  new s y s t e m s o f n o m e n c l a t u r e . (VL)  connections,  l e d t o f u s i o n o f r e g i o n s w h i c h have  Because o f s p e c i e s d i f f e r e n c e s . i n studies  has a r i s e n because  and d e f i n e t h e v a r i o u s p a r t s o f t h e t h a l a m u s .  recognized  and  Much o f t h e d i f f i c u l t y  anatomists  to separate This  o f t h e d o r s a l t h a l a m u s have p o s e d , -and  t o these  p r o b l e m s as much as any  nucleus. Walker's thalamus h e l p e d thalamic  [1938] e x t e n s i v e to achieve  terminology.  studies of.the  primate  some measure o f a g r e e m e n t on  H i s d e s c r i p t i o n s were b a s e d  partly  2  on the  cytoarchitecture, t h a l a m u s and  but  also  cortex.  on  Most N o r t h A m e r i c a n  u s e d W a l k e r ' s d e f i n i t i o n o f VL, considered receives nuclei  as  that  part  and  w h i c h has  the  ventral  is  quite  large  by  the  and  of  the  d o r s o l a t e r a l l y by  cerebral  by  l a m i n a and  N.  several  authors  differences the  cells  o f VL  are  (VPL)  N.  N.  connections The  nucleus  dorsomedially  at  medialis  (VA),  (N.  lateralis  varied  which  cerebellar  ventralis  and,  Retic.)  and  i t s more  posterior  i n s i z e and  (LP).  density,  [ e . g . , S h e p s , 1945;.Dekaban, 1953]  have  i n these c h a r a c t e r i s t i c s i n d i f f e r e n t parts  and noted of  nucleus. Some a n a t o m i c a l d e s c r i p t i o n s  definitions  o f VL.,  For  a dorso-ca.udal  input  from t h e . c e r e b e l l u m , but  tural  similarities  Hassler  [1959] has  part  to  markedly  ventral  o f VL  parts  and  N.  which does not  and  rise  to  from t h a t VA  included  receive  o f VL.  The  a direct-  cytoarchitec-. work  of  a system of  nomenclature  of Walker.  He  i n t o N.  ventralis oralis  [1951]  which does have  other parts  given  which d i f f e r s  have u s e d d i f f e r e n t  example, O l z e w s k i  i n VL  (Vop)  deep  cortex.  N . . r e t i c u l a r i s thalami  l e v e l s , d o r s a l l y by  The  nuclei  and  have  generally  ventralis anterior  ventralis postero-lateralis  posterior  from the  is.bounded medially  i n t e r n a l medullary  ventrolaterally  tier  between  authors  i t i s now  r e c i p r o c a l monosynaptic  motor p o r t i o n  N.  of  and  monosynaptic connections  with the  (VM),  f i b r e connections  divided  ventralis oralis  anterior  (Voa)  the  posterior  respectively.  3 More d o r s a l p a r t s  o f VL  and  because H a s s l e r  has  receives  from the  fibres  VA  were g i v e n  found t h a t only cerebellum  (BC).  Though t h e r e  a p p e a r s t o be  to the  ventral part  o f VL  196 8 a ] ,  1961;  Cohen, Chambers and findings.  The  human s u r g e r y  this  system o f - H a s s l e r than i n s t u d i e s  this  brachium  on  and do  VL  conjunctivum  specificity .  and  Westerman,  anatomical  studies  Westerman,  1968b;  not  support  Hassler's  i s u s e d more f r e q u e n t l y experimental  i n Macaca m u l a t t a  in  animals. i s s i m i l a r to  i n sterotaxic cat brain atlases referred to i n  study . [Jasper  1961;  other  S p r a g u e , 1958]  W a l k e r ' s d e s c r i p t i o n o f VL those used  v i a the  some c h e m i c a l  McCance, P h i l l i s  names,  v e n t r a l p a r t of  [McCance, P h i l l i s  e l e c t r o p h y s i o l o g i c a l , and  [Appelberg,  the  different  and  Ajmone-Marsan, 1954;  R e i n o s o - S u a r e z , 1961]  and  will  be  Snider  and  Niemer,  the  one  followed  b o r d e r between VL  and  VA  in  thesis. Some p a r t s  difficult  of  the  t o d i s t i n g u i s h , and  to overlap  parts  relatively  poor d e f i n i t i o n  it  been s t u d i e d  has  not  Cerebello-Thalamic The  a g r e e m e n t on  a f f e r e n t systems  of both these n u c l e i .  appear  However, b e c a u s e o f  o f a f f e r e n t s and  in this  very  e f f e r e n t s of  VA,  thesis.  Pathway  m a j o r , and  to.VL a r i s e s from the pathway has  various  are  even the  d e f i n i n g a f f e r e n t pathway-.  deep n u c l e i o f t h e  been s t u d i e d  extensively  its.characteristics  has  cerebellum.  This  and  a l a r g e measure  of  now  been a c h i e v e d .  The  the  • 4 results  c i t e d i n the  studies  on  cats  and  following  description  are  monkeys, i n w h i c h t h e s i m i l a r l y organized..  cerebellar  usually  groups,.the  are  fastigial  i n t e r m e d i a t e n u c l e u s and  N.  interpositus posterior  on  differences  two  parts,  The  major p a r t  form the  N.  the  of  In  the  interpositus w i l l the  efferents  brachium conjunctivum  peduncle.  Flood  and  Jansen  positus  and  be  treated  from the (BC)  or  of  BC  fastigial  to brain nucleus  various  as  the  hook b u n d l e o r  A  of  the  hook b u n d l e t h e n  part  inferior  cerebellar  tralateral dorsal two  to  BC, the  groups of  caudal part rostral  or BC  portion  the  of  The  within  j o i n s the  nuclei  nuclei,  the^ i n t e r the  efferents A  the  fibres originate  fastigial  contribute  nucleus.  f i b r e s to  the  cerebellar  uncinatus. contralateral the  conjust  Pines1958].  These  p r i n c i p a l l y from Most c e l l s  the  of  portion  forms a s e p a r a t e a s c e n d i n g b u n d l e and  here.  Gudden method  fasciculus  [Carpenter,.Brittin  these  cerebellar  peduncle, while a p a r t , j o i n s  crossed  of  a unit  pathways.  midline  white matter  information  in cerebellar  stem s t r u c t u r e s .  t h i s f i b r e group c r o s s e s the  large  as  s e n d t h e i r axons v i a  follow  anterior,  f i b r e s of  superior  [1966] u s i n g  nucleus.  cerebellar  perhaps a l l c e l l s  dentate n u c l e i  ipsilateral the  most and  into  efferent  to determine retrograde degeneration h a v e shown t h a t  lateral  divided  the  cell  interpositus  absence of d e f i n i t e  connections of  of  deep  into three  dentate or  i s sometimes f u r t h e r  parts.  The  or m e d i a l n u c l e u s , the  or  and  separated  from  cerebello-thalamic  pathways a p p e a r t o be nuclei  derived  in  ipsilateral  the  the inferior  5 c e r e b e l l a r peduncle. n u c l e u s does not One  of Flood,and  the c e r e b e l l a r  BC  fibres  the  nuclei  indicated  after  and  that  t o the  resulting o f BC  probably not  crepancy  originating may  be  i n the  o f Cohen, Chambers and  noted  that  do  although  the  The  Jansen's  and  dentate  nuclei  failed  a p o r t i o n of the levels  rostral  to the  findings  fibres  that  from  from  from  the  and  electro-  The  projection dis-  degeneration These  fastigial  t h e y do  the  observations  nucleus.  [1958].  authors  nucleus  c r o s s i n a more  t o the d e c u s s a t i o n .  some c e l l s  of the  Flood  interpositus following  l e d them t o t h e c o n c l u s i o n t h a t the n u c l e i  o f most o t h e r w o r k e r s . way.  the Nauta technique lesions  from  ascend  uncrossed  to  t o the d e c u s s a t i o n , a c o n c l u s i o n c o n t r a r y  explained i n another  using  latter  t o show d e g e n e r a t i o n  s e c t i o n o f t h e d e c u s s a t i n g BC  be  Sprague  rostral  observation that  fibres  r e f e r e n c e t o the  n o t e n t e r t h e d e c u s s a t i o n o f BC,  and  study  degeneration  anatomical  fastigial  fibres  d i s p e r s e d manner a t l e v e l s  BC.  allowed  an a s c e n d i n g b i l a t e r a l  r e s o l v a b l e by  study  ipsilateral  originating  a l l of the  i n t e r p o s i t u s n u c l e i do.  p h y s i o l o g i c a l , which i n d i c a t e fibres  fastigial  cross the m i d l i n e i n t h i s r e g i o n ,  are a t v a r i a n c e with other s t u d i e s ,  of  the  experiments  fibres  not  that  section of the.decussating  The  the  n u c l e u s do  w h e r e a s most, b u t dentate  Jansen's  i n the midbrain.  fastigial  likely  contribute fibres  of  patterns  I t appears  in either  The.observation  Cohen, Chambers and  Sprague,  for terminal degeneration  interpositus  or dentate  can  showed  nuclei  re-  6 suit and  i n f i b r e degeneration reticular  send  their  nuclei.  not  to. d e g e n e r a t e  at higher levels, The  BC  Thus c e l l s  sites  e.g.,  of c e r e b e l l a r  i n answering  that  the  thalamus  lesions  t o BC  ascending  The  fastigial  or c e r e b e l l a r  the  interpositus  and  dentate  perhaps  t h o u g h some end  1956],  part of  fibres,  collaterals  after  VPL.-  the  Fibres  n u c l e i which ascend  rostral  i n the  crossing,  to the red nucleus  w h i l e many c o n t i n u e i n a r o s t r a l d i r e c t i o n VL,  the  Chambers,  probably cross completely  Some o f t h e s e  t e r m i n a t e i n or send  and  found  upon  [Thomas, e t a l . , 1 9 5 6 ] ,  t o t h e d e c u s s a t i o n o f BC decussation.  effectively  does n o t a p p e a r t o c o n t r i b u t e t o  c e r e b e l l o - r u b r a l pathway from  i n the  nuclei, a l -  projects bilaterally  intralaminar nuclei  nucleus  the  terminal degeneration  [ e . g . , Thomas, Kaufman, S p r a g u e and VL,  of  some q u e s t i o n s . - M o s t w o r k e r s have  f a s t i g i a l . nucleus  r e a c h i n g VA,  which  regions  section  t h o u g h e l e c t r o p h y s i o l o g i c a l methods have b e e n used  nuclei  to these  following  of termination of f i b r e s  following  vestibular  a t the d e c u s s a t i o n .  h a v e . b e e n m o s t l y . e l u c i d a t e d by  studies  ipsilateral  a x o n s , o r e v e n axon c o l l a t e r a l s  may.be e x p e c t e d BC  i n the  either (NR),  to terminate i n  i n other thalamic nuclei  [Cohen, e t a l . ,  1958]. The nuclei in  that  part  projections  from the d e n t a t e  to the red nucleus interpositus  and  interpositus  a p p e a r t o have a d e f i n i t e p a t t e r n ,  projects  t o t h e more c a u d a l m a g n o c e l l u l a r  o f NR,_. whereas t h e d e n t a t e n u c l e u s  sends f i b r e s  to  the  7  more r o s t r a l  parvocellular  demonstrated  i n the  and  A n g a u t and  endings been  i n NR  shown by  who  were able  and  NR  cells  activation of  the  to  c o l l a t e r a l s of  to  activate  NR  cells  precise i n the  and  Thomas, e t  was  thalamus  parts  and  of  VA  a l . , 1956].  It  will  s u f f i c e here  of  the  Rubro-Thalamic  BC,  to  is s t i l l  has  and  Matsunami,[1970],  cells  antidromically The  v i a axon c o l l a t e r a l s  cerebello-thalamic i n doubt.  Many  have i n d i c a t e d  and  VPL  [e.g.,  i n CM  or  conclude  (CM),  to  the  at  (CL))as,well  Cohen e t  a l . , 1958?  hasvigorously  Pf. [Mehler, that  anatomical  projections  c e n t r u m medianum  centralis lateralis  projects  ascending  or  the  t o VL  s t i m u l a t i n g VL.  shown t o be  [1966]  1966,  least a  1969].  large  contralateral  denied  portion  VL.  Pathway  have been d i f f i c u l t destruction  Courville  l e a s t some o f  However, . M e h l e r  fibres terminate  a s c e n d i n g BC  been  fibres projecting  by  nuclei(N.  (Pf)  has  fibres.  t h a t "BC  The  at  d i s t r i b u t i o n of  intralaminar  t o VL  of  interpositus  manosynaptically  parafascicularis as  That  electrophysiological studies the  pattern  studies  [1965].  interpositus—VL  terminals  This  Toyami, Tsukahara, Kosaka  of  The  and  anatomical  Bowsher are  part.  fibre  of  to determine because of  a c t i v a t i o n of  when l e s i o n i n g o r  Reasonable evidence  projections  other  stimulating  for  the  fibre  the the  of  nucleus  inevitable  systems, p a r t i c u l a r l y  respectively  existence  red  a  that  nucleus.  rubro-thalamic  8  pathway  i n t h e c a t may [1957]  and B r o d a l anterior and  p a r t o f NR  o f Bowsher  and,  after  degeneration.  were  The after  time and  CM,  concluded bution  VA  [1968]  studied  that  who  the resultant found  lesions  no  lesions thalamic  seen  t o VA  was  and VL  fibres  were  ended  sparse  to the dentate  fibres,  terminal  ascending  to the r o s t r a l  p a t h w a y was  the rubro-thalamic f i b r e s  degeneration  o f BC  preterminal degeneration  the ascending  of fibres  levels,  t o t h e c a u d a l p a r t o f NR,  after  similar except  were  n u c l e u s , and  than  to that  but  i n zona part. i n  that  incerta,  They  distrithe  i n VL.  than  The  resulting  the degenerating  calibre  degener-  r e v e r s e d , i . e . , more  i n VA  compared  of finer  i n the  ablated the cerebellum  t o the d e n t a t o - t h a l a m i c pathway,  proportions  Pompeiano  a t more r o s t r a l  authors  lesions  of  retrograde degeneration  lesions  latter  and VL  i n t h e work  f o r degeneration  able t o demonstrate  caudal  of  found  and Angaut  i n NR  fibres  found  after  allowing  made l e s i o n s  ating  who  be  from  rubro-  dentato-thalamic  axons.  Cortico  - VL  Pathway-  A major pathway terminates in  area  pathway  i n VL.  originating  In primates  4 of the motor  cortex  has been d e t e r m i n e d  Kusama, O t a n i and Kawana, in  the precruciate  cortex.  i n motor  these  fibres  [Petras,  arise  1969].  b y many a u t h o r s  1966  cortex  [1968]  from  In cats;  cells the  [e.g.,.Auer\  a n d P e t r a s , 1969]  Rinvik  also  has  to  found  1956;  originate terminal  9 degeneration well  i n VL a f t e r  as n e i g h b o u r i n g  ectosylvian  gyrus.  VL, b u t does have [Kusama,  et al.,  lesions  to pericruciate  r e g i o n s such The pathway  as c o r o n a l and  appears  will  be r e f e r r e d  as  anterior  to reach  a somatotopically organized 1966] w h i c h  gyrus  a l l parts of  projection. to at a  later  stage.  Pallido-Thalamic The (GP)  Pathway-  e x i s t e n c e o f a pathway  t o t h e t h a l a m u s was  first  from  the globus  demonstrated  i n t h e monkey by  Ranson  and Ranson  [19 3 9 ] , a n d R a n s o n , R a n s o n  [1941]  using both  retrograde degeneration  The  pathway has s i n c e been  techniques  [Nauta  Carpenter  and Strominger,.1967]  only  the internal  from  homologue, [Fox, this  pattern  degeneration  found  of primates  nucleus  1966; to originate  and i t s  (EN) o f c a r n i v o r e s 1966].  The f i b r e s  of  i n V A , V L a n d CM, w i t h t h e d i s t r i b u t i o n  i n VA a n d VL o v e r l a p p i n g t h a t o f t h e c e r e b e l l o -  thalamic  pathway  much l e s s  proposed  fibres  1965].  that arising from  t o end i n VL.  o f each  teristics  [Szabo,  dense than  Nerve  tence  and Marchi. t e c h n i q u e s .  and has been  H i l l m a n , Siegesmund and S e t h e r , terminate  Ranson  1961, 1966; M e h l e r ,  s e g m e n t o f GP  the entopeduncular  pathway  and  s t u d i e d by t e r m i n a l  and M e h l e r ,  pallidus  of these  are not well  The p r o j e c t i o n from  three other  EN i s  the cerebellum. c e n t r e s have  Though evidence pathways has been defined.  from  been  supporting the exisfound,  their  charac-*  10 Nigro-Thalamic  Pathway  C o l e , N a u t a and  Mehler  [1964] f i r s t  of a n i g r o - t h a l a m i c  pathway i n c a t s and  that  substantia nigra  l e s i o n s i n the  heavy t e r m i n a l d e g e n e r a t i o n is  now  supported  [1967] on rats. ation  by  s t u d i e s o f SN  nigro-pallidal  nucleus SN  Faull  [1970],  as  and  the  a r o u n d VL.  pathway, b u t pathway.  and  feels  projection  l e a d i n g him i s either  main f i b r e s  small or  p r o j e c t i n g to the  deny t h e  i t may  be  t h a t the  l e n t i f o r m nucleus..  presented  Frigyesi  grounds.,  Mitchell  to intralaminar n u c l e i . McMurtry  and  t o VL  Nauta.and W h i t l o c k  [1967] f o u n d  degeneration  Machek  of  the  Electro-'  pathway  has  [1970],  has  been p r o p o s e d  [1954] and i n VL  after  on  Kaelber lesions  In a d d i t i o n , P u r p u r a / S c a r f f  [1965] h a v e f o u n d  to  of  Pathway-  A n e u r a l pathway f r o m CM  and  secondary  composed o f c o l l a t e r a l s  recently.been  anatomical  existence  nigro-thalamic  confirmation of a nigro-thalamic  - VL  degener-  degeneration  physiological  Intralaminar  on.  A b l a t i o n of the l e n t i f o r m  to conclude  by  finding  Strominger  of retrograde  by M e t t l e r r e s u l t e d i n a l m o s t t o t a l  neurons,  showing  This  Carman ' (1968)  result  evidence  (SN) r e s u l t e d i n , q u i t e  i n monkeys, d o e s n o t  of a nigro-thalamic the  monkeys by  t h e work o f C a r p e n t e r  monkeys and  Mettler  i n and  presented  and  short latency excitatory post-  11 synaptic medial  potentials in cells  non-specific  experiments medullary  are,  possible,  to  the  fibres  of  evidence of  therefore,  passage i s yet  retrograde  n e u r o n e s as VL.  non-specific  intralaminar  Even  through  rostral  i s predictable remain  Reticulo-Thalamic  of  stem  i n dispute  reduced  The  stimuli  be  confused  antidromic  on  internal  that for  or  It  lesions  effects  lamina.  pathway  from  to  projections to.the of  on  No  applied  subject  nature  some  ascending  studies  a c t i v a t i o n of  way  the  the  centres.  by  stimuli  their  these  CM to  similar course  striatum. the  CM  -  VL  time.  Pathway  reticular  evidence  found  evidence  formation  particularly  was  or  therefore,  specific  [1963]  r e s u l t s of  i n t e r n a l medullary  thalamus  The  Lewis  other  of  from  of  n u c l e i and  intralaminar-striatal  available. or  consist mainly  e v i d e n c e w o u l d be  Some a n a t o m i c a l brain  to  a r e s u l t o f , l e s i o n s i n or kind  drawn  to c r i t i c i s m . -  a v a i l a b l e f o r t h e . C M - VL  since  p a t h w a y may  conclusions  nuclei could  i n the  objections,  It  that  degeneration  this  the  after stimulation  i s closely associated,with  n u c l e i , appears  from the  is  The  however,.liable  lamina which  intralaminar fibres  nuclei.  o f VL  f o r a d i r e c t pathway (RF)  does not  to  the  thalamus  indicate that  h e a v y p r o j e c t i o n t o VL.  there  the  RF,  and  therefore  the  is is  Shute  t h a t c h d l i n e s t e r a s e s t a i n i n g i n the  a f t e r lesions;- to  from  a and  thalamus postulated  12  the e x i s t e n c e Although  of c h o l i n e r g i c r e t i c u l o - t h a l a m i c connections.  electrophysiological  been s e e n i n t h a l a m i c strongly  suggestive  relay nuclei,  of d i r e c t  a r e v a r i e d and o f r e l a t i v e l y Phillis  effects  clarify  degeneration  the r e s u l t s  connections, long  and Westerman, 196 8 a ] .  retrograde  o f RF s t i m u l a t i o n have  latency  to various  as t h e r e s p o n s e s [ e . g . , McCance,  I t m i g h t be e x p e c t e d  studies after  that  l e s i o n s i n VL w o u l d  t h e p i c t u r e , b u t as t h e a s c e n d i n g  collaterals  are not  regions, negative  f i b r e may send o f f r e s u l t s would n o t  be o f any v a l u e . From  the preceding  many r e g i o n s role to  description,.it  i s apparent  of the b r a i n which a r e recognized  as h a v i n g  activity  Efferent  Pathways  of c e l l s  i n VL.  By f a r t h e h e a v i e s t p r o j e c t i o n o f f i b r e s the c e r e b r a l cortex, p a r t i c u l a r l y  pathway  has been i d e n t i f i e d  orthograde  degeneration  organized.  t o t h e motor a r e a .  by W a l k e r t o be s o m a t o t o p i c a l l y  p a r t s o r l e g areas  the intermediate  arm and t r u n k  cortical  areas.  largely  o f t h e motor c o r t e x , t h e  p a r t s p r o j e c t t o t h e l a t e r a l motor c o r t e x ,  region with  This  [ e . g . , W a l k e r , 1938; S t r i c k ,  Thus t h e l a t e r a l p o r t i o n s o f VL p r o j e c t  the medial  medial  f r o m VL i s  on t h e b a s i s o f r e t r o g r a d e and  studies  197 0] , and has been f o u n d  to  some  i n c o n t r o l and c o - o r d i n a t i o n o f movement have t h e means  alter  to  that  regions  sending  o r head  fibres  t o the  13 A Johnson found  few  workers  [1961]  and  agree  while  caudate  degeneration  posterior  nucleus.  these  results.  through  fibres  i n CM  pathways, rather caudate  and  than  CL  from  to  intralaminar-striatal  for  has  VL  nucleus  been proposed  [Massion,  1968],  in  part  of  the degeneration  suggested.  a VL  The  pathway which opportunity cortical  superior  t h a t VL  and  t o LP  i n the  and  and  the  CL  target  validity  course  nuclei.  seen  by  cells.  that in It  the  i n t e r r u p t i o n of  these  Degeneration  explained  cells  which  project  by  damage  to N  retic-  superior  feed-back  i s thought  No  to  alternate  colliculus  however, t h a t  i s r e a s o n a b l y documented a major  (MD)  Intermedius,  to provide a negative  f a c t remains,  pathway.  dorsalis  retic.  passage.  association nucleus.  to play  CM  similarly of  N.  shown i n t h e monkey  damage t o VL  fibres  These  and  to assess  r e s u l t e d from  be  CM  VL. have  colliculus  the degeneration  could  seems r e a s o n a b l e  as  lateralis  route to their  that  [1969]  i n CL,  i n N medialis  [1969] has  en  the  which  i s seen  d i r e c t e d toward  in  It  Maharry  a f t e r l e s i o n i n g VL..  ( L P ) , VA,  VA-and VL  authors  and  i t i n N,  Petras  possible therefore  above  other e f f e r e n t s of  I t i s again d i f f i c u l t  cortico-thalamic  is  degeneration  Smaha e t a l . f o u n d  lateralis  part  Smaha, K a e l b e r  that  J o h n s o n a l s o saw  of  studied  sub-cortical degeneration  authors  N.  have  and  can  the which  system function  explanation be  only has  efferent the  r o l e i n motor c o n t r o l i s the  VL-  14  I t would position  seem t h e r e f o r e  t o a c t as  an  t h a t VL  i n t e g r a t i o n centre  subcortical  structures  involved  t o pass the  integrated  information  It a  i s also possible "final  and  undoubtedly.occurs at which s e l e c t i v e l y nized  at  on  t o the  i n t h i s way  are  been shown by  L e b l a n c and  Cordeau the  from  i n motor c o n t r o l , and  may  That such c e l l s  a c t i v a t i o n has  [1966]  t h a t VL  favourable  for signals  motor  cells  strongly  cortical  i n f l u e n c e the  part  the  influenced  Further  level,  in  of  Y o s h i d a , Y a j i m a and [1969].  then  cortex.  provide  common pathway" t o p y r a m i d a l t r a c t  motor c o r t e x . VL  is in a  Uno  integration  but,other  motor c o r t e x  by.  are  pathways  not  recog-  present.  N u c l e u s C e n t r u m Medianum The  i n c l u s i o n of  ( c e n t r u m medianum - CM)  the  not  i n motor mechanisms. become c l e a r i n t h e on  this  median o f  requires  generally The  structures  con-  some j u s t i f i c a t i o n ,  been a s s i g n e d  reasons  Luys  any  major  L u y s i n 1865  for i t s inclusion w i l l  following discussion  n u c l e u s . c e n t r u m medianun was i n the  human b r a i n .  variations in this  traditional  nucleus,  i n c l u s i o n i n the  as  role,  o f e x p e r i m e n t a l work  nucleus. The  species  centre  i n a d e s c r i p t i o n of  c e r n e d w i t h motor f u n c t i o n s t h i s n u c l e u s has  nucleus  first  Because of and  defined  by  significant  because of i t s  "intralaminar  n u c l e i " which  15 have o f t e n been  considered as a f u n c t i o n a l  in  and i n proposed  nomenclature  arisen.  I n an attempt  and anatomical  to rectify  connections  this  of  into  cytoarchitectural  studies.  centrum  Crouch  of the nucleus  lateral  p a r t composed o f s m a l l e r , l e s s  regarded  comprehensive  of N i i m i ,  as absent,  densely  centrum  or at best poorly  o f Uemera's work  and Morimoto on t h e n u t r i a  has  prompted  the nucleus celled  squirrel  based part  gained  and n u t r i a . from  as N centrum  portion  on f i b r e  connections  that the  and r a t ,  i n the guinea  T h e i r comparison  human f e t u s e s a t d i f f e r e n t  medianum p r o p e r ,  parafascicularis.  agrees  i n t h e mole  them t o c o n s i d e r t h e s m a l l - c e l l e d  dorsomedial  nucleus  cells.  developed.  indicate  a higher degree o f d i f f e r e n t i a t i o n  data w i t h those  arranged  [1960] a n d t h e i r  but  rabbit,  and a  medianum i s  part i spoorly developed  pig,  Olzewski  cells,  small-celled achieves  o n the b a s i s  p h y l o g e n e t i c a n d human o n t o g e n e t i c s t u d i e s  Katayama, Kanaseki  description  [1934],  having moderate-sized  l o w e r mammals, t h e s m a l l - c e l l e d  The  medianum h a s been  [1941] h a v e d e s c r i b e d a m e d i a l  portion  variously  Mehler  summary o f t h e c y t o a r c h i t e c -  two p a r t s by v a r i o u s anatomists  [1952] a n d V o g t a n d V o g t  In  situation  have  of the nucleus..  In primates, t h e nucleus subdivided  differences  anatomical connections  [1966] h a s p u b l i s h e d a n i m p o r t a n t ture  unit,  as a l a t e r a l Mehler s 1  unique  with that of Niimi  stages  portion of  and t h e l a r g e r -  sub-group o f t h e  1966 d e s c r i p t i o n  to the small-celled  et a l .  o f these  I t does  o f CM, lateral  seem r e a s o n a b l e ,  16 therefore, comprises  t o consider at least  small-celled  that  three- subgroups  lateral  CM,  w h i c h may b e c o n s i d e r e d better  referred In  CM. w i l l  t h e p h y s i o l o g i s t ' s CM - P f c o m p l e x - N parafascicularis,the  and a t h i r d  part  a medial part  between these  o f CM, b u t i s p r o b a b l y  t o as N p a r a f a s c i c u l a r i s  lateralis.  the ensuing description therefore,  designate  that  area defined  two  references  by -Mehler  [1966] a n d  Niimi  e t a l . [1960] a s t h e CM a n d r e f e r e n c e s  t o Pf should  taken  to include  parts  both  the medial  and l a t e r a l  to  be  of that  nucleus.• Nauta degeneration pallidus Pf, of  and Mehler i n CM  [19 66]  following lesions  free  cortico-thalamic  projections  l e s i o n s demonstrate  Petras,  t o P f and N 1964,1969].  connections  cortex  t h e sensory, motor  that  f i b r e s t o CM a n d t h e p r e m o t o r  projects  fibres  i n which  than  motor  cortex  t o CM In the and premotor  (area  (area  4)  6 a n d 8)  (CL) [ A s t r u c ,  An a d d i t i o n a l d i f f e r e n c e  1964;  i nthe  o f t h e s e n u c l e i i s s e e n when t h e i r  are considered.  are  i n carnivores,  cortex  centralis lateralis  degeneration  there  a n d F u j i t a , .1963] .  a r e more d i s c r e t e l y l o c a l i z e d  selective  that  i n t h e c a t from t h e p r e c r u c i a t e  monkey and c h i m p a n z e e  of the cat.  Further,  pathways has i n d i c a t e d  Miki  terminal  i n the i n t e r n a l globus  from degeneration.  [ A u e r , 1956 ; N i i m i , K i s h i ,  sends  shown  o f t h e monkey o r t h e N e n t o p e d u n c u l a r i s  h o w e v e r , was  cortex  have r e c e n t l y  Because o f the p r o x i m i t y  efferent of these  17.  nuclei is  to the  i n t e r n a l medullary  encountered  in trying  lamina,  to i n t e r p r e t  great  the  difficulty  results  of  orthograde  degeneration  studies after  Retrograde  degeneration  s t u d i e s , however,.have shown t h a t  the c e l l s  o f CM  e x h i b i t marked d e g e n e r a t i o n  ^the putamen b u t Cellular  project  not  of the  degeneration  to the caudate  lesions, i n this  caudate  i n P f was  nucleus.  in part directly  The  N.  after  lesions  [ P o w e l l and  more p r o n o u n c e d  area.  1956].  Cowan,  after  lesions  q u e s t i o n of whether these  t o the c e r e b r a l c o r t e x i s  of  nuclei  still  undecided.  ELECTROPHYSIOLOGY  Nucleus  Ventralis  Intrinsic The  Lateralis  Activity  thalamic relay  spontaneous rhythmic work on,  and  been r e v i e w e d activity by A d r i a n  nuclei  electrical  have b e e n f o u n d  activity.  possible significance  The  of t h i s  by A n d e r s e n and A n d e r s s o n  and  the p r e c i s e nature  clarified,  particularly  phenomenon  [1968].  of t h i s  been p u r s u e d  and  intacellular  r e c o r d i n g s ^ , by A n d e r s e n , E c c l e s and  Though t h e work by A n d e r s e n and centrated  with  (VBC)  has  Rhythmic first  observed  activity  the  of the  has  a i d of co-workers.  h i s c o l l e a g u e s has  i n t h e v e n t r o b a s a l complex  exhibit  experimental  r e p r e s e n t a t i v e o f t h a l a m i c r e g i o n s was [1941]  to  been  con-  thalamus  18  (N.  v e n t r a l i s p o s t e r o l a t e r a l i s a n d N. v e n t r a l i s  their  observations  VL by v a r i o u s  appear  cell of  discharges  this  (spindles)  generally  varies  extracellular at  activity  consists  considerably.  recording,  single unit  Within  per second.  cell  i s recorded  each c e l l  may  discharges  not f i r e  which  with  suitable  are generally  (Figure  la).  amplitude.  After  a few o f t h e s e p o t e n t i a l may  o f an a c t i o n p o t e n t i a l , o r more  of action potentials.  also  (Figure  lb).  The  with  normally  hyper-  resulting  frequently  a  are rapidly,  the size of the hyperpolarization  end  although  and r e p e t i t i o n o f  the depolarizing p o t e n t i a l s cease,  polarizations  occur,  Such d i s c h a r g e s  by a f u r t h e r h y p e r p o l a r i z a t i o n  i s  recurring  in  reduced,  than  potentials of  a'depolarizing  until  that  before  synchronized  polarizations  pattern,  just  o f more  the onset of the spindle  increasing  the  recording  Intracellular  of hyperpolarizing  followed  using  e a c h wave o f s p i n d l e , t h e  by a s e r i e s  burst  second,  be s e e n t o o c c u r  i t i s seen  signalled  generation  frequency  per minute.  spindle,  I f the activity  are observed  h a s shown t h a t  patterned  a minimum  a c t i o n p o t e n t i a l s a r e seen  p o s i t i v e wave p a t t e r n .  recording  each  With  by an e l e c t r o d e ,  of  o f a b o u t one  p o s i t i v e w a v e s may  each o f t h e p o s i t i v e waves.  the  with  have a d u r a t i o n  o f a b o u t 6-12  a rate  techniques  one  of groups  which recur  seen i n  1969).  2 p e r m i n u t e b u t more, c o m m o n l y a t 4-6  about  The s p i n d l e s but  t o match c l o s e l y those  w o r k e r s ' (.also A n d e r s e n e t a _ l . ,  The r h y t h m i c  posteromedialis)  becomes  and t h e h y p e r -  hyperpolarizing  potentials  have been r e l a t e d  potentials  by Andersen  they  be r e d u c e d  the  could cell  ions. of  and Sears  [1964]  or inverted  Thus t h e h y p e r p o l a r i z a t i o n s  depolarization  acting  post-synaptic  on grounds  injection of are generated  upon t h e c e l l s .  has n o t been a s c e r t a i n e d ,  thought by Andersen  generation  by  zations.  i s facilitated  I t i s conceded  caused by synaptic however remain By  but i t i s exaltation  excitatory  recording  with  multiple  a n d L0mo,  19.6 4]  that  and  with  cells  i n a related  cortical  thalamic  field  within  full  been judged  axon  which  t o be as s m a l l  synchronous b u r s t i n g  interneurones  i n full  neighbouring  perform  proposed  provide  be  which  activity  controlled  [Andersen, ventrobasal  synchrony with area.  each  a s 1 5 0 - 2 0 0 ]i. Andersen  other  The s i z e o f t h e  s y n c h r o n y may b e  observed  To e x p l a i n t h e  and E c c l e s , [ 1 9 6 2 ]  a model i n v o l v i n g a c t i v a t i o n o f i n h i b i t o r y located  within  t h e same t h a l a m i c  collaterals of thalamo-cortical  interneurones  cells  evidence has been p r e s e n t e d  cells  have  could  independently  thalamic  has  by the h y p e r p o l a r i -  the depolarization  a c t i v a t i o n from  cells,  unidentified.  microelectrodes, Anders son  that  activity  The n a t u r e o f  t o be due t o a p o s t - a n o d a l  of which  of  chloride  (PAE), and t o be a c h a r a c t e r i s t i c o f t h e t h a l a m i c the  that  by h y p e r p o l a r i z a t i o n  membrane, o r i n t r a c e l l u l a r  i n h i b i t o r y , neurones  the  to inhibitory  activated  by a - r e l a y  a i n h i b i t o r y feed-back  relay  cell  t o nearby  nucleus  cells.  discharge relay  by  Inhibitory would  cells  20  Figure  1 ( a ) . S p o n t a n e o u s b u r s t i n g " s p i n d l e " o f VPL n e u r o n e s e x t r a c e l l u l a r recording.. . «,  IOmV\  V i oo msec Figure  1 ( b ) . S p o n t a n e o u s b u r s t - o f ' s i n g l e VPL n e u r o n e , f o l l o w e d by h y p e r p o l a r i z a t i o n — i n t r a c e l l u l a r r e c o r d i n g . 1  CORTEX  THALAMUS  I Figure  j  2,  *I "I ICE  I  MEDIAL LEMNISCUS  Axon ' e o l l a t e r a ' r - l n h x b l t o r y i n t e r n e u r o n e model. of< s u b s t r a t e f o r r h y t h m i c b u r sting., .in--.^t-h^'Lamic; relay nuclei. • •-»_•>..•» r-v.  (Figure 2 ) .  By t h i s means, a p a t t e r n o r i g i n a t i n g i n  one  or a few neurones could be spread to a neighbouring group of cells.  The  involvement of axon c o l l a t e r a l s r a t h e r  independent a f f e r e n t f i b r e s i s i n d i c a t e d  than  from  experiments which showed t h a t s t i m u l a t i o n of c e r e b r a l  cortex  a f t e r d e g e n e r a t i o n of c o r t i c o - t h a l a m i c f i b r e s evoked.a powerful p o s t - s t i m u l u s  s e r i e s of d i s c h a r g e s ,  s i m i l a r to  s p i n d l e s o c c u r r i n g spontaneously, but commencing w i t h  the  large  amplitude h y p e r p o l a r i z a t i o n s , r a t h e r than small ones [Andersen and  Andersson, 1 9 6 8 ] .  theory  1.2  i s the  msec  f o l l o w i n g antidromic appropriate  In agreement w i t h t h i s  l a t e n c y o f the  hyperpolarization  a c t i v a t i o n of the c e l l s — a b o u t  the  time f o r s y n a p t i c a c t i v a t i o n f i r s t of an i n h i b i t o r y  interneurone,  then the thalamic  relay c e l l .  A c t i v a t i o n of  r e l a y c e l l s by a f f e r e n t s , e,.g., from s t i m u l a t i o n of the medial lemniscus i s a l s o followed by a s e r i e s of b u r s t s , as would be r e q u i r e d by the axon c o l l a t e r a l theory.  That an  substrate  been demonstrated,  f o r such a mechanism does e x i s t has  p a r t i c u l a r l y by the work of Tombol [ 1 9 6 7 ] .  She  has  anatomical  shown,  u s i n g the G o l g i technique, t h a t axon c o l l a t e r a l s are seen i n thalamic  c e l l s , branching o f f the axon at short  from the c e l l body, and thalamic 1963]  nucleus.  probably t e r m i n a t i n g  Tombol, and  have a l s o d e s c r i b e d  other  interneurones  Some workers have d i s a g r e e d Andersen and E c c l e s .  authors  Massion  distances  w i t h i n the same (e.g., McLardy,  i n the r e l a y n u c l e i .  with the model of  [196 8] has  argued t h a t neurones  o f N. the  reticularis  inhibitory  reticularis of the  feed-back to the  [ S c h e i b e l and  of  Purpura  relay  inhibitory  appropriate to c e l l s  feed-back t o the  same c e l l s  recurrent  by  BC  thalamus.  are  inhibition  claimed  f r o m PAE  an  cells  after  Desiraju  cells  by  intracellular  The  suitable  electrode.  proposal  IPSPs.  that  one  group of workers  have n o t  been a b l e t o f i n d  Massion,  1969].  The  unknown, b u t  Electrical  t o the p o s t u l a t e d i n h i b i t o r y  activity  one  [1968, 1969]  groups  thalamic and  role  p l a y e d by  reasonable has  the  interneurones  [Marco and  rhythmic  suggested  t h a t the  the  influences  thalamus t o the  cortex.  f r o m t h e b a s a l g a n g l i a and  In the  Brown,  electrical  responses  p r o p o s a l has  observed  discharge  studying thalamic such  a  membrane  [e.g., activity  been o u t l i n e d . rhythmic  a c t as a g a t i n g mechanism f o r t r a n s m i s s i o n o f  through  and  EN  i n c o n s i s t e n t with  h y p e r p o l a r i z a t i o n of the  However, o t h e r  may  the  i s d i s p u t e d by Maekawa  19 6 6 ] .  Massion  have b e e n  having  s u c c e e d e d by  t o be  hypothesis.  have been r e p o r t e d by  is  and  interior  [1967] b e c a u s e l a r g e d e p o l a r i z a t i o n s were n o t  thalamic  patterns  i n VL  s t i m u l a t i o n are  neurone b u r s t s r e s u l t  through  the  a r e n o t , whereas m o n o s y n a p t i c EPSPs e v o k e d i n  These o b s e r v a t i o n s  in  axons i n t o  of N  [1969] have shown t h a t m o n o s y n a p t i c e x c i t a t o r y p o s t -  stimulation  Purpura  provide  Cells  S c h e i b e l , 19 66]  s y n a p t i c p o t e n t i a l s (EPSPs) e v o k e d  the  cells.  may  M a s s i o n t o have s e v e r a l e l e c t r o p h y s i o l o g i c a l  c h a r a c t e r i s t i c s which are role  interneurones  a p p e a r t o send b r a n c h i n g  thalamus,  shown by  r a t h e r t h a n VL  case  activity  signals of  VL,  c e r e b e l l u m would  be  23 filtered so the as  at the thalamic  that during cortex  bursting  level  by t h e r h y t h m i c  activity  i s hindered.  the flow  The g a t i n g  of s i g n a l s t o  s y s t e m c a n be v i s u a l i z e d  a d i f f u s e one, a f f e c t i n g t h e whole n u c l e u s  related  to sleep  w h i c h may  and w a k e f u l l n e s s ,  a f f e c t small  parts  discharges  and p e r h a p s  o r as a l o c a l i z e d  of the nucleus,  thus  one  playing  a r o l e i n s e l e c t i v e movement.  Cerebello-Thalamic The capacity  pathway f r o m t h e deep c e r e b e l l a r n u c l e i h a s t h e  to influence  strongly  the a c t i v i t y  Several  w o r k e r s have u s e d t h i s  studies  o f p h y s i o l o g i c a l and p h a r m a c o l o g i c a l  pathway as p a r t  t h a l a m u s and t h e motor s y s t e m , b u t o n l y characteristics  o f VL  o f t h e pathway i t s e l f  cells.  of t h e i r  features  a few have  studied  i n any d e p t h .  Of t h e  evoked p o t e n t i a l s t u d i e s , p r o b a b l y t h o s e o f A p p e l b e r g and  A n g a u t and c o - w o r k e r s  [Angaut, G u i l b a u d  i n d i v i d u a l c e r e b e l l a r n u c l e i of cats  been a b l e  t o study t h e i r  [1961]  & Reymond, ' 1969;  Conde and A n g a u t , 1970] a r e most p e r t i n e n t . the  of the  By  these  individual projections  stimulating  authors to  have  thalamic  centers. Appelberg N. i n t e r p o s i t u s . postsynaptic  These p o t e n t i a l s , judged t o  e v e n t s were f o u n d o n l y  contralateral in  f o u n d p o t e n t i a l s e v o k e d by s t i m u l a t i o n o f  these areas  red nucleus, following  and V L .  stimulation  represent  i n the region  of the  He f o u n d no p o t e n t i a l s of the dentate or f a s -  tigial  nuclei,  ascending  pathways would  Electrical  events  were recorded stimulus along 18  activity  be  representing  i n VL  with  Appelberg in his  1.0  used  by  small.  the  fastigial  pre  similar  to  crossed  and  Angaut et  those  differences  were  stimulation  of  These workers  Conde and crossed apparent  a  bilaterally  the  Angaut  ascending i n the  fields  of  electrical  were  study  electrodes,  projection is i n and  the  notable after  responses  synaptic of  VM.  projections,  representing synaptic  red  in  of N i n t e r p o s i t u s .  thalamic  parts  responses  No  observed  with  VL.  responses  (VM).  nucleus  post  and  largely  around  type  distributed  and  [1969]  interpositus  responses  t o VL  of  macro  anterior parts  projection with anterior part  Reymond  medialis  of dentate  [1970] f o u n d  probably  i n t e r p o s i t u s were  f a s t i g i a l nucleus,  restricted  about  tungsten  post-synaptic  found  velocity  or  wave i s s e e n  p o s t e r i o r or  post  glass  from the  ventralis  msec,  c a l c u l a t e d t o be  i . e . , the  the  similar  activity  recording  seen between the  largely  In  N.  such  postsynaptic  findings for N  Appelberg  and  s t i m u l a t i o n of  responses  was  of  methods.  conduction  that the  and  a l . also recorded VPL  The  using  1.8  his recordings  a post-synaptic  o f VA,  -  existence his  A n g a u t , G u i l b a u d and  Their of  and  1.5  pathways o r i g i n a t i n g  nuclei.  the  small-tipped  chloralose anesthesia  studied  that  r u l e d out  and  s t u d i e s , so  represented  comparatively  to  not  cerebello-thalamic fibres  electrodes  parts  conceded  latencies respectively.  M/sec.  using  t h o u g h he  nucleus,  a  wholly  responses VL,  CM,  parts  o f VA,,and  postsynaptic in for  the  in Forels' field  responses of  the  medial p a r t , i . e . , Pf  a rubrothalamic  which occurred  only  stimulating  t h a l a m u s and  the  nucleus,  dentate  ponding to the  direct  seen, i n d i c a t i n g not  due  that  to a c t i v a t i o n  from the  cerebellum.  by  authors  these  responses, latency  BC  the of  i s the  longer  after  short  only  thalamus,  arid 0.8  - 1.3  Other authors  of t h i s  work, and Single  dentate  Uno,  0.5  Y o s h i d a and  given  msec, the  reported  evoked  who  have s e e n s u c h on  S a k a t a , I s h i j i m a and  Hirota  sodium p e n t o b a r b i t a l a n e s t h e s i a . l a r g e number o f c e l l s  - 0.7  f o r some o f  s t u d i e s have b e e n c o n d u c t e d  c e r b e l l o - t h a l a m i c pathways by [1966] and  fibres  cerebello-thalamic  msec, f o r  f i n d VL  was  the the  responses  s t i m u l a t i o n i s p u z z l i n g i n view  t h a t of others  cell  group of  have g e n e r a l l y  to  be  t o NR  However, d i f f e r e n c e s i n  failure  in  corres-  unexpected data  latency of.the  i n the  than these.  and  By  responses  s l o w e r wave s e e n r o s t r a l a slower-conducting  Appelberg's  fastigial  response  red nucleus.  means o f m e a s u r i n g l a t e n c y m i g h t a c c o u n t discrepancy.  fibre  post-  c e r e b e l l o - t h a l a m i c pathway c o u l d  f o r the p r e s y n a p t i c  latencies  form of a  antidromic  only  Evidence  latency response  Perhaps the  waves.  defined.  in.the  to the  a short  diagrams,  complex were f o u n d  pre-synaptic  recording  i . e . , recording  postsynaptic  - Pf  found  rostral  only  From t h e i r  as e a r l i e r  pathway was  s y n a p t i c wave f o l l o w i n g t h e and  CM  H^.  responses. the Toyoda  [1970] , b o t h g r o u p s  using  Sakata e t a l . s t u d i e d  i n VL.Stimulation  of the  BC  evoked  a  26  a presynaptic p o t e n t i a l with synaptic msec.  unit  responses with usual  The p o s t s y n a p t i c  an i n t r a c e l l u l a r  cells  by BC f i b r e s . i n VL  w i t h a mean l a t e n c y  o f 1.7 msec, a f t e r  interpositus  t h e BC a t v a r i o u s  cerebellar  delay of 0.7 msec..indicative  Stimulus  i n t e n s i t i e s required  a c t i v a t i o n o f i n d i v i d u a l VL c e l l s interpositus  smaller  stimuli  those having  nucleus. to N  and a  of monosynaptic  f o r threshold  The number  pattern.  of c e l l s  activated  were a b o u t e q u a l t o T h e s e a u t h o r s were  also  t o d e m o n s t r a t e an i n h i b i t o r y pathway t o VL j u d g e d t o  di-synaptic,  a r i s i n g s e l e c t i v e l y from t h e  The  i n h i b i t o r y , n e u r o n e i n t h e pathway l i e s  red  nucleus  excited  stimulation, exitatory  more r e a d i l y by i n t e r p o s i t u s  of-VL neurones.  Unitary  interpositus.  The  stimulation  projects  to a selected  EPSPs e v o k e d  cells were  t h a n by d e n t a t e  indicating that N interpositus  and i n h i b i t o r y i n f l u e n c e s  N  r o s t r a l to the  and i s t h o u g h t t o be i n VL i t s e l f .  which r e s p o n d w i t h IPSPs t o i n t e r p o s i t u s also  f o r the  were compared f o r d e n t a t e  interpositus  the a l t e r n a t e  By  l e v e l s , t h e y were a b l e t o  f i b r e s , thus c o n f i r m i n g Appelberg's data,  mean s y n a p t i c action.  relay  stimulation.  a mean c o n d u c t i o n v e l o c i t y o f 18 m/sec  calculate  be  Uno e t a l .  f o u n d EPSPs e v o k e d  stimulating  able  2.5  study  and 2 . 2 msec, a f t e r d e n t a t e  by  -  r e s p o n s e s were j u d g e d t o r e p r e s e n t  stimulation  versus  o f 1.5  latencies  m o n o s y n a p t i c e x i t a t i o n o f VL c e l l s in  o f 0 . 7 msec, and p o s t -  latency  i n VL c e l l s  both  group by a  single  • 27cerebellar  v o l l e y were l a r g e  (0.8  those seen i n o t h e r  c e l l s e.g./  izing  BC's  for strongly  o f VL  cells.  capacity  Cortico -  i n cats  cortex  t o VL.  excitatory, synaptic  range of  2.7  -.13  msec, and  had  msec., and  latter  m e d i a t e d by  was  should  period  after decortication.  to e x c i t a t i o n of thalamic  relay  cells the  i n the  The  the  observed  (Figure  the  that  the  a  evoked  duration  decortication. is  cortico-thalamic  three-week s u r v i v a l  i n VPL  2).  This  a usual  depression  the  [1966]  latency  stimulation.  Uno,  and by  seem  attributed  axon  Yoshida  3-5 msec. EPSPs i n VL  i n t e r n a l capsule  they concluded  o f BC  the  Toyoda  phenomenon w o u l d  s t i m u l a t i o n were t r a n s m i t t e d  stimulating  from  with  msec, and  i n h i b i t o r y interneurones  [1970] showed t h a t  VL,  c e l l s , as  have d e g e n e r a t e d  analogous, then,.to that  electrophysio-  even a f t e r c h r o n i c  indicates that  axons o f VL  i n VL  cortical  a b o u t 20  present  observation the  of  fibres  cortical  emphas-  activity  I s h i j i m a and  a depression  depression  a latency  connections  responses  following precruciate  of  i n f l u e n c i n g the  Sakata,  potentials  The  with  s p i n a l motorneurones,  of n e u r a l  •recorded  200  compared  g r o u p s o f w o r k e r s have r e p o r t e d  evidence  pericruciate  of  mV)  VL  Several logical  - 3.2  cells  collaterals and  Hirota  following  monosynaptically.  at varying  distances  conduction v e l o c i t y of  the  By  from exitatory  28 cortico-thalamic extrapolation invaded in  the  only VL  fibres  that 0.5  the  -0.7  cells,  ranged  terminals  msec, b e f o r e  the  appearance of  demonstrated  a topographic  them, i s t h a t cortex  Massion  to medial  i n . more  lateral  lateral  VL.  Area  regions  of  axial  parts, 6 of  the  This  looks  for  pattern feline  Dormont and Using  low  stimulus  activation, with 30%  short of  they  latency  discharge.  polarization of  the  cell.  was'  area  whereas  being to  [1970]  by  also  only  5%  4 send  fibres as  particularly described  the  the  VL  distal  well  and  represented.  Kawana  cortico-VL  for precruciate of  the  anatomically  Kusama, O t a n i studied  to  representing  4 i s related to  that  prefer-  those o r i g i n a t i n g  i s depicted  area  precruciate  6 project  the  cortex  by  cells  [1966].  pathway.  cortical were  activated  e i t h e r a n t i d r o m i c a l l y or s y n a p t i c a l l y .  cells,  polarization with  delay.  noted  the  area  fibres  found  as  of  comprising  intensities  latency  these  o f VL,  similar  Massion  EPSPs  fibres originating  distribution  designated  forelimbs  cortico-VL  of  medial regions  body, w h i l e  musculature>  be  synaptic  p r o j e c t i o n t o VL  part  areas  one  would  [1970] have e l e c t r o p h y s i o l o g i c a l l y  i n the  i n c l u d i n g the  entially  for only  The.pattern  cells  by  fibres  leaving time  cortex.  M/sec. and  the  and  motor  4-10  of  Rispal-Padel  in  from  however, were  5-10  msec, These  seldom  found  latency  exhibit a  followed  authors noted  associated  to  with  that  by  a  the  antidromic  hyper-  long hyperactivation  29 The all  the  short  latency  above w o r k e r s seem t o be  differences being  i n the  hyperpolarizations VPL  [ A n d e r s e n and  not  associated  few  explanations  of  t h e VL  project be  via  t o the  are  axon c o l l a t e r a l s  negative  of very i.e.,  The  a c t i v a t i o n of  The  cortical  and  Cortico-VL  feed-back with  o r no  t h o u g h t t o be Dormont and  of  influences  activity  latter  are  of  could  can  longer  not may  ventro-  be  mediated but  little  or  no  originally  provide  an  example  i n , VL,  in  VPL,.  a l t e r a t i o n s of  surround  inhibition  f e e d - b a c k , more s u i t e d  between one  cell  and  its  inhibition  is  in the.retina for shown t h a t  i n f l u e n c e VL  latency  Many  d i f f e r e n t functions,  t y p e of. s u r r o u n d  importance  areas  (1)  surround-inhibition  self-inhibitory  M a s s i o n have a l s o  cortical.sensory  with  of rhythmic e x i t a b i l i t y  d i s c r i m i n a t i o n of  n e i g h b o u r s . " The  could  whose axons were  two  A  inhibitory fibres  surrounding c e l l s ,  possibility  are  cells.  i n h i b i t o r y interneurones,  g r o u p , o f n e u r o n e s , and  little  the  l e s s numerous i n t h e  cells  for  s t i m u l a t i o n may  hyperpolarizations  latter  to. g e n e r a t i o n  The  for this difference.  absent or  only  i n that they u s u a l l y  s i m i l a r mechanisms s e r v i n g  a localized having  (2)  feed-back t o the  a negative  suited  possible  l a r g e l y to  stimulated.  1968]  antidromic  cortex;  (3)  ranges r e p o r t e d .  d i f f e r e n t from those d e s c r i b e d  d e p r e s s e d by  1  by  b a s i c a l l y s i m i l a r , the  latency  Andersson,  which are  complex;  distributed  fine  are  with  cells  present  basal  excitatory effects described  example.  stimulation bilaterally.  than those  to  from  of These  precruciate  30  cortex  and t h o u g h t  t h a n one  t o be t r a n s m i t t e d  by pathways t h r o u g h  more  synapse.  Pallido-thalamic,  A v a r i e t y of responses of  EN  has been r e p o r t e d .  o f VL n e u r o n e s t o s t i m u l a t i o n  Using extracellular [1969]  D o r m o n t , Ohye and A l b e - F e s s a r d potential to  as s h o r t  as 0.5  presynaptic  activity  and a l a t e r  negative  wave w i t h  40  msec.  -  the  100  that 30  from  -  cellular  o f VA-  responses 200  msec,  responses  potentials. while  latency  o f 10-12  The p r e s y n a p t i c  medial parts  found  a negative  a latency  with  represent  found  VL  were  EN  seen,  Reports  small  msec.  EPSPs  Purpura 0.9 or  [1969]  msec, EN.  with  i n VL  after  cells  after  of bursts  l a t e n c i e s o f 2.5  EN  found EPSPs w i t h  10  than  -  These short  a single cellular  3.0  msec,  this On  the basis 8-10  Desiraju  l a t e n c i e s as s h o r t  action potential.  of action  reported  stimulation.  l a t e n c y EPSPs were  also  msec.  investigation of  s t i m u l a t i o n of the ansa  in  Thirteen excitatory  r e c o r d i n g s , , F r i g y e s i [1969]  intracellular  of  depressed  p a t h w a y h a v e b e e n made b y t w o g r o u p s o f w o r k e r s . of  amplitude  These workers  i n the form  of intracellular  appeared  were d e t e c t e d  s t i m u l a t i o n were  had l a t e n c i e s g r e a t e r  field  and d u r a t i o n  stimulation.  T h r e e had minimum  the others  responses  t o somatic after  msec, w h i c h  msec,  a n d i n CM.  recording,  a s 0.7  lenticularis generally  and -  (AL)  associated  They n o t e d ,  however,  3  t h a t when a s p i k e of  10-20 msec.  apparently also Of  was n o t g e n e r a t e d  PSPs o f 2-6 msec, l a t e n c y w h i c h  o b s e r v e d , as were 10-30 msec.  t h e AL e v o k e d  could  short  EPSP and IPSP s e q u e n c e s .  the p r e v i o u s l y  latency  mentioned  EPSPs were r a r e l y  by  I P S P s , w h e r e a s BC e v o k e d EPSPs were f r e q u e n t l y  by  IPSPs.  F r i g y e s i and Machek  [1970] r e p o r t e d  latency  EPSPs a f t e r EN s t i m u l a t i o n  by  Polysynaptic  BC.  duration  be e i t h e r e x i t a t o r y o r i n h i b i t o r y i n n a t u r e were  p a r t i c u l a r i n t e r e s t was  that  t h e EPSPs had a  1  superimposed  EPSP l a t e n c i e s t h e r e f o r e  3-6  msec,  i n VA - VL c e l l s  of the short  of. 0.7  succeeded, followed  EPSPs s u c c e e d e d by p r o l o n g e d  on t h e s h o u l d e r s  observation  evoked  IPSPs were  latency  excitations  — 0-.9 msec., 2-6 msec. , 8-1.0  msec, and 10-30 msec, have b e e n f o u n d .  This  spread of  l a t e n c i e s m i g h t be a t t r i b u t a b l e t o t h e d i f f i c u l t i e s o f selectively  s t i m u l a t i n g EN, t o t h e e x i s t e n c e  pallido-thalamic indirect  o f groups o f  f i b r e s of d i f f e r e n t s i z e s , or direct.and  p a t h w a y s f r o m EN t o V L .  these p o s s i b i l i t i e s  Probably  a combination of  i s involved.  Nigro-thalamic Frigyesi  and Machek  [1970] h a v e r e p o r t e d  s t i m u l a t i o n of the substantia which could  give  rise  nigra elicited  that  2-4 msec. EPSPs  t o s i n g l e s p i l e s i n VL c e l l s .  EPSPs d i d n o t g e n e r a t e a s p i k e , (5-lQ.msec.) h y p e r p o l a r i z i n g  I f the  t h e y were s u c c e e d e d by  potentials.  Such s h o r t  brief  latency  32 EPSPs were s e e n most f r e q u e n t l y VL  in cells  f r o m BC.  identified  not  be  r e c e i v i n g a monosynaptic  identified  s t i m u l a t i o n , and  responded  t o EN  Intralamino  -  200  msec.  described  imity  the  It  i f this  1969]  latency  In  o f VL,  therefore  stimulated  at a frequency  brain  McMurtry,  S c a r f f , 1966].  msec.  recording  represented  t o see  of  The  a  1965;  The  latency  appears  Because of sites,  indirect  any  the  prox-  i t would  transmission  be  along  neurones  through the  of  a  during and  a n t i d r o m i c a l l y invaded, c e l l s .  t h a t the  pathways.  short  duration  Desiraju, Broggi,.Prelevic, Santini  activation  effectively  which  n u c l e i evoked  a study of medial thalamic  failed  seems p r o b a b l e ,  transmission  in cells  i n these papers but  a b o u t 10  s t i m u l a t i n g and  pathway.  Purpura,  cells  internal  I P S P s w h i c h h'ad;  S c a r f f and  M c M u r t r y and  f i g u r e s t o be  stimulation  later  [Purpura,  from the  direct  observed  of medial-intralaminar  o f t h e EPSPs i s n o t  surprising  found i n  VL.  Purpura, F r i g y e s i ,  of  input  r e l a y n e u r o n e s by  were n o t  l a t e n c y EPSPs s u c c e e d e d by to  as  of  stimulation.  Stimulation  o f up  caudomedial p a r t s  N i g r a l r e s p o n s e s - were most commonly  which could capsule  as  i n the  e f f e c t s are  due  to  When t h e m e d i a l n u c l e i were  7 / s e c . , i t was  cerebello-thalamic  found  that  pathway  was  blocked. e f f e c t s on VL  stem RF  neurones of  have a l s o b e e n s t u d i e d  stimuli  to  [Purpura,  the McMurtry  and  33 Maekawa, 1 9 6 6 ] . a  latency  at  RF  slightly  frequencies  of  s t i m u l i . o f t e n e v o k e d EPSPs u s u a l l y longer  frequencies  resulting  f r o m BC  and  RF  play  respectively  o f VL  two  r o l e s i n the  of  F r i g y e s i and  systems  1968]  relatively  can  long  mulfeisynaptic It by  Machek, 1970]  appear e.g.,  and  afferent that  of d i v e r s e  are  probably  been  and  Purpura,  sensory  1965a,  b;  responses  transmitted  cells  are  activity  have by  and  BC  found.  brain  a f f e r e n t pathways do of  Machek, 1970]  have b e e n f o u n d t o r e s p o n d EN,  i s influenced  o r i g i n a t i n g i n other  and  subnuclear.divisions  cortex.  not  neurones but to  some  several  I t i s probable  w i t h i n VL,  c o r r e l a t i o n between p h y s i o l o g i c a l and has  The  same p o p u l a t i o n  EN,[Frigyesi  systems, e.g.,  there  [Frigyesi  cells.  some c a s e s d i f f e r e n t  and  individual  VL.  pathways.  to i n f l u e n c e the SN  nuclei  f a c i l i t a t i o n ...  through  Albe-Fessard,  a c t i v a t e VL  latency  or  i s a p p a r e n t t h e n t h a t VL  In  co-workers have  and  of caudate nucleus  a w i d e v a r i e t y of. i n p u t s  centres.  depression  IPSPs  VL  [ M a s s i o n , A n g a u t and  Massion,  increased  eliminated  P u r p u r a and  signal transmission  Stimulation  and  Stimulation  systems, the m e d i a l - t h a l a m i c  O t h e r Systems I n f l u e n c i n g  1964;  neurones  stimulation.  t h a t the  may  evoked EPSPs.  50-75/sec. g e n e r a l l y caused  discharge  proposed  t h a n BC  with  but  anatomical  I t i s also probable that within  little  sub-groups any  one  area  o f VL, d i f f e r e n t types o f neurones w i t h r e l a t i v e  icity  of connections e x i s t .  i n d e f i n i n g such c e l l  VL  p r o g r e s s h a s b e e n made  types.  Efferent The  e f f e r e n t pathway o f VL t o motor c o r t e x  been s t u d i e d VL  Little  cells  electrophysiologically.  following  o f c a t s has been r e p o r t e d  Toyoda  [1966] Uno, Y o s h i d a and H i r o t a  and  Massion  cortical  and  Massion  cortex for  Sakata e t a l .  using  Thus t h e a s c e n d i n g  one s y n a p s e i n V L .  t o motor  Rispal-Padel  showed a t o p o g r a p h i c p r o j e c t i o n o f VL c e l l s t o  with a pattern  similar to that previously  the cortex-VL p r o j e c t i o n , i . e . c e l l s send  Rispal-Padel  antidromically  pathway a p p e a r s t o have a d i r e c t l i n e  i n v o l v i n g only  invasion of  of precruciate  [1970] and  to activate  a l m o s t h a l f o f BC e v o k e d VL c e l l s .  cortex,  has a l s o  by S a k a t a , I s h i j i m a and  [1970] t o name a few.  s t i m u l a t i o n were a b l e  cerebellar  Antidromic  stimulation, particularly  cortex  VL  specif-  f i b r e s to medial parts  l a t e r a l VL c e l l s This  pattern  that  shown  project  of medial parts of  of precruciate  to l a t e r a l  described  c o r t e x and  precruciate  cortex.  f o r t h a l a m u s - c o r t i c a l f i b r e s appears s i m i l a r t o  by S t r i c k  [1970] .  L-  Y o s h i d a , Y a j i m a and Uno [ 1 9 6 6 ] , A m a s s i a n [1966] and L e b l a n c a n d C o r d e a u  [1969] have shown  and W e i n e r organized  short  latency  motor c o r t e x  e f f e c t s o f VL  which c o n t r i b u t e  Yoshida et a l . i d e n t i f i e d in  cerebral cortex  the  stimulation  by  to the  fast.and  The  activated with a latency  fast  cells  appropriate o f VL.  activated  was  same c e l l s ,  s y n a p s e i n VL  and  ing pyramidal, c e l l s longer  and  of  on  the  activity  is  s u i t a b l e t o the  pathway i n t h e  responses  of  of  BC  cortex.  fast  The  over a p o l y s y n a p t i c  after  slowly  only  conduct-  and  with  pathway.  seems t o have  a d i r e c t and  strong  The  the  influence  conducting pyramidal c e l l s .  This  r o l e some a u t h o r s have a t t r i b u t e d t o  Cordeau  o f movement  [1969] h a v e a l s o  fast-conducting noted  [Evarts  1969].  latency VL  following prolonged i n h i b i t i o n s  at. v a r i o u s  rhythmic a c t i v i t y t o VL  These authors p o i n t e d  this  Thach,  pyramidal neurones to  e x c i t a t i o n s a t a b o u t 200-250 and  responded o p t i m a l l y  and  shown s h o r t  s u c c e e d e d by  the  be  VL,stimulations,  but  that  to  less frequently  latencies after  to exert  from  stimulation  judged t o occur  were a c t i v a t e d  initiation  s t i m u l a t i n g VL  tract.  were f o u n d  stimulation,  By  the  f o r a monosynaptic  pathway, t h e r e f o r e  required  L e b l a n c and  a t the  transmission  cerebello-thalamic properties  and  one  more v a r i a b l e  indicative  pyramidal  of  slow p y r a m i d a l neurones  pathway f o l l o w i n g s t i m u l a t i o n  one  cells  a c t i v a t i n g them a n t i d r o m - i c a l l y  medullary pyramids.  the  on  out  frequencies,  i n the  concluded  large pyramidal  volleys at-rates that  they  400-450 msec.  this  cells  of  4-5/sec.  frequency  i s about  the  same as t h a t of P a r k i n s o n i a n tremor and rhythmic  electrical  a c t i v i t y noted  Monkeys  i n VL of P a r k i n s o n i a n p a t i e n t s .  e x h i b i t i n g tremor a f t e r mesencephalic  l e s i o n s have synchronous  e l e c t r i c a l a c t i v i t y i n v a r i o u s b r a i n r e g i o n s which i s l o s t i n some a f t e r i m m o b i l i z a t i o n w i t h gallamine  triethiodide,  but i s r e t a i n e d i n VL, motor cortex and pyramidal [Lamarre and Cordeau, 1964].  These o b s e r v a t i o n s  the c o n c l u s i o n t h a t the VL-cortex  pathway may  p a r t i a l l y supported  by the well-known  allowed  play a r o l e i n  the genesis of tremor of the P a r k i n s o n i a n type. is  tract  The  conclusion  e f f i c a c y of  VL  l e s i o n s i n reducing P a r k i n s o n i a n tremor, [e.g., Cooper, e t al.1968] The responses  obtained i n neurones of medial non-  s p e c i f i c thalamic n u c l e i a f t e r VL s t i m u l a t i o n have been s t u d i e d by D e s i r a j u e t a l . [1969]. s h o r t l a t e n c y IPSPs and repetitive stimulation.  They f r e q u e n t l y found  complex EPSP and The  IPSP p a t t e r n s a f t e r  authors presented no  evidence,  however, on the pathways by which these e f f e c t s were t r a n s m i t t e d , whether they arose s p e c i f i c a l l y  from e x c i t a t i o n  of VL c e l l s or whether a c t i v a t i o n of f i b r e s p a s s i n g VL could have been r e s p o n s i b l e .  through  37 ROLES OF  The difficult in  the  r o l e or  r o l e s of  to perceive  i n part.as  AND  the  at t h i s  number of" p r o p o s a l s  That i t acts  VL  v e n t r o l a t e r a l nucleus  t i m e ,• and  a r e l a y nucleus  c e r e b e l l a r n u c l e i to the  in  light  of  by  BC  fibres.  very The  strong  large  f r o m a c t i v a t i o n o f BC factor  on  many o f  simultaneous effect  synaptic  made e v i d e n t . b y fibres brain part the  to  i t .  centres as  an  basal  relay  s i z e of  motor.cortex  the  transmission,  only  a few  so t h a t  a given of  VL  safety  though  cell,  them i s r e q u i r e d  to  l a r g e number o f n e u r a l  centres  send  profusion  from d i f f e r e n t .  This leads  t o the  The  of  afferents  postulate  notion  l a r g e number o f  t h a t VL  that  the  on  basal  descending  classical  c a r r i e d out  may  for information  the  Two  which  function  supplied ganglia  in  by are  .  extrapyramidal  reasons e x i s t f o r  anatomical basal  show a d e s c e n d i n g pathway o f any and  a large  the  ganglia.  rubrospinal  cells  is  stations in a multisynaptic  to  VL  relay nucleus  anatomical studies failed  on  i s much more t h a n a s i m p l e  i n t e g r a t i o n centre  The  is.undeniable  discharge.  system i s r a p i d l y , l o s i n g p o p u l a r i t y . this.  passing  u n i t a r y EPSPs r e s u l t i n g  t e r m i n a t e on  a c t i v a t i o n of  T h a t VL  for signals  f i b r e s probably confers  f i b r e s may  a post  is reflected  influence exerted  cerebello-thalamic  these  this  are  t h a t have b e e n made f o r i t s f u n c t i o n s .  from the  the  CM  r e t i c u l o s p i n a l pathways a r e  and  ganglia  electrohave  magnitude, i f the excepted..  The  38 two  nuclei  large  giving  numbers o f  apparently or  very  to these  afferent  the  systems has  indicates  that descending  vestibular  these  from major  are  cerebral  available  telencephalic by  way  nuclei  o f VL  not  and  and  VA  selective  known, t h e y  do  and  of  o f VL  VL  i n the  with sensory  nuclei  provides the  regulation t h a t VL but  and  role  definition.  nuclei ing  correction  i t s relative  as  a  importance p l a y e d by  also  The  afferents the  seem t o for  CM.  to support  the  the  be  connections  with other  It.seems aspects  one  i s not  of  motor,  the  may  movement,  farther  intralaminar .  comprising a p a r t of  system  probable  known.  i n movement i s e v e n  consideration of  activating  centres  for i t to act.as a centre for  t o each  group  motor  possible  in circuits  of these  CM  1968],  d i e n c e p h a l i c and  o f movement.  i n each  functional  reticular  and  of  Therefore  o f movement; and  potential  plays a role  The from  systems  nucleus  movement w o u l d  w i t h some r o l e  initiation  medullary  receive  cerebellum.  extra-  lesions  in  other subcortical  to influence  i s that  [Kuypers,  V a r i o u s • e v i d e n c e s have been c i t e d role  reason  interstitial  means f o r t h e . S N  cortex,.and  o f , p y r a m i d a l and  red nucleus  of  relatively  the d i e n c e p h a l i c  second  s t u d i e d by  c o r t e x and/or  nuclei  from  pathways o r i g i n a t e  connections  nuclei  the  The  reticular,formation,  Though d i r e c t to  been  the motor  i f any,  importance  pyramidal  Cajal,  from  basal ganglia.  i n which  and^pontine  pathways r e c e i v e  fibres  small-amounts,  telencephalic  r e c e n t work  rise  have obscured  the the  ascend-  potential  r o l e o f c e r t a i n o f t h e component  control.  The  specificity  pallidal  afferent  efferent  connection  refocus  attention  inputs  n u c l e i i n motor  o f , , f o r example, t h e c o r t i c a l t o t h e p a r v o c e l l u l a r CM  to l e n t i f o r m nucleus  should  and  and i t s help  on t h e i n d i v i d u a l n u c l e i o f t h e  to  intra-  laminar group.  Interpretation  p e r t i n e n t , t o CM  i s d i f f i c u l t , b e c a u s e most w o r k e r s have n o t  attempted the  of the p h y s i o l o g i c a l  to d i f f e r e n t i a t e findings  intralaminar  system.  Stimulation  s y s t e m s have b e e n c l a i m e d examination of the data  i n various  to alter  sometimes  shows t h a t  the responses  example  to  sensory  Fessard,  t h e r e s p o n s e s .found i n CM [Conde and A n g a u t , 1970]  l i m i t s which CM.  would  of.the  CM-Pf c o m p l e x .  following  dentate N  a p p e a r t o be  o f t h e c o m p l e x , . a n d t h e CM  s t i m u l i described  [1963] ' were  neural  i n CM,.however,.  For  parts  by A l b e - F e s s a r d  found,only within  e x c l u d e most,  of  activity  l o c a l i z e d t o t h e more m e d i a l p a r t s  from the l a t e r a l  components  of various  are  stimulation  literature  of the  excluded responses  and  medial-lateral parvocellular  40 I O N T O P H O R E S I S AND T H E PHARMACOLOGY OF T H A L A M I C  The  technique  of iontophoresis  microelectrophoresis) and  L i m [1936],  junction  and l a t e r  [Nastuk,  Eccles, 1958]. study  used  that  o f almost every  introduced i n studies  time,  t o record  group o f c e l l s . environment The  is  Salmoiraghi  several region to  glass  cells  pipettes  diameter. having  produced. sectional  In this  diameter  o f about  is  drugs  electrolyte, t o be t e s t e d .  t o be s t u d i e d  assembly small  barrels. Krnjevic  and others  may b e p r e p a r e d  way, a f u s e d  and b r i e f l y  by f u s i n g  one c r o s s - s e c t i o n a l  of the softened cluster of  of 1 p or less,  The t i pi s t h e n broken back t o a t o t a l  a strong  ionized  [1967]  t i p diameter  cells.  o f one o r a  and then h e a t i n g  4-6 u, i n o r d e r  impedance o f t h e- e l e c t r o d e s . with  pipette  [1964],  t o permit drawing  a total  excitable  into the extracellular  by C u r t i s  The e l e c t r o d e s  i n .a m i c r o f o r g e  a fine  o f t h e mammalian  from t h e neighbouring  and S t e f a n i s  capillaries  [ C u r t i s and  (2-9) g l a s s  I o n s may b e e j e c t e d  of these  as f o l l o w s .  region  the electrical•,activity  method has been d e s c r i b e d  [1964],  of the neuromuscular  and i n v e r t e b r a t e  One b a r r e l o f a m u l t i - b a r r e l e d used  by. S u h , Wang  i t has been employed i n  cellular  CNS a n d o f m a n y v e r t e b r a t e  is  (microiontophoresis,  1953] and t h e s p i n a l c o r d Since  :  the  was f i r s t  NEURONES  The r e c o r d i n g  and the.others  microc a n be  cross-  t o reduce the barrel i s filled  with  solutions of  The a c t i v e i o n o f a d r u g  c a n be s e l e c t i v e l y  glass  discharged  from t h e  which  41  e l e c t r o d e by p a s s i n g anions,  the a p p r o p r i a t e  current  (-ye t o e j e c t  +ve t o e j e c t c a t i o n s ) through the drug s o l u t i o n . T h i s technique i s of p a r t i c u l a r value  i n pharmaco-:  l o g i c a l s t u d i e s o f the CNS> not only because s m a l l populations  cell  can.be s e l e c t i v e l y exposed t o the d r u g — t h u s  a v o i d i n g secondary drug e f f e c t s , but a l s o because many i o n i z e d drugs do not gain access tration:.  Iontophoresis  d e f i n e chemical  t o the CNS a f t e r systemic  adminis-  has been used mostly i n attempts.to  t r a n s m i t t e r s a t s p e c i f i c s i t e s by f i r s t  e s t a b l i s h i n g the e f f e c t s of p o s t u l a t e d  t r a n s m i t t e r s on the  neuronal a c t i v i t y and then t e s t i n g p o s s i b l e b l o c k i n g agents on these induced  e f f e c t s and on s y n a p t i c  Because some chemical  agents, p a r t i c u l a r l y some of the d i a c i d i c  amino a c i d s , have strong and u b i q u i t o u s on neurones, i o n t o p h o r e s i s physiological studies. which do not d i s c h a r g e  transmission.  excitatory actions  can a l s o be of value  i nelectro-  Such agents can be used to f i n d  cells  spontaneously, and a l s o t o induce a  steady l e v e l o f a c t i v i t y  i n such c e l l s so t h a t  inhibitory  or depressant i n f l u e n c e s can be s t u d i e d . There are many u n c e r t a i n t i e s a s s o c i a t e d . w i t h the i o n t o p h o r e t i c method. achieved due  The c o n c e n t r a t i o n  around a c e l l i s impossible  o f an agent.which i s  t o estimate  accurately,  t o u n c e r t a i n t i e s about the amount of drug being  by a given  extruded  c u r r e n t , the d i f f u s i o n c h a r a c t e r i s t i c s o f the  agent from the e l e c t r o d e t i p and i n the e x t r a c e l l u l a r f l u i d , and  the extent o f i t s i n t e r a c t i o n with t i s s u e components,  e.g.,  enzymes and  membrane b i n d i n g o r t r a n s p o r t  Further,  the  uniform,  particularly  extensive  concentrations  dendritic  have more t h a n tested, for  the  e f f e c t e d are u n l i k e l y  about l a r g e c e l l s ,  fields. one  particularly  local  Phillis,  I960].  the  d r u g may  affect  recorded, the cell  electrical  agent.  cell  activity  and  thus  action i n  [Curtis  modified  few by  the  masking the  muscle r e l a x a n t s )  i s necessary,  i s that  cells  and  occur,  effects  d r u g s may effects.of  the and  [e.g., P h i l l i s  t h e r e f o r e t o be  being of  which i n t e r a c t with  i n t e r a c t i o n s between s y s t e m i c  It  The  or  may  Atropine,  [McLennan, 1 9 7 1 ] .  i n passing  a number o f i n s t a n c e s  of  single  c o u l d be  i o n t o p h o r e t i c a l l y may  of r e s u l t s  the  i s recorded  in  The itself the  drugs  substances have b e e n  and  cautious  chemical (e.g., being  demonstrated  Tebecis,  i n the  the  1967].  interpretation  iontophoretic studies.  effects  of  i o n t o p h o r e t i c a l l y a p p l i e d amino a c i d s  have b e e n t e s t e d i n most c e l l u l a r nervous  anesthetic-type  interneurones  c u r r e n t used  Finally,  anesthetics applied  more t h a n  adjacent  whose a c t i v i t y  modify  concentrations.  Another p o s s i b l e c o m p l i c a t i o n  so t h a t r e s u l t s  a g e n t on  used  are u s u a l l y  to i t s cholinergic blocking properties  and  be  with  chemicals  a c t i o n f o r which they  at high  to  o r ones  Some.of t h e  example seems t o have a l o c a l  addition  systems.  system.  s u c h as g l u t a m i c  regions  S e v e r a l of the d i a c i d i c acid,  aspartic acid,  of the  central  monobasic  acids  homocysteic acid  and  many of t h e i r d e r i v a t i v e s have strong e x c i t a t o r y a c t i o n s on. neurpnes,while the monoacidic monobasic ones such as g l y c i n e , g'^-alanine and Y -  a m i r  iobutyric  and Watkins, I960].  a c i d a r e depressant [ C u r t i s  The e x c i t a t o r y amino a c i d s have been  shown t o e x c i t e neurones i n the s p i n a l cord Watkins, 1960] , l a t e r a l g e n i c u l a t e nucleus  [ C u r t i s and [ C u r t i s and Davis,  1962] , c e r e b r a l cortex  [ P h i l l i s and K r n j e v i c , 1961] and ,  apparently  region tested.  property,  every other  Because of t h i s  these amino a c i d s are r o u t i n e l y used i n i o n t o p h o r e t i c  studies to locate e l e c t r i c a l l y c o n t r o l s f o r drug e f f e c t s .  q u i e s c e n t neurones and as  T h e i r a c t i o n s are so widespread  t h a t i t has been presumed t h a t the e x c i t a t i o n i s due t o  a  n o n - s p e c i f i c e f f e c t on neuronal membrane, and not r e l a t e d t o a c t i v a t i o n of t r a n s m i t t e r r e c e p t o r  sites  [ C u r t i s and Watkins,  1963] . The  r e l a y n u c l e i o f the thalamus have been s t u d i e d  e x t e n s i v e l y with the i o n t o p h o r e s i s  technique i n attempts t o  i d e n t i f y the t r a n s m i t t e r agents r e l e a s e d by t h e i r a f f e r e n t pathways.  The f i r s t study of VL was r e p o r t e d  His r e s u l t s were very f o r the v e n t r o b a s a l Iontophoretic  s i m i l a r t o those p r e v i o u s l y  complex  [1966].  reported  [Anderson & C u r t i s , 1964 a & b ] .  a p p l i c a t i o n of a c e t y l c h o l i n e  caused the VL neurones t o d i s c h a r g e facilitated  by Davis  (ACh) or c a r b a c h o l  a t h i g h r a t e s and  s y n a p t i c a c t i v a t i o n a f t e r BC s t i m u l a t i o n .  Muscarone, a c e t y l - 3 - m e t h y l c h o l i n e excitatory effects.  had s i m i l a r , but l e s s potent  The ACh e x c i t a t i o n was blocked by  atropine,  dihydro-3-erythroidine  (DHBE) a n d t r i h e x y p h e n i d y l  but  the synaptic^activation of cells  not  affected.  both  t h e ACh  blocked, (DLH)  exitation  b u t s o was  indicating  and.the  earlier  that  atropine  reports  a n o n - s p e c i f i c manner  BC  other - VL  also  were t h a t  thalamic  muscarinic  observation  though  that  1966  muscarinic  blocker  a,b]  likely  classes  of drugs.  t h a t VL  and  This  and P h i l l i s ,  receptor  may  both  &  Curtis,  blocker  t o t h e Renshaw  e x c i t e d by n i c o t i n i c  agents  types  dihydrocells,  [ C u r t i s and  a r e a f f e c t e d by  1963; C r a w f o r d  n e u r o n e s a r e e x c i t e d by be  I t may  by e i t h e r t h e  or the n i c o t i n i c  the thalamic  of both  Davis'  as were t h e  be p r e v e n t e d  In contrast  [Krnjivic  1966],  I960].  mediated.  complex [Andersen  atropine  with  have c h o l i n e r g i c i n p u t s ,  and c o r t i c a l _ n e u r o n e s w h i c h  drugs  Further  acid  excitation  t h e VL n e u r o n e s were e x c i t e d by  (DH3E).  Curtis,  presence  neuronal  i s not cholinergically  are selectively  Ryall,  i s i n accord  and n i c o t i n i c c h o l i n e r g i c d r u g s ,  0-erythroidine which  i t seemed  and ACh e x c i t a t i o n c o u l d  muscarinic  a c t i v a t i o n were  [ C u r t i s and P h i l l i s ,  neurones of the ventrobasal 1964b]  can block  r e l a y n u c l e i may  transmission  be n o t e d  ejected,  a n o n - s p e c i f i c b l o c k i n g o f membrane latter  the  synaptic  were  t h e e x c i t a t i o n b y D, L - h o m o c y s t e i c  This  conclusions  s t i m u l a t i o n was  I f l a r g e r amounts o f a t r o p i n e  excitability.  in  b y BC  and  both  i n t e r p r e t e d as due t o a or a hybrid  s t u d i e s on t h a l a m i c  receptor.  relay nuclei including  VL were c a r r i e d o u t by McCance, P h i l l i s  and Westerman  [1968a]  45  and  McCance, P h i l l i s ,  findings  Tebecis  were s i m i l a r  and Westerman  t o those  of Davis  number o f s u b s t a n c e s were t e s t e d and a c e t y l - 3 m e t h y l c h o l i n e  ACh  potent  cholinomimetic  and  mecamylamine  neurones. actions but  also depressed  inhibitors  often  had e x c i t a t o r y  the tertiary  compound e s e r i n e ,  and sometimes t h e  were  The l a t t e r  the greatest  authors  that  s e n s i t i v e neurones were more d o r s a l In  synaptic Westerman  parts,  their  prolong  t h e e x c i t a t i o n caused by L-  also reported  that  o f ACh s e n s i t i v e c e l l s  p e r c e n t a g e (41%)  i n t h e v e n t r a l VL t h a n i n  (23%).  i n v e s t i g a t i o n of i n t e r a c t i o n s o f drugs  [1968b] from  iontophoretically  were N  T h e y a l s o made t h e  a much h i g h e r  found  eta l . ,  the nuclei  a c t i v a t i o n i n the thalamus. M c C a n c e P h i l l i s  complex c e l l s  atropine  t o enhance and/or  VPL and VL.  observation  compounds,  and C u r t i s , 1964b; McCance  proportions  ventralis medlalis interesting  found  altering  (LG), [Anderson  1968a].  its  t h e A C h e x c i t a t i o n o f some  the quaternary  inhibitors  found  were t h e  DH3E, h e x a m e t h o n i u m  own, p a r t i c u l a r l y  glutamate  of  and hyoscine  of their  e x c i t a t i o n without  with  although  Carbachol,  t o be t h e most  Atropine  agents,  Cholinesterase  quaternary ACh  iontophoretically.  excitants.  most e f f e c t i v e b l o c k i n g  Their  [1966] b u t a l a r g e r  were found  -  [1968].  that  the medial applied  the activation of  and  ventrobasal  l e m n i s c u s was n o t b l o c k e d  atropine  i n a d o s e o f 1 mgm/kgm.  with  o r DH$E, o r b y Cortico-thalamic  by  intravenous responses  46  were t e s t e d w i t h and  DH BE  iontophoretic  with negative  application of atropine  results.  BC e v o k e d s p i k e  were n o t a l t e r e d by i o n t o p h o r e t i c a l l y a p p l i e d  responses  atropine,  h y o s c i n e o r DH(3E, t h o u g h ACh e x c i t a t i o n was a b o l i s h e d . Atropine  (0.25 - 1.0 mgm/Kg) a d m i n i s t e r e d  r e d u c e the.BC evoked  field  intravenously d i d  p o t e n t i a l by 30-40%.  C e l l s which  were e x c i t e d by s t i m u l a t i o n o f m e s e n c e p h a l i c r e t i c u l a r , (MRF) were s t u d i e d  a l s o , and i t was r e p o r t e d  that  formation  i n some o f  t h e s e t h e e x c i t a t o r y e f f e c t s o f b o t h MRF s t i m u l a t i o n and ACh c o u l d  be. b l o c k e d  o r DH3E.  In other  refractory  to the cholinergic blocking  drawn f r o m t h e s e partially  by i o n t o p h o r e t i c a l l y a p p l i e d cells,  studies  r e s p o n s e s t o MRF s t i m u l a t i o n  were t h a t  m e d i a t e d by ACh a n d t h a t  The  MRF e v o k e d r e s p o n s e s were o f l o n g  The  observation  ACh s e n s i t i v i t y  altering in  (2-4  that  f r o m t h e MRF. indicating  T h a t t h e MRF e f f e c t s were i f a cholinergic  i t was a t t h e l e v e l  o f VL.  sodium p e n t o b a r b i t a l  o f thalamic  neurones without  e x c i t a t i o n by amino a c i d s was more f u l l y  another p u b l i c a t i o n  report  latency,  iontophoretically indicates that  synapse had been b l o c k e d ,  the  t o t h e thalamus  pathway.  The c o n c l u s i o n s  s u p p o r t was f o u n d f o r  idea of c h o l i n e r g i c inputs  blocked  agents.  showed t h a t v e r y  [Phillis small  were  t h e BC - VL pathway i s  the  a probable multisynaptic  atropine  & Tebecis,  1967].  d o s e s o f I.V.  mgm/kgm) m a r k e d l y r e d u c e d NA d e p r e s s i o n  depressed significantly reported This  pentobarbital o f LG f i r i n g i n  one  cell,  leaving  and  completely  t h e LG e x c i t a b i l i t y  blocked  t h e ACh s e n s i t i v i t y  w h i l e LG e x c i t a t i o n was o n l y The  effects  apparently unaltered,  o f ACh and a t r o p i n e on t r a n s m i s s i o n i n i n an e a r l i e r  by  Frigyesi  and P u r p u r a  [ 1 9 6 6 ] , who n o t e d  of  ACh i n t o  the c a r o t i d  artery  by 250  field  potential  y g and m a r k e d l y r e d u c e d  subject  t o t h e same c r i t i c i s m ;  blocked  systemic  could  iontophoretic effects  and  5-hydroxytryptamine  from  were  o f VL  cells  a threshold to a . • In t h i s afferent  by a t r o p i n e .  [1967] s t u d i e d t h e e f f e c t s o f  o f monoamines on t h a l a m i c  of noradrenaline  some d e p r e s s e d  I f this  e v o k e d b y any o t h e r  application  The  excited,  tonic discharge to  f o r t h e BC e v o k e d EPSPs  and T e b e c i s  The  i f atropine  depolarization  a l s o have b e e n r e d u c e d  Phillis  a t 750-1000 y g .  m i g h t have b e e n e x p e c t e d .  s i t u a t i o n , , the responses pathway s h o u l d  a t a dose o f  Therefore  pathway w i t h  change t h e membrane p o t e n t i a l level  administered  t h a t no o t h e r pathway t o V L  the removal o f a t o n i c  subthreshold  injections  and McCance e t a l . a r e  atropine.  any c h o l i n e r g i c  t h e same e f f e c t  the case,  and P u r p u r a ,  report  e n h a n c e d t h e BC  atropine  the response  of F r i g y e s i  VL  transiently  i n VL, w h i l e  reports  had  that  t h e same r o u t e had some b l o c k i n g a c t i o n  was t e s t e d w i t h  neurone,  reduced.  t h e BC - VL pathway had b e e n i n d i c a t e d  evoked  o f another  neurones.  (NA), a d r e n a l i n e , i s o p r e n a l i n e  (5HT) were m i x e d , some c e l l s and o t h e r s  being  s h o w i n g no a p p a r e n t . e f f e c t .  Cells  of the v e n t r o l a t e r a l  more o f t e n regions.  e x c i t e d by Dopamine  group  of n u c l e i  these drugs  (DA)  (VBC  than c e l l s  d i d not e x c i t e  and VL)  i n other  thalamic  neurones,,  but r a t h e r e i t h e r  d e p r e s s e d ' them o r d i d n o t a l t e r  excitability.  interesting  An  s e p a r a t i o n o f a and from  this  might in  study.  have b o t h  concept  o b s e r v a t i o n was  3 - r e c e p t o r e f f e c t s was  Rather,  their  that not  i t . a p p e a r e d as t h o u g h  t y p e s o r mixed r e p o r t s .  a  clear  possible the  neurones  This i s similar  t o the o b s e r v a t i o n s r e g a r d i n g the e f f e c t s  muscarinic  and  nicotinic  drugs  on  were  thalamic  of  neurones.  PARKINSON'S DISEASE  That lateral  t h e r e i s some r e l a t i o n s h i p between t h e v e n t r o -  n u c l e u s and  efficacy  of.lesions  rigidity  typical  1968].  The  n o t known.  Parkinson's disease i s indicated t o VL  in relieving  of Parkinsonism  the tremor  [Cooper,  reason  f o r the e f f e c t i v e n e s s  I t has  been thought  important  f o r the  the  and  Samra and of such  by  Bergmann,  lesions i s lesion  interrupt  t h e p a l l i d o - t h a l a m i c pathway, b u t C o p p e r e t a l .  feel  the l e s i o n  that  posterior  part  t h a l a m i c and induced  o f VL,  I960].  Parkinsonian  in a position  interrupting  c e r e b e l l o - t h a l a m i c pathways.  i n monkeys by  [Poirier,  i s most e f f e c t i v e when l o c a l i z e d  selective  If this  tremor,  lesions  tremor  further  both  Tremor c a n  to the  to  to  the  pallidobe  midbrain  i s a c c e p t e d as a m o d e l o f  evidence  f o r an  involvement  of  VL may be f o u n d . several fire  regions  I n such a n i m a l s u n i t d i s c h a r g e s from of the nervous  i n synchrony with the tremor.  curarizing disappear remain  agent causes t h i s  with  and C o r d e a u , 1964;  [Albe-Fessard, Guiot,  1966; J a s p e r and B e r t r a n d , 1 9 6 6 ] . that  synchronous  activity  fully  used  were t h e f i r s t  congeners  of atropine  are s t i l l  be p r o p o s e d .  Belladonna  among t h e most p o p u l a r  agents; but the l i s t  f o r which  success  d r u g s t o be u s e d , and c h o l i n o l y t i c  now a l s o  h i s t a m i n e s , p h e n o t h i a z i n e s and L - d o p a .  includes  L-dopa  anti-  i s the only  a reasonable pharmacological r a t i o n a l e can  Parkinson's disease  i s often  a degeneration or depigmentation of c e l l s nigra  type.  o f p h a r m a c o l o g i c a l agents has been  alkaloids  agent  I t i s possible  i n the treatment of Parkinsonism.  therapeutic  Lamarre  i n VL i s i n v o l v e d i n  g e n e r a t i o n o f tremor o f the P a r k i n s o n i a n A variety  synchronous  r e c o r d e d i n VL and o t h e r t h a l a m i c n u c l e  Parkinsonian patients.  therefore  a c t i v i t y to  In addition,..rhythmic a c t i v i t y  tremor has been  of a  but the synchronous d i s c h a r g e  i n VL and motor c o r t e x . [Lamarre  and A r f e l ,  the  Administration  synchronous  f r o m some l o c a t i o n s ,  Cordeau,,1966].  of  s y s t e m have b e e n . f o u n d t o  [Greenfield  and B o s a n q u e t ,  s t r i a t a l . p a t h w a y h a s been [Sourkes & P o i r i e r ,  1953].  postulated  associated with of the substantia  A dopaminergic  on n e u r o c h e m i c a l  1965] and h i s t o c h e m i c a l  Fuxe and L a r s s o n , 1965] grounds.-  [Anden, D a h l s t r o m  The c o r p u s s t r i a t u m o f  P a r k i n s o n i a n p a t i e n t s has been,found  nigr  to contain  lesser  50 amounts  o f dopamine than  [Ehringer  and H o r n y k i e w i c z ,  therefore, systemic ments  those.of  non-Parkinsonian  I960].  t h a t L-dopa c r o s s e s  I t has been  the blood  administration, is converted  the s t r i a t a l  brain  individuals  proposed, barrier  after,  t o dopamine and s u p p l e -  dopamine d e f i c i e n c i e s  of Parkinsonisn  patients. The n e u r a l b a s i s f o r e f f e c t i v e n e s s o f t h e o t h e r of drugs results and  i s unknown, a s - i s obtained with  Marshall  tremorine  other  such.widely  potency  studied the latter  of drugs.  anticholinergic  h i s t a m i n e s were inhibition  o f ACh a c t i o n  a definite  relationship  drugs the  i n blockage  Parkinsonism. are  effective  character.. Parkinsonian who  found  acerbated  i s found  that systemically  p i g ilieum.  They  found  inhibition  o f some r o l e  of  of  that the various  drugs  anticholinergic  o f ACh i n  i n t h e work o f D u v o i s i n  [1967],  administered physostigmine  ex-  r e v e r s e d by ' B e n z t r o p i n e  [1969] o n t h e o t h e r  anti-  of the various  tremor,  manifestations of Parkinsonism.  were.promptly & Snyder  indication  atropine  and c o m p e t i t i v e  l a r g e degree because o f t h e i r  A further tremor  and  o f ACh and t h e a l l e v i a t i o n  I t i s p o s s i b l e then to a  tremor  between t h e potency  anti-  including  phenothiazine  on guinea  Ahmed  using  m o d e l f o r CNS  of the experimental  peripheral effects  question  on t r e m o r i n e  therapeutic  compounds.  Several drugs  agents,  tested both  f o r the positive  different  induced tremor as an assay  cholinergic and  [19 62]  the reason  groups  These  effects  or scopolamine.  hand have t r i e d  Coyle  to relate,the  effectiveness  of antiparkinsonian  block  the uptake  Their  i n vitro  drugs  t o be i n h i b i t o r s  Ljungdahl  studies  histochemistry  with  various  Parkinsonism.  antihistaminic did  by a s s e s s i n g  of.dopa  found  by s e v e r a l  i n antiparkinsonism  and a-methyl--  and ones  that  amine uptake  pre-r  seemed  o f t h e d r u g s , b u t some including  I t seems p r o b a b l e '  of striatal  by  i n the treatment of.  and a n t i c h o l i n e r g i c d r u g s ,  though b l o c k i n g  atropine  therefore  that  d o p a m i n e u p t a k e may h a v e  some  therapy,  anticholinergic activity  important. If  least of  Fuxe, G o l d s t e i n and  i n vivo  the uptake  agents used  n o t seem e f f e c t i v e .  role  idea  to  antiparkinsonian  i n control animals  They a l s o  p a r t i a l l y .blocked  is  this  process.  ability  synaptosomal  a variety of  of this  into the neostriatum  injected  into striatal  showed  [1970] t e s t e d  fluorescence NA  o f dopamine  drugs t o t h e i r  i n part  their  recent  i t i s assumed  site  by b l o c k i n g  antiparkinson  drugs  actat  c h o l i n e r g i c f u n c t i o n , the problem  o f action remains.  P o s s i b l y because of the  i n t e r e s t i n dopamine and t h e n i g r o - s t r i a t a l  and  because.of  has  been  the high  focussed  drugs were  experiments  injected into parts  been c a r r i e d . o u t [1970].  pallidus  cholinesterase  on t h e corpus  Interesting  Baker  that  by Nashold  Nashold  content,  attention  striatum. i n which  small  of the corpus  amounts o f  striatum  [1959] a n d L a l l e y , R o s s i  found .that ACh i n j e c t e d i n t o  (GPj. o f P a r k i n s o n  pathway  patients  have and  globus  increased c o n t r a l a t e r a l  52 tremor, while reduced  tremor  injected  or  small  carbachol found  the  rigidity  i n most c a s e s .  amounts of  into  that  a n t i c h o l i n e r g i c agent oxyphenonium  the  caudate  nucleus could  of  be  either cholinesterase inhibitors  by  local  m i c r o i n j e c t i o n s of  of  of  two  c h o l i n e r g i c pathways  as  a pacemaker  o f VL  neurones to  i n the  carbachol  the  a part  thalamus.  t o VL,  production  p o s s i b l e support  Tremor  and  produced  was  antagonized  the  of  The  least great  the  suggested  tremor  Parkinsonian  f o r this  possibility at  a p p l i c a t i o n o f ACh,  lesions in relieving  provide  exert  a c t i o n i n the  tivity  cats,  scopolamine.  a n t i c h o l i n e r g i c a g e n t s may.  VL  or  a l s o ' seems r o o m . t o c o n s i d e r  anti-Parkinsonian  and  anesthetized  produced.  by  that  et a l .  cholinesterase inhibitors  r e s t i n g tremor  There  Lalley  bromide  of  their  sensi-  proposal role  of  VL  and  the  efficacy  tremor  and  rigidity  idea.  CHOLINESTERASE  Studies have  shown t h a t  found Koelle  i n the [1954]  anterior study has  and  i n the  shown low  of  cholinesterase distribution  the  highest  neostriatum reported lateral  concentrations, of  [e.g.,  relatively  thalamic  monkey by  B u r g e n and intense  n u c l e i of  O l i v i e r , Parent  staining density  i n VA,  i n the this  brain  enzyme  Chipman,  1951].  staining in  the  r a t , but  and  Poirier  VL,  VPL  and  are  the a  recent  [1970] VPM.  These  authors reported, Hassler's "  N.  . . . the  h o w e v e r , . t h a t i n an  ventro-oralis i n t e n s i t y of  accentuated  . . ..."  within  the  This  c e l l s was"found  intralaminar  nuclei  regions  [Olivier,  a l s o has  enhanced  are  there  is a relatively  BC,  side is  Olivier,  and  of  a  that  l e s i o n of  a property  of  Hebb and choline but  the  acetylase  t h i s a l s o was  et  small  BC  be  o f VL. than  The  surrounding  geniculate  [Phillis,  ACh  nucleus  Tebecis  [1968] has  and  shown  cholinesterase  that  within  this t r a c t , indicating that  the  staining  cerebellar Silver  fibres.  [1956] f o u n d m o d e r a t e amounts  i n the very  efferent  part  small  of  the  then  that  cholinergic  to  by  afferents  a major c h o l i n e r g i c  of  thalamus c o n t a i n i n g  i n comparison w i t h the  some c h o l i n e r g i c  the  of  cerebellar  be  t o be  part  lateral  amount o f  i n t e r e s t i n view  proportion  stained  Phillis  part)  the  t h e r e may likely  the  ventral  s t a i n i n g i s i n t e n s i f i e d on  I t would appear,  may  ventral  al.].  content.  not  i s of  i n the  and  the  to  geometrically  a greater  staining properties  1967;  is  that  more d e n s e l y  etal.]  York,  the  reaction  (i.e.,  observation  o f McCance e t a l . ' s r e p o r t sensitive  VL  area corresponsing  striatal  these enzymic t o VL,  pathway.  some d e g r e e .  but  VL,  criteria  there  Similarly,  is  scribed  The  purpose  was  to i n v e s t i g a t e  in  the thalamus,  to  iontophoretically  physiological t o VL,-and  of the s e r i e s  o f e x p e r i m e n t s t o be  the e l e c t r i c a l  p a r t i c u l a r l y VL,  activity  of  cells  to study t h e i r s e n s i t i v i t y  applied drugs, to define  the  electro-  c h a r a c t e r i s t i c s o f some o f t h e pathways  t o t e s t whether  de-.  t h e s e pathways a r e  afferent  cholinergic.  55  CHAPTER I I METHODS  PREPARATION OF  The either  animals used  sex w e i g h i n g  occasions  i t was  weight.range. hours.prior  - 3.5  necessary  The  to  2.5  i n these  Dial  compound 400  or  by  periodic  agent.  was  few this sixteen  anesthetized  Anesthetic  small  acid  - 400  animals  agents used - 100  mgm/ml, '  mg/kg  When t h e  10  for decerebration,  n o s e cone a t t a c h e d  vapourizer  animal appeared  removed f r o m t h e  intravenous  halothane  box,  - 0.65  to the  intraAnesthesia  injections  of  chloralose  anesthesia  a box  t o be  vapourizer.  ml/kg.  the  was  was  i n .oxygen (2-' Lv/min) v i a  into  anesthesia  were:  mgm/ml) 0.6  When p e n t o b a r b i t a l o r  i n t r o d u c i n g 4-5%  a F o r e g g e r model SA animal.  and  sodium p e n t o b a r b i t a l , 2 5 - 3 0  i n preparation  by  a  a- c h l o r a l o s e 60-70 mg/kg i n t r a v e n o u s l y .  same a n e s t h e t i c  induced  decerebrate  mgm/ml, m o n o e t h y l u r e a  maintained  u s e d , and  on  specimens o u t s i d e  (Ciba-diallyl barbituric  intraperitoneally; venously;  although  of  anesthesia.  for experimentation.  urethane-  was  t o use  e x p e r i m e n t s were c a t s  c a t s were f a s t e d f o r a minimum o f  Non-anesthetized were u s e d  Kgm,  ANIMALS  holding  deeply  being A  the  anesthetized, i t  maintained  tracheotomy  by was  a  performed  and  a glass  Y-tube  trachea.  The  anesthesia  was  connecting  the  vapourizer  the  arm  being  second  cannula of  was  other  second  then  drugs.  The  anesthetic  I.V.  cannula.  into  the  the  2%  animal  halothane  i n the  seven  into  the  parallel  the  of  was  midline  21  gauge  brain at  was  using  skull to  the  20  mA  -using  at  the  the  through  the  were  inserted  c a t mounted  in  i t was  tracheal cannulation,  e x p o s e d by A  a hand d r i l l  stainless.steel right  angles  were s e t  The  corresponded  the  scraping  rectangular  the  of  the  the  slot  fitted dura,  The  a high  with  a  a row  cut,  small of  six  lowered  f o r two  to  the  These  3),  and  mm.  The  the .  the  e l e c t r o d e s were frequency  at  shape of  of  pair,  electrodes  the  lowered  current  of each adjacent  a W y s s . c o a g u l a t o r , , m o d e l OC-60.  skin  then  arrangement of  approximately  tips  the  was  (Figure  except  vertical  and  s a g g i t a l plane.  apart  clear)  b r a i n , and  passed between  to the  brain.  back  main-  sagittal  e l e c t r o d e s was  2 mm.  ( I n s l - X , e-33  base  base of was  while  decerebrated,  A f t e r c u t t i n g the  electrodes  tips  t o be  after  each e l e c t r o d e .  electrode  Y-tube,  intravenous  s t e r e o t a x i c frame. A f t e r a m i d l i n e skull  were i n s u l a t e d tip  by  frame.,  round d e n t a l burr. or  introduced  and  the  the  the  for introduction  discontinued  slowly  into  indwelling  external auditory.meati,  on  of  cephalic vein was  stage,  temporal musculature.  across  a  An  arm  bars  incision, and  off.  halothane  this  t o one  ear  When t h e  mounted  2% , 1 } , L y / m i n .  at  the  stereotaxic  tained  continued  into  a g e n t was  At  secured  directly  clamped  secured  i n s e r t e d and  were  57  t h e n r a i s e d b y 2 mm In  total,  at  2 mm  coagulations  frequently  types  published  it  necessary,  of  first  i n the frontal  line.  cently  skull,  w e r e made i n s e v e n v e r t i c a l  of decerebration  u s e d was  inter-aural  was  This  by K o l l e r  was  to d r i l l  s e c t i o n o f bone c o n t a i n i n g  forceps.  With  slit  the s a g i t t a l angles  on each  sinus  thus  to the sinus  side, to avoid  i n the dura,  then  on e i t h e r s i d e o f t h e s i n u s .  Pretrigeminal  single  eat  transverse  posterior  fossa,  A single s l i t  type  i n the side The  from the midsuture.  This  removed w i t h  bone  the dura  f o r a distance  into  of itself.  the brain  the middle p a i r  as d e s c r i b e d  passing  The c o a g u l a t i o n p r o ^ previously.  of decerebration  u s e d was  o f Z e r n i c k i (1968).  s l o t was just  with  type,  sinus.  exposed,  lowered  closely  The o t h e r  slot  cutting the sinus  the cuts  followed  away  carefully  through  then  In this  o n e on«-either  the s a g i t t a l  then  The b a n k o f s i x e l e c t r o d e s was  c e d u r e was  (1969).  slots,  most  t o t h e method r e -  s i n u s were then teased  o f b o n e was  at right  a b o u t s i x mm  anterior to  1 mm  damaging the s a g i t t a l  line  piece  plane,  similar  two s m a l l  the midline, to avoid  remaining  The one  when c u t t i n g t h e r e c t a n g u l a r  and s a g i t t a l  the  levels  were used.  and Jenny  dura  was  repeated.  intervals. Two  the  and t h e s e r i e s o f c o a g u l a t i o n s  similar  In this  case  to a  c u t i n t h e bone o v e r l y i n g t h e •  posterior to the tentorium  was made i n t h e d u r a  cerebelli.  and a row o f s e v e n  electrodes  58 lowered  into  the brain  the  vertical.  and  roughly  the  halothane  the  surgery  anesthesia  was  completed,  the decerebration  with  the major  surgical  t h e b r a i n was  to  the inter-aural about  electrodes  were t o be u s e d ,  in  regions  to  be i n t r o d u c e d .  by  applying  Bleeding  small, pledgets stopped with  m o i s t by c o v e r i n g balls  soaked  glass  electrodes  white  matter  dura  A period  before  By  or  surgical the  removing on one  from the f r o n t a l the midline  side  pole  laterally glass sagittal  contralateral cortex  of the inter-aural then  slit  line  t o about  o r removed  and s t i m u l a t i n g e l e c t r o d e s  were  f r o m d u r a o r b r a i n was c o n t r o l l e d of Gelfoam bone. wax.  (Upjohn) w h i l e The  cortex  and exposed . c o r t e x w i t h  i n warmed m o d i f i e d w e r e t o be  of  experimental  t h e bone o v e r l y i n g t h e  The d u r a was  where r e c o r d i n g  f r o m bone was  the rest of  when t h e more b u l k y  of the adjacent  anterior to i t .  decerebration  the cortex  and from near  removed, from t h e l e v e l  16 mm.  until  followed-.  forceps,  Particularly  a n d a f e w mm.  of  had been achieved,  e x t e n s i v e l y exposed,  15 mm.  tentorium  had been completed,  anesthesic  and bone  line,  the  types  to elapse  procedures were  drill  posterior to  then discontinued.  r o u t i n e l y allowed  of  was  maintained  Once  bone w i t h  sinus  was  30°  behind  With both  made.  following  for  to i t .  inclined  passed  were  anesthesia  the  The e l e c t r o d e s  parallel  t w o h o u r s was records  i n a plane  overlying the part  was  the c o r t i c a l  kept  small  Locke's .solution.  used,  bleeding  cotton  When  grey, and  of the thalamus being  studied  59 was r e m o v e d b y s u c t i o n , vessels witha^Birtcher m a t t e r was removed electrode  tips  incurred 10 mm  The  cavity  Locke's  solution,  position  a  partly  t o a new  the experiment,  i n a l lexperiments.  external  auditory  inter-aural of  meati  the target  when  temperature  a Beckman model LB-1 end-tidal  throughout  Steel  structures  the experiment.  Cinematographique)  T h i s instrument uses t h e  electrodes  f o rhead  t o be used  beforehand  at the midline  CC>2 l e v e l s  PROCEDURE  and lower o r b i t  were c a l i b r a t e d line  temperature of  w a s m a i n t a i n e d a t 37-38°C b y  instrument (Precision  was u s e d  experiment  warmed  track.  available,  STEREOTAXIC  A stereotaxic  the thalamus.  electrode  the rectal  tube were monitored  points.  with  through the  h e a t i n g pad p l a c e d under t h e animal.  Gas A n a l y z e r became  reference  filled  cortical  plugging of  overlying  b y a n E K E G T C U 691  The t e m p e r a t u r e  the tracheal  The  and t i s s u e  tissue  i n the experimental series,  Medical in  breakage  was k e p t  6 V battery-supplied  Later  755 c o a g u l a t o r .  of cortical  was b e i n g c h a n g e d  unit.  of the surface  by. p u s h i n g t h e e l e c t r o d e  a n i m a l was m o n i t o r e d  control  coagulation  except while the recording  Throughout the  model  t o avoid  approximately resulting  after  with  position.  were determined  fixation  i nt h e  reference tothe The c o - o r d i n a t e s  from  the stereo-  taxic  atlas  additional Marsan for  o f S n i d e r and N i e m e r  r e f e r e n c e t o the a t l a s e s  [1954] and  Reinoso-Suarez  t h e e l e c t r o d e t i p was  t h e e l e c t r o d e was if  used  used  [1961].  from  their  The  then c a l c u l a t e d ,  in a vertical  often  with  o f J a s p e r and  axis,  a t some a n g l e t o t h e v e r t i c a l .  c a l i b r a t i o n marks on t o 1°  [1961] b u t  Ajmone-  proper  position  algebraically i f or  trigonometrically  Because  t h e i n s t r u m e n t were f o u n d  the  to vary  up  d e s i g n a t e d v a l u e s , t h e e l e c t r o d e s were  c a l i b r a t e d w i t h r e f e r e n c e t o a plumb l i n e ,  after  placing  the  frame i n t h e h o r i z o n t a l p l a n e w i t h t h e a i d o f a  spirit.level.  I t was  precise  found  placement  this  t e c h n i q u e a l l o w e d a more  of electrodes,  calibrated the  that  nucleus  therefore,  lowered  and N  activity  activity  enough t o  of  be this,  ensure  structures  such  as  Whenever  o f t h e e l e c t r o d e was  checked  a t the t i p of the e l e c t r o d e  into position,,using  spontaneous e l e c t r i c a l  In s p i t e  c e n t r u m medianum.  the p o s i t i o n  by m o n i t o r i n g e l e c t r i c a l i t was  not r e l i a b l e  of e l e c t r o d e s i n s m a l l t a r g e t  the e n t o p e d u n c u l a r possible  permitted a l l electrodes to  a c c o r d i n g t o t h e same s t a n d a r d .  s t e r e o t a x i c method was  placement  as  and  and  o f known n e u r a l pathways as a g u i d e .  the nature of  responses  to  the  activation  61 ELECTRODES  One were u s e d  o r b o t h o f two t y p e s  i n most e x p e r i m e n t s .  electrodes with stimulation  2 mm.  insulated with  Square-wave  that  This  constructed  o f 0.1 msec,  type  pair of  and deep c e r e b e l l a r n u c l e i . f r o m 23 gauge n e e d l e for 0.5-1  duration  o f e l e c t r o d e was  t h e d e s i r e d s t r u c t u r e were  current  spread  and pathways may  activation  mm.  a l s o used  type  stainless  tubing  until  tubing.  s t e e l wire  the wire The o t h e r  the w i r e ,  extended  cement a t t h e o p e n i n g  apparent  I t a l s o seems  of electrode to  probable  adjacent  t o cause u n i n t e n t i o n a l one.  problem, s t i m u l a t i o n o f  by t h r e a d i n g  1/2  - 1 mm  end o f t h e w i r e  microconnector  and t h e w i r e  initially  fixed  fine  teflon-  t h r o u g h 23 gauge s t a i n l e s s  o p e n i n g w h i c h had been g r o u n d An Amphenol  amplitude  e f f e c t e d by 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 .  T h e s e e l e c t r o d e s were c o n s t r u c t e d coated  V  electrodes  than the d e s i r e d  t o minimize t h i s  BC and VL was  slim.  tubing  a t the t i p .  and 7-10  of both  be s u f f i c i e n t  o f pathways o t h e r  In order EN, CM,  from t h i s  steel  u s u a l l y used f o r  the chances o f p l a c i n g the t i p s  nuclei  the  electrodes  s t i m u l a t i o n o f EN and BC, however, i t became  within that  s e p a r a t i o n was  Insl-X,.except  stimuli  were u s e d . for  A parallel  of the c e r e b r a l cortex  T h e s e e l e c t r o d e s were and  of stimulating  was  steel  beyond t h e t i p o f l e d t h r o u g h an  i n the side of the tubing.  was  then s o l d e r e d  to this  i n p l a c e by a p p l y i n g  i n the tubing  (Figure 4 ) .  end o f  epoxy The  outside  61a  Figure  4.  Concentric  bipolar  stimulating  electrode.  of  the electrode  which, tip. tip  after  below  this  d r y i n g was s c r a p e d  back  1/2 mm  Similarly,  the teflon  insulation  of the inner  electrode.  Voltages  electrodes  varied with  i n t h e 4-8 V r a n g e .  through  t h e two types  occasions  using  corresponding  used w i t h  from the  these  intensity  o f e l e c t r o d e were measured  a Tektronix  t o the usual  I n a l l cases  Insl-X  o r l e s s from the  was r e m o v e d  The c u r r e n t  Current-Probe.„ voltage  stimuli  of  stimuli  on a few  The  range were  t h e c o n c e n t r i c a n d 1.0 - 1.5 mA  trodes.  with  t h e s t r u c t u r e s t i m u l a t e d , b u t were  usually  for  j u n c t i o n was c o a t e d  currents  0.05 - 0.1  f o r the p a r a l l e l  o f 0.1 m s e c , d u r a t i o n  mA  elecwere  used. The  recording  e l e c t r o d e s were a l s o o f two  steel  needles  and e l e c t r o l y t e - f i l l e d  steel  e l e c t r o d e s w e r e made  eroding  the shaft with  similar  to that described  had  been etched  washed  into  filled  uppermost.  microscope,  by Green  and shape,  :  i t was  insulated.  The  vertically  the t i p of the elec-  using  t h e e l e c t r o d e was l o w e r e d  over  by  When t h e n e e d l e  the needle  Insl-X, with  Under o b s e r v a t i o n  and s t e a d i l y  insulation  [1958].  w a t e r , d r i e d , and then  with  The  10 b e a d i n g n e e d l e s  diameter  amount a t t h e t i p was n o t i m m e r s e d . slowly  capillaries.  a c i d , i n a procedure  was e f f e c t e d b y l o w e r i n g  a beaker  trode  size  phosphoric  to the desired  i n distilled  insulation  from  glass  types;  a Zeiss  until  only  operating a  small  The e l e c t r o d e was  raised, leaving a thin,  even  a l l but the t i p of the electrode.  coat  then of  The  insulation ture  d r i e d b y l e a v i n g f o r 24 h o u r s  o r by b a k i n g  region of  was  a t 70°C f o r o n e h o u r .  at the t i pvaried  the electrode.  field  t i p was  A  similar  the decerebrating  that  bare  on t h e p u r p o s e  f o r recording  f o r 200-300 only  y.  were  glass  recording  barrels  of 5-barrelled glass  barrels  being  substances.  lowered  used The  scraped  electrodes electrode  for iontophoretic  glass  glass  capillaries,  2.5-4  mm.  (Figure  a vertical  resulting  tips  microscopic (Figure  the  electrode  back  except  from  with  thet i p  used were t h e assemblies,  filtered  5a).  blanks  were  o f 0.5  The  supplied  by  of five  were heated  to a total  fused  of  and p u l l e d  puller.  water  w a t e r was  diameter  were then  The  f o r 20 m i n u t e s .  removed from  o f 4-8  filled  by  After  the wide p a r t  and 2 9 gauge needle>  under  y.  boiling cooling, of the  and r e p l a c e d  e l e c t r o l y t e (4 M N a C l < f o r t h e r e c o r d i n g  outer  chemical  - 1 y d i a m e t e r were broken back,  electrodes  a syringe  the  diameter  Canberra-type microelectrode  distilled  distilled  These blanks  centre  application of  drawn o u t t o an o v e r a l l  observation,  5b).  shaft with an  followed  into the Insl-X  V a n c o u v e r S c i e n t i f i c i G l a s s b l o w i n g as an a r r a y  in  left  drying. The  in  For  2 0 - 4 0 y was  i n s u l a t i n g p r o c e d u r e was  down, t h e i n s u l a t i o n b e i n g  after  depending  tempera-  uninsulated  and s t i m u l a t i n g e l e c t r o d e s ,  these electrodes  tips  The  t o be u s e d  of single unit activity  uninsulated. for  When i t w a s  responses,,the  recording  i n size,  a t room  barrel).  by, The  64 solutions  diffused to the t i p within  experiments, e l e c t r i c a l recording  and i o n t o p h o r e t i c  platinum  and s i l v e r  solution.  Steel chuck  modified shige  soldered  fitted  electrodes  movement p l a n e s  response,  with  and moving  steel  glass  distilled  reference  water,  - 25.  A larger  electrode  t o t h e frame  holder  Because  were  frame, responses were After  was o r i e n t e d  to this  Nara-  electrodes.  routinely  finding the desired i n t h e same Further  initial  excessive  used  through  axis  exploration  position of  a millipore filter.  s o l u t i o n s was a d j u s t e d checking  upward by  t h e pH w i t h  Some o f t h e p o t e n t b l o c k i n g  low concentrations,  iontophoresis drugs  small  drugs were d i s s o l v e d , u s u a l l y i n  and f i l t e r e d  NaOH t o t h e s o l u t i o n w h i l e  very  the glass  of the responses.  iontophoresis,  pH o f t h e a m i n o a c i d  avoid  i n a  panel.  electrode.  For  pH m e t e r  a  which  or iontophoretic  were h e l d  electrodes.  electrode  t o t h e depth  was c a r r i e d o u t w i t h  in  leads  t h e s t e r e o t a x i c frame.  of the latter  the glass  lowered  through  t o a N a r a s h i g e m i c r o m a n i p u l a t o r w h i c h was  f o rholding  first  t othe  into the  m i c r o m a n i p u l a t o r mounted on a b a r a t t a c h e d  located  the  the solutions  t o copper  t o the a m p l i f i e d probe recording  During  a p p a r a t u s was a c h i e v e d  independent o f the s t e r e o t a x i c  and  from  respectively extending  were  f o ruse w i t h  was u s e d the  wire  The w i r e s  were connected  steel  coupling  24-48 h o u r s .  impedances  of small  and d i s s o l v e d  adding  a Radiometer  agents were  used  i n 0.15 M N a C l t o  f o rt h e s o l u t i o n s  drug q u a n t i t i e s .  The  and t o a l l o w  Table  and t h e c h a r a c t e r i s t i c s o f each  I lists the  solution.  Before  65 TABLE I DRUG S O L U T I O N S USED FOR  Drug  IONTOPHORESIS  Concentration  pH Adjusted Solvent To  Active Ion cation  Acetylcholine  bromide  1.0  M  water  Acetylcholine  chloride  1.0  M  water  -  cation cation  0.05 M  0.15 M NaCl  Dihydro-3-erythroidine  0.025 M  0.15 M NaCl  -  cation  Strychnine  0.025 M  0.15 M NaCl  -  cation  0.1 N  water  -  cation  Atropine  sulphate  sulphate  Hydrochloric  acid  —  •  L-glutamic  acid  0.2  M  water  8-8.5  anion  D-glutamic  acid  0.2  M  water  8-8.5  anion  L-aspartic  acid  0; .2 M  water  8-8.5  anion  0.2  M  water  8-8.5  anion  N-methyl-D,'. L - a s p a r t i c acid  0.2  M  water  8-8.5  a-methyl-D, acid  0.2  M  water  8-8.5  anion  0.2  M  water  8-8.5  anion  D, L - h o m o c y s t e i c  N-methylacid  use  D,.L-glutamic  electrodes,  was m e a s u r e d .  During were a p p l i e d  of  t h e DC r e s i s t a n c e  The u s u a l  a n d 70-90 M  diffusion  anion  ,,  L-glutamic  of glass  barrels  acid  were  Q, f o r i o n t o p h o r e s i s  use of glass  t o each  ranges  electrodes,  of the drug  of the active  ACh B r . , a n e g a t i v e  i o n from current  of each  barrel  5-12 M Q f o r  recording  barrels. retaining  currents  containing  barrels  the t i p .  Thus  was a p p l i e d  t o impede  fora  to hold  solution  back t h e  J  positively  c h a r g e d ACh  pass  iontophoretically  drugs  galvanometer through  not  and were passed  1000 M Q  variations  series  i n resistance  appreciably  alter  Excitatory after  same p o l a r i t y permits  the current  tips  small  therefore d i d  flow.  occurring with o f drugs  by e j e c t i n g  of the electrode  Relatively  at the electrode  from a d i f f e r e n t  separation  current used  to the barrels  application  were checked  to retain or  were m e a s u r e d on a Cambridge  resistors.  effects  iontophoretic  effects  i o n . Currents used  very short  latency  and d e p r e s s a n t  a non-active i o nwith the  drug b a r r e l .  of drug effects  from  This  procedure  t h o s e due t o t h e  i n passing the drugs.  EQUIPMENT  The led  into  electrical.signals  a Grass  P6-12 p r e a m p l i f i e r .  s i g n a l was f u r t h e r amplifier  plug-in  oscilloscope.  recorded from t h e b r a i n  amplified unit  The p r e a m p l i f i e r  i n the type  2A  the  signals  ratemeter  differential  P h o t o g r a p h i c r e c o r d s w e r e made b y a 565.  A  Grass parallel  ( T e l e q u i p m e n t t y p e D43R) was a l s o u s e d being photographed.  the Tektronix  output  o f a T e k t r o n i x m o d e l 565 d u a l . b e a m  C4 c a m e r a f r o m t h e s c r e e n o f t h e T e k t r o n i x oscilloscope  were  scope were a l s o  ( E K E G m o d e l RT  The a m p l i f i e d  t o monitor  signals  from  f e d t o a l o u d s p e a k e r and a  682-L), the integrated  rate  meter  output being  recorded  on an E s t e r l i n e - A n g u s  R e c o r d e r m o d e l AGOIR.  The t r i g g e r i n g l e v e l  was v a r i a b l e one  cell  sizes  so that  were recorded  of the action  of  the signals.  be  represented  is  the block  recording  encountered  In  i n the rate  position  the electrodes.  the it. the  cortex, After  were p l a c e d  of  of a single  output  than i nthe  selection  cell  signal.  could  Figure  6  and  indicated,"problems  the smaller  pair  this  according  lateral  allowed  the other  comparison  and medial p a r t s  coordinates  the cortex;to  be, r e c o r d e d  from  of the electrode  response.  of concentric  in.the  stimulating  to stereotaxic  could  t h e maximum  stimulations  be d e s c r i b e d  discovery,  One o f t h e s e w a s p l a c e d  This  o n e s E N a n d CM.  t o be e v o k e d by  The p o s i t i o n  above method, w i t h  o f some  characteristic f o r the lateral  as w i l l  response  were  stimulation  checked by s t i m u l a t i n g  to obtain  a parallel  used.  response  was f o u n d  'Results'.  the appropriate  CM,  differences  the iontophoresis  particularly  part  if  adjusted  o f more  permitted  i n the selective e l e c t r i c a l  the sensorimotor  this  meter  has been p r e v i o u s l y  t h e c a s e o f CM,.a  electrodes and  Thus t h e a c t i v i t y  structures,  section  usually  diagram depicting  parvocellular of  potentials  by t h e e l e c t r o d e ,  potentials  of the ratemeter  system.  As  brain  i fthe action  Rectilinear  bipolar  the t i p was  then  For stimulation electrodes  i n the parvocellular located  see  1.5 mm.  of the effects  of  of  was CM b y  medial t o stimulating  o f t h e CM - P f c o m p l e x .  This  68  Figure  Figure  5.  F i v e - b a r r e l e l e c t r o d e used f o r i o n t o p h o r e s i s . (A) e l e c t r o d e b l a n k , (B) e l e c t r o d e d r a w n t o fine t i p .  6.  Block diagram f o r iontophoresis r e c o r d i n g equipment.  and  signal  p r o c e d u r e was amount o f bipolar  entopeduncular  to  nucleus  lies  capsule,  and  also  spread  estimate  of  from the  at  ventral border  the  be  bundles of the  the  maximum  concentric  placed  region  of  the  i t was  of  the  latency  the  of  part  of  difficult  to  that  the  lies  [see  evoked  Ventral  flashing a  represented  optic tract activity.  positioned,  therefore,  i n the  and  optic  and  to  The  be  electrode  Machek,  animals  electrode quiet  responses.  The  stimulation  spontaneous  electrically tract  could  above i t gave a  i n the  optic  optic tract.  response  t o EN,  light  the  to  responses  a l s o F r i g y e s i and  i n t e r n a l capsule  internal  stimulating  a f t e r f i n d i n g the  small  cortex  i n t e r n a l capsule  the  This  f i b r e s appear  b e l o w EN  i n t e r n a l capsule  response.  which responded  Just  found  a very  precruciate  1970], whereas  nucleus.  most  discretely.  i n t e r n a l capsule  accurately  showed  stimulate  the  c h a r a c t e r i s t i c evoked response  i n EN,  characteristic EN  to  n u c l e u s was  and  T h o u g h no  identified  the  an  locate  through  tract.  short  give  electrodes.  structure  could  to  e f f e c t i v e current  The  course  found  large, activity eyes  tip zone  was between  70 HISTOLOGY  At with  t h e end o f an e x p e r i m e n t ,  an overdose  of pentobarbital.  through the carotid then with  200  1% p o t a s s i u m in  formalin  ferrocyanide.  aligned  axis  sections,  plane.  signals  required  containing  t h e animal; s t i l l  mounted  parallel  a  and  were c u t so  to electrode  tracks  localization  reference  t o spots  seen  of previously marking  recorded  some o f t h e  electrode  t r a c k s were marked by t h e method d e s c r i b e d  through marked.  Iron  electrode  Positive current while  was p a s s e d  t i p , and l a t e r  i s easily  reaction) located  recording by  (20 y A f o r 30 s e c . )  i t was i n t h e p o s i t i o n t o b e  i s electrodeposited  (Prussian blue which  The s t i m u l a t i n g and s t e e l  the electrode  with  i n histological  tracks.  [1958],  that  plane.  electrode  Green  of the  sharpened  carrier  Thus b l o c k s  t r a c k s were o f t e n  but accurate  M Na C I , ,  the dorsolateral surfaces  i n the frontal  Electrode  perfused  M Na C I  b l a d e mounted on an e l e c t r o d e  i n the frontal  killed  m l 0.15  a n d t h e b r a i n was c u t w i t h  s e c t i o n s w o u l d be c l o s e l y their  100  i n 0.15  With  the stereotaxic holder,  pallet-knife  T h e h e a d was  a r t e r i e s , . f i r s t with  m l o f 10%  b r a i n were exposed  t h e a n i m a l was  only  complexes w i t h t o leave  at the uninsulated the  a distinct  i n the unstained  ferrocyanide blue-green  brain.  Figure  spot 7  shows a n e x a m p l e o f s u c h m a r k s . The method o f McCance and P h i l l i s for  marking  the glass  electrode  tracks.  [196 5] w a s For this  used  purpose  Figure  8.  Spot marking t i p l o c a t i o n o f g l a s s e l e c t r o d e — H C 1 method.  iontophoretic  72 0.1  N H C I was  barrels. site  A t t h e end o f . t h e  was  passed  usually carried  experiment,  t o be m a r k e d , p o s i t i v e c u r r e n t  through  more d i f f i c u l t detected  t o l o c a t e because they  i n the unstained  had been passed  sections.  H  was  i n s e r t e d and marked n e a r b y track.)  spots  w h i c h were u s u a l l y d e t e c t a b l e  When o n l y  gross  when i t was similar  to obtain  the results  overnight  fixed  freezing  and  In this  blue  permanent records mounting  spots.  day.  clearly  used.  rapidly, and  the blocks  Sections  Sections  and p r i n t i n g  example of such a photograph  when g l a s s  sections.  a  Fernandez of brain on  a  o f 50 y - 1 0 0 y  the electrode  tracks  were photographed f o r  electrodes  as from a n e g a t i v e .  i s shown i n F i g u r e  second h i s t o l o g i c a l  or technique  by p l a c i n g them between two m i c r o s c o p e  i n an e n l a r g e r  The  to the  had been used  i n 10% f o r m a l i n and ' s e c t i o n e d  c u t , and u s u a l l y showed Prussian  lateral  Guzman, A l c a r a z  procedure,  microtome the next  after  electrode  p r e p a r a t i o n s , were  important  t o that described.by.  were  mark.  electrodes  were  therefore,  i n the stained  recording  used.  These marks  l o c a t i o n of the acid  steel  [ 1 9 5 8 ] was  were  to facilitate  of histological  specific  were n o t u s u a l l y Often  8 shows an e x a m p l e o f an a c i d types  a  (4 y A f o r 30 s e c . ) w a s  ( e . g . 1 mm.  electrode  Two  iontophoresis  iontophoretically,a steel  glass  Figure  or where  the H CI containing b a r r e l .  the  +  i n one o f t h e f o u r  m e t h o d was  slides, An  9.  u s u a l l y employed  and a c i d m a r k i n g had been u s e d  i n the  74  experiment. in  The b l o c k s  10% f o r m a l i n ,  o f b r a i n were  then dehydrated,  fixed  cleared  according  Sections  were c u t a t 25-35 y and t h e d e s i r e d  cresyl  violet.  days  a n d embedded  paraffin  with  f o r 2-3  t o standard h i s t o l o g i c a l  in  procedures. sections  stained  CHAPTER I I I  RESULTS  Experimental by  midbrain  tidal  C0  chloralose  under a n e s t h e s i a  decerebration breathed  levels  2  animals  o f about' 4% i n d e c e r e b r a t e  Bradycardia  frequent  characteristics  animals,  and t h i s  prepared  spontaneously.  or b a r b i t u r a t e anesthetized  consistently.  or  End  and 4 1/2% i n  animals  were  found  and marked c e r e b r a l oedema were  of the p r e t r i g e m i n a l  decerebrate  p r e p a r a t i o n was t h e r e f o r e u s e d i n o n l y  a  s m a l l number o f e x p e r i m e n t s .  NUCLEUS VENTRALIS LATERALIS  Electrophysiology The occurred  action potentials of c e l l s  i n spontaneous b u r s t s  inactivity. cell,to be  The n a t u r e  cell,  observed  separated  fire  by p e r i o d s o f  b u t i n any r e g i o n where more t h a n  simultaneously,  shown i n F i g u r e  cells  characteristically  o f t h e b u r s t s v a r i e d somewhat  the spikes recorded  f o l l o w e d t h e same b u r s t i n g p a t t e r n .  indicated  i n VL  10.  The d i s c h a r g e s  from  one c e l l from  could  each  An example o f t h i s i s of several c e l l s  by t h e s p i k e a m p l i t u d e ) h a v e b e e n r e c o r d e d . i n g r o u p s a t a b o u t t h e same t i m e ,  (as The  t h o u g h e a c h one  does not  necessarily discharge  of bursts  or  s p i n d l e s are  wave  activity  high  pass  which  filter  correspondence in  Figure  of  14.  The the  of  Very  5-10/sec.  induced  in cells  cortex,  as  will  Using the  usual  of  0.8  lation  -  of  of  shorter  stimulus  by  short  to  -  The  all-or-none  spikes  not  the  (Figure  p e a k was  superimposed  v e n t r a l border particularly  a  amplitude  i n more d o r s a l r e g i o n s .  correspond  activity  t o BC  large  and  presynaptic  respectively .  system. is  Such  frequency  of  frequency  could  or  a  apparent  a usual  11A)  be  precruciate  in  with  i t .  with  slightly  duration The  there  VL  of  the  of  or decrease  and  and  second the  basis  had  first  of  the  in  peak  smaller  second peaks were and  Stimu-  to v a r i a t i o n  whereas  On  VL,  latencies  usually large,  longer  o f VL  t o be  to  because  electrode  increase  on  was,found  first  slow  cerebellar nuclei  responded  a gradual  s e c o n d peak had  characteristics,,the  the  response, but  earlier  with  had  series  2 msec, r e s p e c t i v e l y .  d u r a t i o n . , and  intensity  seen a t  peaks  a similar The  a  large recording  1.5  The  subsequently.  s t i m u l a t i o n of  negative  amplitude.  with  s t i m u l a t i o n o f BC  a relatively  gave  recording  bursting activity  be. d e s c r i b e d  latency.  relatively  i n the  10  s l o w wave a c t i v i t y  similar  msec, and  BC  i n Figure  spindles occurred  o f VL  two  1.2  and  burst..  associated with  intra-spindle bursts  response  consisted  every  apparent  included  spike  5-11/min., and  normally  i s not  was  with  was peak  in these  considered  postsynaptic  electrical  77 Electrodes a negative  of  BC-evoked in  followed  of  this  l i t t l e variation  (Figure  burst  was  occurred spike.  usually  kind,  of  The 4-6  11B).  3-5  msec and  of  not  burst  both.  I t was  response to  stimulus  strength.  conversion  will  early burst frequently  be  a short  stimulation  frequencies  the  i n i t i a l spike  a single  "early burst" spike,  but  latency  described  or  spike  by  in a later  i n deeply anesthetized  animals, but  further  a long-latency  chloralose.  type of  rarely  than  occasionally  two  types  of  cell  would  respond  a later  burst, an  increasing this  section.  early the  type  also  seen i n  i n decerebrate  response  s e r i e s of b u r s t s  f o l l o w i n g BC  of  The found  animals, p a r t i c u l a r l y  I t was  the  short-latency  r e s p o n s e t o c e r e b e l l a r s t i m u l a t i o n was  anesthetized  same of  response  the  i . e . , the  s i n g l e spike  of  fail.  g e n e r a t e d by  the  resulted  cerebello-thalamic  O t h e r means o f e f f e c t i n g  with  was  single  sometimes-possible to convert  anesthetized  A  any  with  a  showed more v a r i a b i l i t y  r e s p o n s e were m u t u a l l y e x c l u s i v e , latency  described  evoked w i t h  of the  spikes  latency  exhibiting this  either with a short  one  stimulus  i n c e l l s which responded with Cells  responses  For  repetitive At  BC  r e s p o n s e began t o  showed a s i n g l e s h o r t - l a t e n c y  but  first spikes  stimulation  a burst  11C).  recorded  the  (Figure  spike  some c a s e s ,  pathway e v o k e d  to  in latency.  second, the  In  cell  tips  by.all-or-none  1.5-2.2 msec. spike  20-40 p e r  small  peak c o r r e s p o n d i n g  above o f t e n latency  with  most those  barbiturate  preparations. stimulation  which resembled  those  78  200  1 SEC  Figure  10.  S p o n t a n e o u s b u r s t i n g p a t t e r n o f gc&up o f VL neurones, recorded w i t h high-pass f i l t e r . N e g a t i v e i s up i n t h i s and a l l s u b s e q u e n t figures.  ' j  400  200 B  __V_  r  10 MSEC  C iv '  Figure  11.  \  200  1  B C - e v o k e d r e s p o n s e s , r e c o r d e d i n VL; (A)' p r e and p o s t s y n a p t i c f i e I d ' r e s p o n s e s ; (B) p r e s y n a p t i c f i e l d and p o s t s y n a p t i c . u n i t 'spike r e s p o n s e s ; ( C ) - p r e - and p o s t s y n a p t i c - f i e l d r e s p o n s e s and e a r l y burst of s i n g l e neurone.  ;  occurring a  spontaneously  100-200 msec, p o s t  bursts. but  The c e l l s  stimulus  spontaneously interrupt (Figure  but  latency  These  activity  whether  bursts  bursting  activity  the resulting bursting  patterns  were o f t e n  during  i n t r a - s p i n d l e frequency  The lation  electrical  as t h a t  high  cortex  early  burst  described  most f r e q u e n t l y animals. was a l s o  described.  induced  i n anesthetized,  convertible  progress,  activity.  was a b o u t t h e  i n VL c e l l s  o f 2-6 m s e c , by e v e r y  As w i t h  sometimes  The e a r l y b u r s t  evoked  abbreviated  f o r BC s t i m u l a t i o n .  of stimulation.  r e s p o n s e was  was i n  be  stimu-  seen  b y BC s t i m u l a t i o n w a s o f t e n  at  13 B ) , a g a i n ,  i n decerebrate  to a single short-latency activity  latency  BC s t i m u l a t i o n , a n  (Figure  but never  The most  stimulus  response t o c o r t i c a l  Late bursting  by  h a d t h e same t y p e s o f  13 A ) , w h i c h w a s n o t e v o k e d  frequencies  could  bursting  bursts  evoked  common r e s p o n s e w a s a s i n g l e s p i k e (Figure  spikes  ones.  activity  of the precruciate  variation  spontaneous  of evoked  temporarily  of the  or not spontaneous  was g i v e n  often,  occurring  would  firing  stimulus-induced  of the  a single, short-  o r g e n e r a t e d by a s t i m u l u s , regular  usually  t o the f i r s t  series of bursts,  same a s f o r t h e s p o n t a n e o u s  be  T h e r e was  responded with  any spontaneous  a stimulus  The  Such  12 B ) .  whether  12 A ) .  e x h i b i t i n g such b u r s t i n g  not necessarily, also  l a t e n c y 'Spike.  if  (Figure  similar  seen a f t e r  stimulation spike  as  will  to that stimulation  A  i<fr H  '  # "inii mi  •  t  500 MSEC  B - HI Ml I  Figure '  12.  200^  1 SEC  B u r s t i n g p a t t e r n s i n V L i n d u c e d b y BC s t i m u l u s , - ; (A) q u i e s c e n t n e u r o n e s ; (B) s p o n t a n e o u s l y d i s c h a r g i n g neurone. BC s t i m u l u s a t a r r o w s .  10 MSEC  B J,  Figure 13.  Responses o f s i n g l e VL neurones t o s t i m u l a t i o n o f p r e c r u c i a t e c o r t e x ; ^ . (A) s i n g l e s h o r t l a t e n c y spike; (B) e a r l y b u r s t r e s p o n s e . -  81 of  the precruciate cortex.  Figure  14,  which  because  of  In  the bursts  just  record  before  the b u r s t i n g spikes  a relatively  The  bursting spikes  not  evoked  with  VL stimulation dromic  with at  an  of the  latency  range  of  cortical  spike,  and  chloralose  spike  and  cortical  response  the a b i l i t y  stimuli.  was  an  characteristic  sometimes  per  judged cells  The from  to  second  orthodromic  i n VL  anti-  the  This  would or  15).  cells  had  was  respond  antidromic  Figure  31).  single cells  In  were  t o b o t h BC  One  type of response  the  peak o f  shortest  0.8  -  latency  and  gave  were u s u a l l y found  latency negative  response  short  respond  (Figure  early burst  which  of the nucleus.  a small, short  latency.  (see e.g.  to  stimulus,,even  found which  an  were  of the entopeduncular nucleus a l s o  responses  more m e d i a l p a r t s  with  complex.  stimulation.  cortical  particularly,  to respond  Stimulation  was  were o f t e n  t o s t i m u l a t i o n o f BC  cortical  occur  i n a manner u n i q u e  of the  s e v e r a l hundred  preparations,  activity.  to  i.e., antidromically.  stimulation with  found  msec,  l a t e n c y by  cortex  Cells  sometimes  seen  seen  l a t e n c i e s f o r a n t i d r o m i c a l l y evoked  0.7-2.2 m s e c . to  c a n be  of  the  s l o w n e g a t i v e - p o s i t i v e wave  action p o t e n t i a l to every  a frequency of  The  spikes  t o s l o w wave  sometimes responded  nature of the  invariant  of  record  a l s o shows  i n some c a s e s w e r e , b u t  short  cells  i s shown, i n t h e  i t i s unfiltered  correspondence this  This  in often 2.0 when  500 MSEC Figure  14.  J  B u r s t i n g p a t t e r n o f VL n e u r o n e s i n d u c e d b y ; precruciate c o r t i c a l s t i m u l u s — u n f i l t e r e d record. 1  200 10M B Figure  15.  Unitary spike potential i n VL—evoked antidromi c a l l y by p r e c r u c i a t e c o r t i c a l s t i m u l u s with 1.5 m s e c l a t e n c y a f t e r s t i m u l u s a r t i f a c t ; (A) superimposed:records a t about 100/sec stimulus frequency; l a t e r s m a l l peak due t o s t i m u l a t o r synchronous pulse a r t i f a c t ; (B).train of five s t i m u l i a t 300/sec evokes spike f o r every s t i mulus.  83 the  recording  e l e c t r o d e was  near  VL  (0.8 - 1.0  msec.-Figure  16 B)  dorsal  parts  Clearly posed  response.  (1.0 -2.0  The  response  i n a few c e l l s  latency  msec - F i g u r e were never  t o BC  of spikes  and c o r t i c a l  single spike  of  i n more 16 A ) .  seen  superim-  other type of response  consisted usually of a burst  early burst  though  and l o n g e r  distinguished unitary spikes  on t h i s  f r o m EN the  of the nucleus  the v e n t r a l extremity  evoked  similar  to  stimulation,  responses were n o r m a l l y  evoked. The b u r s t s a wide were 2-3  latency  found  thirty-two short  cells  latency  responded  with  of  these c e l l s  to  EN  EN  studied, only  (1.8 msec)  bursts.  or  though  to  with  sometimes often  four  18.  with  twenty-seven latency  The b u r s t  about  using  a single  others responded  and t h e o t h e r  seen w i t h  with  Of  f o r each responses  equal frequency i n No  spike  responses  barbiturate-anesthetized  s e v e r a l e x p e r i m e n t s were  tried  using  Nembutal. Two -of t h e EN  invaded  t o EN, b u t more  one r e s p o n d e d  i n Figure  found  spikes,  These responses  The mean r e s p o n s e  i s shown  s t i m u l a t i o n were  3-6  f r e q u e n c y were r e q u i r e d .  spike;  single spikes  by  and c h l o r a l o s e p r e p a r a t i o n s .  preparations, Dial  17).  a single stimulus  s t i m u l a t i o n were  decerebrate to  (Figure  delivered at a high  latency  longer  range  after  stimuli  were u s u a l l y formed  and t h r e e  cortical  evoked  responded  stimulation.  cells  were a n t i d r o m i c a l l y  orthodromically Though  BC  with  single  s t i m u l a t i o n was  not  spikes  84  Figure  Figure  16.  17.  EN e v o k e d f i e l d r e s p o n s e i n V L — s u p e r i m p o s e d traces; (A) r e c o r d e d i n m i d - r e g i o n o f V L — 1.5 msec l a t e n c y ; (B) r e c o r d e d i n v e n t r a l p a r t o f V L — 1 . 0 msec l a t e n c y .  B u r s t r e s p o n s e s o f two d i f f e r e n t VL n e u r o n e s e v o k e d by EN s t i m u l a t i o n ; (A)Asingle stimulus e v o k e s 5 msec l a t e n c y b u r s t ; (B) p a i r o f s t i m u l i e v o k e b u r s t w i t h 11 msec l a t e n c y a f t e r second s t i m u l u s .  attempted  i n these  EN  cells  evoked  showed  an  decerebrate  found  early burst  response  recurring bursts  f r o m BC  and  of  of  the  i n chloralose anesthetized  latency  Effect  experiments,  of  t o BC  spikes  c o r t e x were not  seen  eleven  animals  stimulation.  similar  Long  to those  f o l l o w i n g EN  two  evoked  stimulation.  Drugs  Acetylcholine Acetylcholine atory  effect  on  cells  responding  applied  m o s t VL with  cells  short  i o n t o p h o r e t i c a l l y had recorded  latency  in this  t o BC  an  excit-  study.  Those  s t i m u l a t i o n were -9  particularly  sensitive,  a m p e r e s = nA)  of  barrel  electrode  The  of  the  excitation  discharge stimuli from  or  o f ACh.  1-2  levels ACh  was  The  of  passed  as  responses.  latency  current.  The until  '"The  of  few the  the  -. t h e i r  rate of BC  19  or  after  and  being  gradual.  filmed  the  the  record  onset of  could  be  sharp  and  also of  short,  high the  varied  short  Spontaneous b u r s t i n g  ACh  as  c e s s a t i o n of  of .excitation  i n some c a s e s b e i n g  non-evoked  exhibited sustained  shortly after  termination  firing.  cortical  is a  between c e l l s , but often  (10  iontophoretic application  excitation  cells  nanoamps  acetylcholine  Increased  increased  considerably, i n others  a  through  Figure  during  varied widely  firing  an  only  e f f e c t i v e n e s s of  obtained  seconds.  often  assembly  seen  a greater  cell  application as  current  in'evoking  a VL  and  latency  activity  86 {  Latencies of EN evoked Cells in VL  i  -. ,  i  1  Latency (msec)  Mean l a t e n c i e s o f t h i r t y - t w o V L n e u r o n e s evoked b y EN s t i m u l a t i o n . Latency measured from a r t i f a c t o f f i n a l stimulus o f t r a i n t o f i r s t spike o f burst response.  | 100 500 MSEC F i r i n g o f VL neurones induced by i o n t o p h o r e t i c | a p p l i c a t i o n o f ACh (10 n A ) . F i r i n g b e g i n s l e s s t h a n 1 s e c a f t e r A C h a d m i n i s t r a t i o n commenced ( a r t i f a c t ) .  87 was n o t e v i d e n t  i n cells  even though they applied. rate  diminished,  behaviour  some c e l l s  occurred  bursting activity  depressed  was s o m e t i m e s  ;  judged  of  before  discharge  t h e ACh was  o f f and t h e  discharge  resumed.  t h e spontaneous  i n VL a n d o t h e r  level  parts  or drug  induced  activity  of the thalamus.  t o be a c u r r e n t  effect  as t h e  This depression  as s o o n a s t h e c u r r e n t was a p p l i e d , and c o u l d  duplicated of  exhibited this  A f t e r t h e ACh was t u r n e d  ACh of  excited to a high  by p a s s i n g  the electrode. i n onset,  or  currents  and c o u l d passed  Sometimes a d e p r e s s i o n between t h e onset response.  This  through  other  U s u a l l y , however, t h e depression  immediate higher  positive current  n o t be r e p r o d u c e d  through^other  barrels was n o t  by  barrels  be  equivalent  (Figure 20).  o f s p o n t a n e o u s b u r s t i n g was  seen  o f ACh a p p l i c a t i o n and t h e e x c i t a t o r y p h e n o m e n o n was n o t i n v e s t i g a t e d p h a r m a c o -  logically. Cell by  firing  induced  by ACh c o u l d  be b l o c k e d  s t i m u l a t i o n o f BC o r p r e c r u c i a t e c o r t e x . "  powerful  and r e l a t i v e l y  followed  a single.stimulus  but cell  long  n o t n e c e s s a r i l y evoked sometimes d i s p l a y e d  period  of depression  Stimulation activity,  duration  (Figure  of  with  short  firing  latency.  than  after  BC o r c o r t i c a l  The  during the  level  the duration  firing  sometimes  o f EN s o m e t i m e s d e p r e s s e d A C h i n d u c e d  b u t when i t d i d . o c c u r  was s h o r t e r  depression  bursting activity  o f the steady  apparently  21 A ) , w h i c h  the spike  late  An  transiently  (Figure 21B). cell  of the  depression  stimulation (Figure 22).  Figure 200  yV 1  sec.  20  ACh d e p r e s s i o n mic neurone; B. 40 n A A C h a b o u t 1-2 s e c C. s p o n t a n e o u s after current not n o t i c e a b l y  of spontaneous b u r s t i n g o f t h a l a A. s p o n t a n e o u s b u r s t i n g p a t t e r n ; depresses spontaneous b u r s t i n g a f t e r c u r r e n t t u r n e d on (artifact) b u r s t i n g resumes about 2 sec t u r n e d o f f ; D. N a 40 n A d o e s a l t e r spontaneous b u r s t i n g . +  89  A « t t  B  t'lfll'fl'iWl  1 "mirn'ij  mm#m  i n«niinniafiiin—ififII  ^ • f • I* i 1  'I  I I  l!h!f'!ff!'ll!!'!  1SEC |  100 wV  500 M  200  t  . >i t t > \ i t t.t t>  Figure 21.  BC s t i m u l u s d e p r e s s e s n e u r o n a l f i r i n g i n d u c e d b y A C h ; A. c o m p l e t e s u p p r e s s i o n o f f i r i n g f o r a l m o s t 0.5 s e c - - s t i m u l i a t a r r o w s ; B. s t e a d y . f i r i n g i s r e p l a c e d b y r h y t h m i c b u r s t s " a f t e r . BC stimulation. Lower t r a c e o f each p a d x i n d i c a t e s , o u t p u t o f p u l s e g e n e r a t o r t o ratenietel:.' Note d i f f e r e n t time and v o l t a g e c a l i b r a t i o n s .  100  iFigure  22.  D e p r e s s i o n o f ACh i n d u c e d a c t i v i t y o f VL neurones by EN s t i m u l i . S t i m u l i a t arrows.  90 Synaptic by ACh. could  Cells  activation  not excitedby  sometimes be e v o k e d  application .(Figure of  23) .  a c t i v i t y , was s e e n  evoked  o f VL c e l l s a stimulus  Another  converted the early bursts  spike  responses  variety Five  responses evoked  of effects with  cells  either  showed  cells  (Figure  ACh were  with  response.  25).  to single short  by E N . s t i m u l a t i o n  and/or  a reduction  Where t h e l a t e n c y was u s u a l l y r e d u c e d cells  Two  of the burst  other  showing  cells  effect  i n the latency  excitation  responded  was e i t h e r a c o m p l e t e marked r e d u c t i o n  with  seen i n t o ACh  to a single spike, but without  o f ACh, a d e p r e s s i o n  EN s t i m u l a t i o n was f o u n d  by ACh.  to a single  the excited or depressed  or.a  a  of the response  response belongs with third  showed  t a k i n g the form  I t i s n o t c l e a r whether  there  latency  t e s t e d were u n a f f e c t e d  The s e v e n  preparations.  a conversion  The  was  ACh a p p l i e d t o s u c h  a change i n l a t e n c y .  to  alteration  f o u n d i n d e c e r e b r a t e a n i m a l s and none were  chloralose  ACh  an e a r l y b u r s t  some s i g n o f e x c i t a t i o n ,  was s h o r t e n e d , t h e b u r s t spike  during  i o n t o p h o r e t i c a p p l i c a t i o n o f ACh.  o f an i n d u c e d f i r i n g  t h e evoked  i n which  cortex  (Figure 24).  o f t h e twenty-two  Seven  of  cell  t o BC o r  form o f such  stimulation.  cells  VL  a l s o be a l t e r e d  b y t h e same s t i m u l u s  i n VL c e l l s  b y BC o r c o r t i c a l  could  i n eight  cells.  suppression  this  type of  group. o f the response  In these  of response  cells  (Figure 26),  i n the frequency of success with  which  91  B  10MSEC  F i g u r e 23,  F a c i l i t a t i o n o f s p i k e d i s c h a r g e e v o k e d b y BC 'stimulus; A. f i e l d r e s p o n s e t o BC s t i m u l u s w i t h o u t A C h ; B. s a m e w i t h 20 n A A C h a p p l i e d iontophoretically.  25MSEC  BN Figure  24. C o n v e r s i o n o f c o r t i c a l l y evoked e a r l y b u r s t o f - • . VL. n e u r o n e t o . s h o r t , l a t e n c y s p i k e ; A. e a r l y ^ . b u r s t e v o k e d w i t h n o .drugs:;.-' B. same c e l l ['•>: e v o k e d d u r i n g a p p l i c a t i o n o f 30, n ,A, ACh.. .; -  4  92 . a s t i m u l u s evoked immediate  a response.  The d e p r e s s i o n was n o t  i n o n s e t and was n e v e r  c u r r e n t s passed  duplicated  through other b a r r e l s  by p o s i t i v e  of the electrode.  D e p r e s s i o n o f r e s p o n s e s was s e e n  i n both  cells)  preparations.  and d e c e r e b r a t e  BC n o r c o r t i c a l  evoked  (5 c e l l s )  chloralose  (3  Neither  r e s p o n s e s were e v e r f o u n d  t o be  d e p r e s s e d by ACh. ACh  d e p r e s s i o n o f EN e v o k e d  responses  c o u l d n o t be  c o r r e l a t e d w i t h t h e l a t e n c y o f r e s p o n s e , as t h e y were in  cells  (6-15 ACh  showing  msec.)  almost  t h e complete  By c o n t r a s t ,  v  range  of latencies  s i x of the•seven  '  <•;  cases i n which  caused' an e x c i t a t i o n were f o u n d w i t h c e l l s i'  w i t h mean l a t e n c i e s between 2 and 8 msec. slight  difference  chloralose ations,  i n t h e mean l a t e n c i e s  (12.6 msec.) and d e c e r e b r a t e  found  responding  T h e r e was a  o f EN r e s p o n s e s i n (10.1 msec.) p r e p a r -  b u t t h e sample s i z e d o e s n o t j u s t i f y  statistical  analysis.  Amino A c i d s The appeared cells  various diacidic  amino a c i d s u s e d  t o have q u a l i t a t i v e l y  o f the thalamus.  These  similar  excitatory  e f f e c t s : on  Most t h a l a m i c c e l l s  o f VL c o u l d be i n d u c e d t o d i s c h a r g e r a p i d l y  relatively  study  e f f e c t s were v e r y s i m i l a r t o  t h o s e d e s c r i b e d . above-for--ACh. outside  i n this  l o n g p e r i o d s o f t i m e b y t h e amino a c i d s .  i n and over Spontaneous  93  200 B  '•1  F i g u r e 25.  VL neurone evoked by EN s t i m u l u s p a i r ;  A.  r e s p o n s e w i t h no d r u g s ; B. s e v e r a l t r a c e s 1 s u p e r i m p o s e d d u r i n g a p p l i c a t i o n o f 30 n A A C h . i N o t e t h a t e a c h s t i m u l u s now e v o k e s s i n g l e s h o r t j. latency spike response.  400 B  25MSEC  'Figure  26,  VL n e u r o n e e v o k e d b y s i n g l e E N s t i m u l u s ; A. l o n g l a t e n c y burs^t r e s p o n s e w i t h n o ' d r u g s ; B. n o r e s p o n s e e v o k e d d u r i n g a p p l i c a t i o n o f 35 n A ACh; C. s h o r t l a t e n c y s i n g l e s p i k e e v o k e d d u r i n g a p p l i c a t i o n o £ 40 n A DLH.  bursting induced  activity activity,  return  after  induced  was n o t a p p a r e n t d u r i n g but i fpresent  the drug  firing  of VL c e l l s  EN s t i m u l a t i o n .  short  i n the r e s t i n g s t a t e , would  stimulation, but less,  drugs  could  responses  could  to single  spikes  with  u s u a l l y be c o n v e r t e d  t h e a i d o f an amino a c i d .  indistinguishable Fourteen these  shorter these  five  An example  ACh. burst  The  to  when D L H  of these  a n d 2-7 m s e c . i n  range when  Figure  as p r e v i o u s l y  a p p l i c a t i o n of DLH,  to a single spike t o 5 msec.  no e f f e c t  of  showed  applied.  The  response  converted  t h e mean  by the  latency  from  "non-excited"  a reduction  a reduction  a  msec,  was d e p r e s s e d  Three o f the f i v e  a  latencies  7-15  however,  and reduced  DLH and  response with The  26 C.  o f D L H , one. s h o w e d  a depression  clearly  D L H was  noted,  short-latency  tested with  was a p p l i e d .  responses had a  burst  f r o m ACh a p p l i c a t i o n .  to a single spike  a single spike without  showed  resulting  Five  early  was  These e f f e c t s were  e v o k e d b y EN w e r e  a burst  i s shown  cell,  15 m s e c , showed  from  drugs  this  those  cells  latency  without  from  9 were e x c i t e d .  conversion  of  with  l a t e n c y when one o f t h e e x c i t a t o r y amino a c i d s evoked  by  cortical  sometimes be evoked  A s f o r A C h , BC o r c o r t i c a l  of  Such  i fata l l  n o t e v o k e d b y BC o r  applied.  of  of  was u s u a l l y d e p r e s s e d m a r k e d l y  VL c e l l s  stimulation without  levels  a p p l i c a t i o n was d i s c o n t i n u e d .  BC o r p r e c r u c i a t e c o r t e x by  high  from  cells a  burst  i n l a t e n c y , and one  o f t h e r e s p o n s e n o t d u p l i c a t e d by  negative  95 current  applied  from other  no. i n d i c a t i o n o f discharge  was  depression  the  qualitatively  during  studies  these  some o f to  same e x t e n t glutamate  of  that  their  pass a cell  (LG).  Of  whereas  twenty  n-methyl-aspartic as  m e a s u r e d by  side  of  VL.  effective  any DLH  Except  for  this  evoked response was  there  firing  applied.,  were q u a n t i t a t i v e For  tested  twenty-eight three  differences  current  glutamate cells  to  (DG)  than  upon w h i c h  were a c t i v a t e d by  comparing T h e s e two  had  their  approximately  e f f e c t s on  amino a c i d s  in exciting cells  to  than  for  L two  l e s s DG  than  DLH  equal  cells  the  these  and potencies  i n and  were g e n e r a l l y  activity  routinely  cause  a p p e a r e d more s e n s i t i v e t o LG. (NMA)  apparent  e x a m p l e , i t was  amount o f for D  case,  resting  s i m i l a r e f f e c t s , i t became  greater  acid  one  or  e x c i t a t o r y amino a c i d s  actions.  drugs were compared o n l y LG,  or  various  demonstrated  necessary  of  s e e n when LG  -Although  between  barrels.  out-  more  either L  or  D,  glutamate. It potencies cells That  of  was, of  however, n o t i c e d  and  those  i s , LG  had  a greater  t e s t e d , w h e r e a s DLH groups.  This  shows t h e  relative  the  the  LG/DLH f o r e x a m p l e , v a r i e d  VL  inducing  that  was  more d o r s a l e f f e c t on  roughly  parts VL  cells  Cells within  DLH  region  by and  encountered the  of  cells  equipotent  e f f i c a c y o f ACh,  the  c o n s i s t e n t l y between  phenomenon i s i l l u s t r a t e d  e x c i t a t i o n of  thalamus.  of  r a t i o s of  the than  thalamus. on  others  i n these Figure NMA  in a  and track  i n which  two 27, LG  which in  through  short  latency  BC  responses  ACh  are found  a n d LG. t h a n  those  a r e shown to. be more s e n s i t i v e outside of i t .  a b o u t t h e same o r h a d a d e c r e a s e d d a t a were t a k e n animal.  Similar  arations. showed track  from  Histological  a close  BC  experiments several  analysis  i s presented  experiments  on VL  were  evoked w i t h s h o r t latency  were  seen  of data  from  these  two c a t e g o r i e s ,  all  i n t h e two c e l l  four agents  were  to excite  were used  the figures  from  t h e same p o p u l a t i o n o f c e l l s . a total  of thirty-seven  evoked  cells.  ACh  evoked  rather  than  for this  on  on t h e two g r o u p s .  compared s t a t i s t i c a l l y  f o r each  The  so  are derived  The d a t a w e r e  w h e r e a s DLH  which  analysis,  collected  e v o k e d and f o r t y - n i n e  non-evoked c e l l s  enough  tabulated,  cells  of the four.groups  BC  cells  f o r each  and LG h a v e a g r e a t e r a b i l i t y  a b o u t t h e same p o t e n c y groups were  Only  those  excitatory  to eject  were c a l c u l a t e d  that  for  each  non-evoked  t h e c e l l was  categories.  tested  within  studied i n  b y BC w i t h o u t t h e a i d o f  t h e means o f t h e s e numbers  27  other  separated into  amount o f c u r r e n t r e q u i r e d  substance  and  Cells  VL.  and  for Figure  i n F i g u r e 28.  within  of the substances  prep-,  recorded.  not evoked, including  each  These  and t h e p a r t o f t h e  and t h o s e  of  cells.  i n decerebrate  drugs,  The  maintained  on a D i a l a n e s t h e t i z e d  b e t w e e n VL  responses  A different  were  a n d NMA  examination of the brain  correlation  i n which  potency  an e x p e r i m e n t  differences  DLH  to  to  nonexcite  a n d NMA two  have  cell  d r u g -using t h e  97  ACh  *•  c  or  T  6 I  Figure  27.  Depth below fornix , mm.  I  S e n s i t i v i t y o f twenty-three thalamic neurones at d i f f e r e n t levels i n a single electrode track to i o n t o p h o r e t i c a l l y applied drugs. Cells between d o t t e d l i n e s were evoked w i t h short l a t e n c y b y BC s t i m u l a t i o n . Note enhanced s e n s i t i v i t y o f e v o k e d c e l l s t o ACh a n d LG.  9.8 Mann-Whitney U t e s t different not  for  cells for  DLH o r NMA.  and t h i r t e e n  a t p = 0.01 f o r  t h eexperiments  at this  minimum e f f e c t i v e c u r r e n t  Blocking (i) agents  v  atropine  intravenously  synaptic  t o block  cells.  blockers  a n d DHBE w e r e  activation  iontophoretically able  applied  t o DLH a n d  groups a r e  for  each  substance..  I f no  110 w a s a s s u m e d a s  calculations.  - The c h o l i n e r g i c tested  o f VL c e l l s  effected  their abilities to  and t h ee f f e c t s o f  Both of.these  agents  was-  stopped  (Figure  for  within 30).  were  and non-evoked  iontophoretically  required  reversible  blocking  i o n t o p h o r e t i c a l l y and  t o determine  ACh.  i nt h etime  DH3E w a s u s u a l l y  application  than  23 a n d 24 a r e b a s e d ,  i n t h e amount a n d d u r a t i o n  n e c e s s a r y .and  indicate  t h e e x i t a t i o n b y A C h o f BC e v o k e d  The b l o c k i n g  drugs varied  The r e s u l t s  . [ M a n n ^ W h i t n e y U. t e s t ] .  level,  for  29.  Agents  Cholinergic  some c a s e s  block  t h etwo c e l l  each drug.  group o f  cells  LG, r a t h e r  on which F i g u r e s  was o b t a i n e d  a smaller  non-evoked  u p t o 110 n A w e r e t e s t e d  excitation the  for  DG a n d LG i n F i g u r e  The d i f f e r e n c e s . b e t w e e n  currents  by  for  They were s i g n i f i c a n t l y  l e v e l f o r A C h a n d LG, b u t  data  DG i s s i m i l a r i n p a t t e r n . t o  significant  in  Similar  i s presented  NMA.  In  1956].  a t t h e 0.01 p r o b a b i l i t y  seven evoked  that  [Siegel,  by these  of current  application  recovery.  Blocking  few minutes  after the  Such q u i c k l y  reversible  Mean Current required to excite Cell (nA) H0 H fD  o  ro  O  o  L_  0>  o  00  o _l  C/5  C D 3  ( / > —••'  M 00  ><  O  -*>  H i 0 Pi > o g 0 3 fD O . H - f D tf H 3 - rt & • rt rt HfD 3 < 0> 1 H - fD 3 rt O 13 H P i P i 3 - C H- rt pj hi 3 •< H i DJ M I"! a> cniM 3 (u (D O H- 3 3 • 3 fD 3 3 H- rt J O < . 0 O ' 3 fD 0 H t 1 3 t r 0) 3 CD ' . fD cn n fD iQ ' < CD fD H C C 0 <! H P i l-j HW O < cn o H fD X pj . 3 fD & fD rt fD P i cn 1 P. H> O O S rt f fD PJ 3 fD c: 0 cn p; cn ' M 3 1—' P i 3 H- fD cn cn 3 x iQ 1  i  W  k  o  CD  <  O 7T CD  o  > a. O a. Q O Q. > > i 3"  3  OA  1  on  3  3D T C CD  Q H. o a 3 3"  i  o O cp_ 5T  [  * 1 fD  to ID rt Hi 3- hi H- Q ~ lS 3 rt fD cn fD CD  O o S O H- fD rt &» 0) CD 3  3  Pi rt 5* (T PJ fD O M 3 • P>  <  3 3  1  3  0  Mean Current required to excite Cell (nA) TO  i  o  cn o  4k  O  cn  <  g? o TO  3  O O  _ 03 O O 3  CD O X-  a. O a. _ S. a. Q O  <  I _  CD a 3  3  =  3  ex-  o 3  o 3 I  66  o o _l  o $  <  3  o  3  <  1  CD  5 o  0 C H H fD  fD fi1 O S fD 0 CD ts 3 CD ft) C D C D *P 0 3 X P i CO d CD HPi 0> P i 0 H 3 fD 3 CD O Pi H fD Pi (D W- cn rt H C O cn P i cn H•  3  |  co s  a.  CD < O  a.  i  a.  dHSE  ACh32  DLH40  F i g u r e ,30.  ACh 32  DLH40  ACh 32  DLH40  ACh 32  50  ACh 32  DLH 4 0  ACh 32  DLH 40  Ratemeter record o f p r e f e r e n t i a l b l o c k i n g o f A C h ' e x c i t a t i o n o f s i n g l e V L n e u r o n e b y DH3E a n d atropine., T r a c e s t o p p e d , f o r 8 r a i n a t ( a ) a n d . 4. m i n a t (b);-Vv% ', •'.  101 blocking but  was sometimes  frequently  seen w i t h  atropine  after iontophoretic  atropine  r e c o v e r y . o f ACh e x c i t a t i o n o c c u r r e d atropine  excitation  excitants  a  small  seemed  the  2.0-30 m i n u t e s  I n a few appeared as w e l l  DH3.E.  occurred. Atropine  after  instances  t o block the as ACh, so t h a t  Non-specific was u s u a l l y DH3E  e f f e c t on about h a l f  effects of atropine b y BC, c o r t i c a l  of control.  blocking  successful i n  h a d e i t h e r no o r o n l y t h e neurones  tested.  a n d DH3E o n s y n a p t i c  a n d EN s t i m u l a t i o n w e r e  To e n s u r e t h a t  excitability  neurones  a non-specific  activation tested.  had not occurred,  block  of  the sensitivity  of  to iontophoretically applied  periodically.  of synaptic  possible  DLH was  The e f f e c t , o f ACh was a l s o  o b s e r v e any. c o r r e l a t i o n o f a r e d u c t i o n  and  partial  t h e s e t e s t s , a t t e m p t s w e r e u s u a l l y made t o u s e t w o  neurone  to  t o have  blocking  of VL c e l l s  types  by amino a c i d s  ACh e x c i t a t i o n s , whereas  The  During  atropine  only  30,  desensitization t o iontophoretically applied  n o t seen w i t h  blocking  applied  of cells  a non-specific  was  even  d e l i v e r y was d i s c o n t i n u e d .  iontophoretically  as i n F i g u r e  activation.  i n c a s e s where  cells  These  tested  usually  o f ACh  tested  sensitivity  c o n t r o l s were n o t always  d i d n o t seem s e n s i t i v e t o  ACh. The was  effect of iontophoretically applied  examined  latency  spike  i n nine  cells  and three  evoked  with  b y BC, s i x w i t h  an e a r l y b u r s t  atropine a  short  response.  No  102 change  i n t h e evoked  r e s p o n s e s was s e e n a l t h o u g h  s e n s i t i v i t y of the cells typical  result  was b l o c k e d .  i n a c e l l . w h i c h was e v o k e d  b y b o t h BC a n d c o r t i c a l  stimulation.  c a s e was s l i g h t l y  smaller  abolished  31 -  (Figure  slight, displacement cell of was  cells, these  markedly  although  reduced  reversibly latency  b y DH3E.  twice  t h e ACh s e n s i t i v i t y  within  1-2 m i n u t e s . a f t e r  a few minutes  after  Atropine  due t o a  respect  tothe  The l a t e n c i e s  of successful  by t h e ACh  BC  evoked  Eight of  or after  t h e DH3E  of the cells  The a c t i v a t i o n cell  responses  block.  early bursts.  This  of the c e l l ' s  was t e s t e d  t i pwith  t h e ACh s e n s i t i v i t y  s p i k e , and t h e s y n a p t i c  cell  had been  was p r o b a b l y  no change d u r i n g  or abolished.  blocked  depression  both  showed  i n this  i o n t o p h o r e t i c a l l y t o nine  i n c l u d i n g two evoked w i t h  application  with  was a p p l i e d  responses  The s p i k e  and t h e r e g u l a r i t y  a  orthodromically  t h e two p h o t o g r a p h s .  not a l t e r e d f o re i t h e r stimulus DH/3E  The  of the electrode  spike  31 shows  a f t e r ACh s e n s i t i v i t y but this  i n t h e time between  t h e evoked  Figure  t h e ACh  was  o f one c e l l  responded with  blocking correlated  sensitivity  i n succession,  t o ACh  were  short  closely  (Figure32)..  and i n each  a n d BC a c t i v a t i o n  a  was  case  blocked  t h e DH3E w a s a p p l i e d a n d  recovered  i t s cessation.  sulphate  three  cases while  cells  t e s t e d responded  was.injected  BC e v o k e d  cells  were  intravenously i n recorded.  t o BC s t i m u l a t i o n w i t h  Two o f t h e  an e a r l y  burst  103  Figure  DLH 20  Figure :  31. •  ACh60  31.  I . S i n g l e V L n e u r o n e e v o k e d o r t h o d r o m i c a l l y by'.: b o t h c o r t i c a l ( f i r s t r e s p o n s e ) a n d BC ( s e c o n d response). A. w i t h no d r u g s ; B. a f t e r A C h e x c i t a t i o n b l o c k e d by i o n t o p h o r e t i c a l l y a p p l i e d a t r o p i n e (see f i g u r e 31-11).  DLH 20  ACH60  DLH 20  ACh 60  DLH 20  ACh 60  DLH 20  AGn 60  I I . , - R e c o r d . o f s p e c i f I c b l o c k i n g o f ACh e x c i t a t i o r i . o f n e u r o n e s h o w r i ' i n ; '31-1. T r a c e s o f 31-1 obtained, a t a and b. ,  104 response, in  and appeared  d o s e s o f 1.0  case, and  a small  That  before  thecells  o f these  (Figure  cells  33).  theinjection,  had n o t been l o s t ,  short  were  rarely  recorded  excitation,  during  and were s t i l l  thecells  stimulation. found 1. V.  after  sensitive  Even d u r i n g  i n DLH s e n s i t i v i t y  iontophoretic atropine  was n e v e r  experiments,  field  o f BC a n d c o r t e x w e r e r e c o r d e d  trode  1 mg/Kg  case  reduced while  of atropine  t h e response that  Synaptic  with  seen  after  i nVL t o  by a s i n g l e e l e c - .  was i n j e c t e d i n t r a v e n o u s l y .  t o BC s t i m u l a t i o n w a s m a r k e d l y  following stimulation of precruciate  c o r t e x was n o t n o t i c e a b l y a l t e r e d  .cortex  sometimes  responses  stimulation  In each  the'DLH  e v e n a t d o s e s o f 2 mgm/Kg.  two other  while  33 C, w h i c h  were n o t evoked by c e r e b e l l a r  The r e d u c t i o n  atropine, In  a DLH a p p l i c a t i o n .  evoked  afterward.  i o n t o p h o r e t i c a l l y a p p l i e d DLH i s shown i n F i g u r e  was  latency,  was d e p r e s s e d b y  The c e l l s  but only  injected  In the third  g r o u p o f n e u r o n e s was e v o k e d w i t h  cerebellar activation  reliably  by a t r o p i n e  a n d 1.5 mgm/Kg r e s p e c t i v e l y .  0. 5 mgm/Kg o f a t r o p i n e  to  t o be u n a f f e c t e d  activation  o f s i n g l e VL c e l l s  s t i m u l a t i o n was t e s t e d  iontophoretic atropine  (Figure 34). by precruciate  f o rblocking i n . four  and i n three  change  i n t h e r e s p o n s e was s e e n  (e.g.,  Figure  with  cases  DHpE.  i n any o f these  No  tests  31).  A total  o f twenty-two  t e s t s were conducted  e v o k e d ; b y EN s t i m u l a t i o n , u s i n g  atropine  o r DH3E.  on  cells  F o r twelve  105  mil ilnirtilij  10 MSEC F i g u r e 32,  1 SEC  B l o c k i n g o f BC e v o k e d s p i k e ( o n l e f t ) a n d i t s ACh e x c i t a t i o n ( o n r i g h t ) b y i o n t o p h o r e t i c DH3E; A. o n l e f t , BC e v o k e d s p i k e w i t h no d r u g s ; o n r i g h t 10 n A ACh i n d u c e d c e l l d i s charges; B.' a f t e r DH$E 65;';n A f o r 1% m i n , B C d o e s n ' t evoke s p i k e , ACh no .longer c a u s e s c e l l firing; C. 2 % m i n a f t e r DH3E-application s t o p p e d , B C s t i m u l u s 'evoke's'..:spike a n d A C h e x c i t a t i o n has returned.  100  r~(^  B  iFigure 33.  10 MSEC 100 MSEC  VL c e l l s e v o k e d w i t h s h o r t l a t e n c y b y BC s t i mulus. E a c h p a i r o f t r a c e s b e g i n s a t same t i m e , b u t sweep t i m e d i f f e r e n t ; A. w i t h n o d r u g s ; B. 4 m i n a f t e r . 0 . 5 i m g / k g a t r o p i n e s u l p h a t e . LV,C. d u r i n g i o n t o p h o r e t i c a p p l i c a t i o n - - o f " 40 n A D L H .  105a  Figure V'^'."':.'•  34.  BC and c o r t i c a l l y e v o k e d f i e l d r e s p o n s e s i n VL ; b e f o r e and a f t e r 1.0 mg/kg a t r o p i n e s u l p h a t e ;j I.V. E a c h c o l u m n d e p i c t s f i v e c o n s e c u t i v e ",b r e c o r d s o b t a i n e d a t 1 s e c i n t e r v a l s . ' ; A".;-BC evoked r e s p o n s e s b e f o r e a t r o p i n e ; B.'.same, 4 min, | after injection; C. c o r t i c a l l y e v o k e d r e s p o n s e s • before atropine; D. same, 5 m i n a f t e r i n j e c t i o n . •  106 of  the thirteen iontophoretic atropine  the  evoked  r e s p o n s e was o b s e r v e d .  r e s p o n s e was p a r t i a l l y evoked was  as f r e q u e n t l y a f t e r  more e f f e c t i v e cell.  than  of  this  by  ACh, and i n each  by  atropine.  depressed  atropine evoked to  the  response  during  two  were  excited blocked  were  was e l i m i n a t e d b y  cases,  i n the remaining  partially  blocked i n  two.  were s t u d i e d w i t h  One o f t h e s e  intravenous  w a s not  of three  DHgE  latency  excitation  short  induced  was  of this  latency  group o f c e l l s blocked  the depression intravenously  blocked  and a n o t h e r one by.DLH, b u t  a f f e c t e d by I.V. a t r o p i n e  I.V. p a r t i a l l y  was t e s t e d  was  a s i n g l e 2 msec,  t o respond with  Atropine  cells  3 5 B ) i 'The s a m e c e l l  (Figure  and d i d n o t a f f e c t  (Figure  were  ACh.  responses were  Neither  the depression i n  i n the third. ( 0 . 5 mg/Kg) o n t w o  t h e ACh d e p r e s s i o n  altered.  Iontophoretic  35C) .  depressed  t h e EN r e s p o n s e s o f w h i c h w e r e b o t h d e p r e s s e d b y  iontophoretic evoked  thirteen cells  ACh a p p l i c a t i o n , and t h i s  DLH e x c i t a t i o n  cells  i n three  altered..  a l s o induced  ACh.  ACh  the response  of s i x of the cells  to stimulation with  The EN r e s p o n s e s by  was n o t  application.  i n depressing  depression  EN-evoked c e l l s  the atropine  were  the c e l l  i n m i n i m u m d o s e s o f 1 mg/Kg a n d i n n o c a s e w a s t h e  respond  spike by  This  case, the  t h e e x c i t a t o r y r e s p o n s e was  The r e s p o n s e s  and u n a f f e c t e d Five  case  atropine  i n that  atropine  no change i n  I n the other  the atropine  Three o f these  by ACh.  iontophoretic one,  depressed  tests,  northe  DH3E d i d n o t  107  i  A  B  C  25 MSEC Figure  35.  E f f e c t o f 1 mg/kg a t r o p i n e s u l p h a t e I . V . o n EN e v o k e d V L n e u r o n e , a n d i t s e x c i t a t i o n by" A C h a n d DLH; A. t o p t r a c e — E N e v o k e d b u r s t w i t h n o drugs; bottom--8 min a f t e r a t r o p i n e i n j e c t i o n ; . B. t o p — A C h 30 n A c o n v e r t s ' l o n g ' l a t e n c y b u r s t to s h o r t l a t e n c y s i n g l e • s p i k e ; bottom--5 min after atropine injection, excitation disappears and ACh d e p r e s s i o n ' o f b u r s t . i s e v i d e n t ; C. t o p — D L H 40 n A c o n v e r t s b u r s t ' r e s p o n s e t o s h o r t latency single spike; bottom—7 min after a t r o p i n e i n j e c t i o n , DLH s t i l l c a u s e s s h o r t latency responses. T o p p a r t s o f B a n d C ar.e; composed o f s e v e r a l s u p e r i m p o s e d t r a c e s . ^ :  5  108  200 B  25MSEC  I. VL neurone evoked i n b u r s t by EN.stimulus; A. w i t h n o d r u g ; B. a f t e r A C h e x c i t a t i o n r e d u c e d b y i o n t o p h o r e t i c DH3E; C. after\<gGhy:A. " e x c i t a t i o n , b l o c k e d • b y i o n t o p h o r e t i c ''atropine,'...  ;Figure 36.  40  (B) dHpE 50  a 20  L0  DLH 40  i  r ACh 40  i  —  i  i  DLH 40  —  i  ACh 40  (D)  Atr. 60  •  1  DLH 40  F i g u r e ' 36. ;>.;',.'•''.'•  ACh 40  ACh 40  DLH 40  ACh  40  I I . Ratemeter.- r e c o r d o f A C h a n d DLH e x c i t a t i o n | of neurone d e p i c t e d i n 36-1. Traces f o r 36-1- j A/ B a n d C o b t a i n e d ' a t ' a , b , a n d c r e s p e c t i v e l y . j J  109 affect  t h e EN r e s p o n s e  excitation blocked.  which had been  seen  cells  tested.  with The  both  atropine  cells  iontophor-  a n d DHBE i s s h o w n i n F i g u r e  results of the cholinergic blocking  EN-evoked  The ACh  i n one o f t h e s e was/ however,  An example o f one o f t h e " c e l l s t e s t e d  etically  on  o f two other  a r e summarized  _  36.  experiments  i n Table I I .  TABLE I I E F F E C T S OF C H O L I N E R G I C B L O C K I N G A G E N T S ON E N - E V O K E D  RESPONSE  DHBE  ATROPINE  TOTAL  iontophoretic  I.V.  iontophoretic  I.V.  EN-evoked  1/13  0/5  0/2  0/2  ACh  excitation  3/3  1/1  1/1  ACh  depression  4/6  2/3  -  *  ratio  (ii)  indicates successful  Amino A c i d  carried  Derivatives  by  (NMG) , t o a l t e r  LG.  -  Several  out to test the a b i l i t y  a-methyl-D, L-glutamic acid  blocking  acid  1/22 5/5  0/2  6/11  attempts/total  experiments  o f two g l u t a m i c  to  or potentiate  depress  action.,  were  acid  cells  The N - m e t h y l d e r i v a t i v e was n o t f o u n d blocking  trials  derivatives  (aMG) a n d N - m e t h y l - D , - L - g l u t a m i c  e x c i t a t i o n of thalamic  consistent  CELLS  I n a few cases  the glutamate  excited,,  t o e x e r t any  i t seemed  excitation  slightly  (Figure 37).  :  110 More i n t e r e s t i n g In  nine  of  fifty-four  partially twenty  others,  LG  cells  of  the  forms..  application  In  and  tested  of  LG  excitation  controls  specificity two  were o b t a i n e d w i t h  specific block  inadequate  in  results  a  for  blocked  were a v a i l a b l e effects. few a  The  cells,  short  a definite  activation  was  to  was  application  after  depression greater  of  after The  not BC  dorsal  to  lation  was  glutamate  aMG  application  be  was  VL.  to  blocking  four  on  LG  actions was  was used  e v e n w h e n LG  was  response  Several aMG  also  of  the  always control,  became l e s s  activation  was  ACh  by  evoked  to  VL  cells  BC  lying  stimu-  w h o s e LG sensitive  however, the  greater. the  BC  did  a definite block cells  In  of  even  evoked  the  although  extent  glutamate  instances aMG,  activation  the  i n non-evoked  by  i n both  In  38).  towards cell  aMG  37).  frequently  the  applications,  a  indeed  and  almost as  whether  found  LG  cells  occurred.  aMG  aMG  of  or  during  (Figure  (Figure  In  was  seen  affected  after  and  least  the  was  d e p r e s s e d by  aspartate  unaltered,  as  In  not  or  w h e r e ACh  related  of  aMG  recovery  ended  at  partially,  occurred  r e s p d n s e was  action  i n n o n - e v o k e d VL  activation  tivity  of  the  stimulation, and  end  antagonistic  appear to  cells  LG  the  by  glutamate.  noted.  only  afterward  a partial  seen  was  blocking  most c a s e s , however, o n l y  and  distinguish  blockade  time  a-methyl  sensito  DLH  effect  those  cases  sensitivity completely  of  was  depressed.  .1.1.1. aMG 9 0  NMG 90  100 r  50  50  50  50  50  50  50  50  50  <o X 2 50  60s.  : F i g u r e '37. 1 ': . • :  Ratemeter. r e c o r d o f e x c i t a t i o n o f VL neurone b y 50 n A L G d u r i n g i o n t o p h o r e t i c a p p l i c a t i o n s o f NMG 9 0 n A a n d aMG 9.0 nA.-  x  25  GUJT  DLH  70  IS  30 s.  Figure 38.  Ratemeter records.obtained from two d i f f e r e n t c e l l s . . • A-D. e x c i t e d by'.*LG.- 75 n A a n d A C h 3 5 " nA;JyE "and'.ivE" e x c i t e d b y -jLG".!70 n A arid'' DLH 1 5 n A ; \0^' '* o l s ;^B:;.'arid' "F ; .3./min a f t e r . t h e s %3$& • a p p l i c a t i o n . ; ' . ( 9 0 . n A ) ; C. 1 m i n a n d . , D . ^ jl- jl- unn m i nar.rer a f t e r ..tnev-aMG ,theV-aMG current c u r r e n t was w a sterminated. terminated, T h e5 • ^S&esponse • i n ' . ' - t h ^ c e l l of Ev--E'-'showed only m i n tirnaRecovery ima; i5.,!M-n>;aftef aMG'.current ter:  A  e:  c  o  f  o  a  n  M  t  r  ;  ;  G  ;  ; 1  minate'd-iT  112  (iii) studied  Strychnine  on t h e s p o n t a n e o u s  VL  cells,  BC  stimulation.  to  nine  and/or  cells  others. of  (iv)  induced  i n any o f these  various  cases  - Observations  different  conditions.  o r BC  (Figure  depression 39) .  in-many e x p e r i m e n t s and  results  could  In chloralose  be  obtained  anesthetized  i n VL e x h i b i t e d l e s s  activity  a n d w e r e g e n e r a l l y much l e s s s e n s i t i v e o r  t h e i o n t o p h o r e t i c a p p l i c a t i o n o f ACh. examined  chloralose sensitivity  i n one d e c e r e b r a t e  was a d m i n i s t e r e d o f a VL c e l l  This  spontaneous  intravenously while (Figure  insensitive  effect  preparation  was t e s t e d  of  c h l o r a l o s e was g i v e n . 30 mg/Kg t h e c e l l  less  time,  2 minutes  h a d become i n s e n s i t i v e  s e n s i t i v e t o DLH.  in. a short  Within  While  t h e DLH  ACh r e m a i n e d u n a b l e  the drug  40).  This  Dial  cells  anesthetized  were  frequently very  animals,  cell before  of the injection t o A C h , a n d was  sensitivity  recovered  to excite the c e l l ,  e v e n when t h e e j e c t i n g c u r r e n t was c o n s i d e r a b l y VL  was  t o which  was e x c i t e d b y i o n t o p h o r e t i c a l l y a p p l i e d AChi.and DLH the  on  decerebrate  f o r example,  directly  by  o f two  animals,  to  cells  firing  the study  i n the bursting a c t i v i t y  that  of  was a p p l i e d i o n t o p h o r e t i c a l l y  and b a r b i t u r a t e a n e s t h e t i z e d  suggested  these  of drug  and i n t r a v e n o u s l y d u r i n g  Anesthetics  chloralose  under  Strychnine  was s e e n  were  and evoked b u r s t i n g a c t i v i t y  the depression  No c h a n g e  firing  animals  - The e f f e c t s o f s t r y c h n i n e  increased.  s e n s i t i v e t o ACh i n  b u t t h e same d e g r e e  of  sensitivity  113 I i  I  A m  MMliMM  B i^w#»f  ><  M"  mmmtm  Wvii^j^  >>j  mm  t  1 SEC  200 JLiV  F i g u r e 39.  E f f e c t o f . i o n t o p h o r e t i c a l l y a p p l i e d s t r y c h n i n e •''"')) o n BC e v o k e d r h y t h m i c b u r s t i n g a n d d e p r e s s i o n of.firing. A. f i r i n g i n d u c e d i n V L n e u r o n e b y 6'riA D L H ' i s d e p r e s s e d b y BC s t i m u l a t i o n ; B. ' same a f t e r 90 n A s t r y c h n i n e f o r 4 m i n ; C. f i r i n g !' i n d u c e d i n V L n e u r o n e s b y 12 n A A C h i s c o n v e r t e d , t o b u r s t i n g b y BC s t i m u l a t i o n ; D. s a m e a f t e r p 90 n A s t r y c h n i n e , f o r 2 m i n .  (A)  (C)  fU  i ACh  10  D L H ACh  55  Figure  10  DLH ACh DLH  55  40.'  10  55  ACh  DLH  10  55  DLH 55  ACh 5 0  ACh 8 0  DLH  DLH 55  55  Ratemeter record o f e f f e c t o f a - c h l o r a l o s e on f DLH •and: A C h i n d u c e d ' f i r i n g o f a V L n e u r o n e i n | decerebrate animal; A..' c o n t r o l ; B. 2 m i n _ j; a f t e r 30 n g / k g a - c h l o r a l o s e I . V . ; C. 28 m i n after chloralose. injection. ' •  o  :  114  1  DLH 40  i 1 ACh 15  i 1 i 1 DLH 40 ACh 15  I : 1 DLH40  -I 1ACh 15  40  60 I  DLH 40  ACh 15  DLH 40  I  DLH 4 0  sec.  1  I  A C h 15  1  ACh 15  ;20-  !  v  co  F i g u r e - 41. ' . ,  -Ratemeter r e c o r d o f e f f e c t o f s o d i u m - p e n t o b a r b i t a l o n DLH and ACh i n d u c e d f i r i n g . ';6f/ a V L neurone i n d e c e r e b r a t e a n i m a l . 2 mg'/kg' p e n t o b a r b i t a l i n j e c t e d a t ( . a ) 1 0 min, l a t e r a d d i t i o n a l 2 m'g/kg i h j e c t e d ^ a t (B;)'. . 10 m i n l a t e r a d d i t i o n a l 4 mg'/kg i n j e c t e d - a t (c) .  115 was  not  u s u a l l y seen i n p e n t o b a r b i t a l p r e p a r a t i o n s .  a g e n t was, was  therefore,  above.  The  injections. cell DLH  Figure  excitability evident  was  was  small  similarly  relatively while  DLH  (Figure  high  43.  recorded lation,  on  effect  sensitivity  An  The  but  the  latency  t o a much  ACh  as were a few  i s apparent  smaller  pentobarbital, h o w e v e r t h e stimulation with  an  early burst  be  a  noted  thiopental  seemed  short  levels  increase  as  in  latency DLH  shown i n  often  of  application  in Figures  After  type response  the BC  to  (Figure  42. spike  stimu-  8 mg/Kg  responded  and  4i &  41,  l a t e n c y by  At  depressed,  control  in Figure  spikes.  cells  the  i . e . a depression  onsets o f ACh  evoked w i t h  in  preparation.  l e s s e r extent  experiment represented  p a p e r was  was  f o r e x c i t a t i o n by  e f f e c t noted e a r l i e r , between t h e  the  VL  as  Sodium  remained a t about the  ACh.  i t  I t should  A more marked e f f e c t was  of a  8 mgm/Kg .  o f ACh  e x c i t a t i o n increased  ACh  small  t o have been  i n another decerebrate  e x c i t a t i o n c a u s e d by In  a s e r i e s of sensitivity  i n j e c t i o n s were g i v e n .  spontaneous f i r i n g the  greater  sensitivity.  o f t h e ACh  also increased,  Figure  o f ACh  sensitivity  chloralose  same t i m e r e d u c e d b u t  the  doses, the  t o e x c i t a t i o n by was  as  as  c u m u l a t i v e dose reached  at the  tested  42).  given  There appears, t h e r e f o r e ,  latency  additional  same way  shows t h a t t h e ACh  when t h e  p r e f e r e n t i a l block the  41  i n s p i t e of  control period.  that  i n the  p e n t o b a r b i t a l was  disappeared  still  tested  This  of BC 44)..  116  ACh 10 40  DLH20  ACh 10  DLH 20  ACh 10 60 sees.  r  20 •  ACh 10  ACh 10  DLH 20  Figure ;  42. •  DLH 20  ACh IQ- •  DLH 20  ACh 10  DLH 20  ACh 10  ACh 10  . DLH 20  ACh 10  Ratemeter r e c o r d o f e f f e c t . o f sodium t h i o p e n t a l on DLH and ACh i n d u c e d f i r i n g o f a VL n e u r o n e i n a decerebrate animal; top•record--control; s e c o n d r e c o r d — a f t e r 2.5 .mg/kg 'sodium ..thiopental I.V. ; t h i r d r e c o r d — 2 0 m i t i ^ later"''Rafter/7.-. 5 mg/kg t h i p p e n t a l t o t a l ; • • bp^om^re.cofd'--'20'- m'in l a t e r a f t e r 20 mg/kg • t h i o p e n t a l ^ t p t a l . I:'y *•'  Effect of Thiopental on Latency of A C h Excitation of a V L Neurone  !  2 0  and DLH  1  "—i  0  i-x  10  20  1  1  T—  30  40  50  Latency (sees.)  Figure  43.  Graph o f l a t e n c y t o c e l l f i r i n g a f t e r a p p l i c a t i o n o f D L H o r A C h f o l l o w i n g I . V . i n j e c t i o n s of,; sodium t h i o p e n t a l . I n j e c t i o n s . admiMlstered.'. at 10 m i n i n t e r v a l s . '.'"1 J'  • A flW"" ••' - 4oo I J 1  [Figure '  44.  B C e v o k e d .VL c e l l s . A. . c o n t r o l ; kg. s o d i u m p e n t o b a r b i t a l . ;  -B. a f t e r ' 8  mg/. , ;  118 N U C L E U S CENTRUM MEDIANUM'  Many e x p e r i m e n t s pathway cortex the  from  short  of  latency  the Pf  (2-10  complex.  as w e l l  a b o v e EN  was  possible  latency  responses. as  neural  precruciate  was  with  found  in  to  evoke  of the  centrum  single  spikes,  C e l l s were evoked  lateral  portions  i n which  in  o f t h e CM  therefore  of response  lying  i n the i n t e r n a l  t o a t t r i b u t e any  specifically  -  h i s t o l o g i c a l , study  gave a s i m i l a r v a r i e t y of r e s p o n s e s .  It  p a r t i c u l a r type  to a c t i v a t i o n of the  or  EN-  pathway. Stimulation  definitive  responses  of the precruciate i n t h e CM.-  negative-positive-negative Checking several in  the  from  in cells  responded  the  Stimulation  nucleus  stimulating electrode  capsule  CM  Most c e l l s  Some e x p e r i m e n t s  t h e EN  not  medianum..  msec.) a c t i v i t y  some s h o w e d b u r s t  more m e d i a l  showed  centrum  the entopeduncular  medianum complex. though  to study  t h e e n t o p e d u n c u l a r n u c l e u s and  t o the nucleus  region  were, c o n d u c t e d  the  Pf  lateral  ments u s i n g  part  of t h i s  was  A  of the nuclear  c o m p l e x and  map  of the  complex  response  i t could  electrodes  be  provide  localization  In  these experiments, a f t e r the response  was  seen. in  elicited three  were t h e r e f o r e  to  more  often  indicated that  large-^tipped a precise  gave  complex.  wave r e s p o n s e  of the anatomical l i m i t s experiments  cortex  of the  only  experirperformed response.  located,  the  119 recording find  e l e c t r o d e was  the v e r t i c a l  t h e n moved vertical the of  m a p p i n g was direction  the response  was  then  until of  repeated.. until  c o u l d no  were  frontal  p r e l i m i n a r y work  that  Figure  absent  45.  I t c a n be  later  seen  6;5.  Very  distribution parts  and A  7.0,  similar  The  and t h e  gave no  same  found.  o f t h e 1 mm  carried  reduced  this  largely  limits  again  vertical,  A l l  from  the  confined to  i n medial parts of the The  a r e shown  figure  a large  large  one,  experiments.  of the boundaries from  procedure  o u t i n two o r t h r e e  of these  was  sign  S e v e r a l examples  adjacent nuclei.  n e g a t i v e waves were  p l a n e s A 7.5  which  the impression gained  recorded over  c o r r e l a t i o n w i t h Mehler's  track  to the o r i g i n a l  l o n g e r be  or markedly  [1966] d e f i n i t i o n  n e g a t i v e wave was  A  found  one o f . t h e m a p p i n g e x p e r i m e n t s  Mehler's  and  medial  the response  CM-Pf c o m p l e x and i n o t h e r from  one was  i n each  confirmed  The e l e c t r o d e was  t o a new  recorded a t each  planes  these-experiments  a n d was  mm  to  F u r t h e r t r a c k s w e r e made i n  The m a p p i n g p r o c e s s was  different  CM  - 0.6  i n tracks  the response  steps.  b y 0.5  a t any v e r t i c a l ' l e v e l .  repeated  the response  intervals  limits' of the response.  laterally  lateral  m o v e d .down i n 1 mm  results  and r e l a t e d o f CM i n  that  the  earlier  area, but the  o n l y i n CM.  i s very  and o n l y s l i g h t l y  close  positive  The-  at  frontal  divergent at  responses, w i t h about.the  i n CM-Pf w e r e r e c o r d e d a f t e r  to  same  stimulation  of the sensori-motor, but not of p a r i e t a l ,  o f .other  occipital  120  Figure  45.  On l e f t — f i g u r e t a k e n f r o m M e h l e r ( 1 9 6 6 ) — \ horizontal bars indicate parvocellular part of CM i n c a t b r a i n a s o u t l i n e d b y M e h l e r o n a n a • j t q m i c a l ; . ' . b a s e s a t f r o n t a l p l a n e s A 6 . 5 , A 7.0 ,• . A"-7v5; c o m p a r e d w i t h CM" a s d e s i g n a t e d b y J a s p e r a n d A j m o n e - M a r s a n (19 54) o n r i g h t si'de£\. Right s i d e o f s e c t i o n s have been m o d i f i e d ( c o u r t e s y C o l u m b i a U n i v . P r e s s , a n d W.R. Mehler.)•;£•-. b y s u p e r i m p o s i n g M e h l e r " s CM l i m i t s (dotted o u t l i n e s ) and e l e c t r o d e t r a c k ^ p s i t i o n s . ; R e c o r d i n g o n r i g h t c o r r e s p o n d t ' d ' t r a c i n g s o b - . ~\ tained after precruciate cortex stimulation at- • p o s i t i o n s i n d i c a t e d by b l a c k s w e l l i n g s on tracks.;- Left-most column of t r a c i n g s corresponds t o l e f t r m o s t r e c o r d i n g t r a c k , t o p row,.,of t r a c i n g s c o r r e s p o n d s t o t o p row o f r e c o r d i n g p o s i t i o n s , . | etc. Black dots over tracings indicate, those , j tracings obtained i n positions, f a l l i n g w i t h i n j M e h l e r • s l i m i t s o f CM. -'I :  d ,  :  121  or  temporal  reliably  cortex.  The  responses were  evoked, however, a f t e r  l a r g e s t , and  s t i m u l a t i o n of  most  precruciate  cortex. Stimulation from  the  lateral  invariably evoked  sponded: w i t h positive  found in  of  were  imposed  VL,  the  a burst  the  5-12  to burst  cells,  again  the  and  2-3  cells  of  the  during  typical '46 .  The in a  followed those  insensitive  by seen  cells  fashion  i n CM  were  similar  to  s e r i e s of  t o ACh  of  superoften those  :  the-precruciate  late The  the  spikes  S t i m u l i of  i n VL.  from  spike  response with  the  The  p o s i t i v e wave v a r i e d initial  with  re-  i t s positive-going slope.  A  to  evoked u s u a l l y  spikes which occurred  less regularity.  similar  above,  bursts  cells  of  of  a p p l i c a t i o n , even  CM in  animals .  i n these after  mgm/Kgm.  wave were  fine-tipped electrode  l a t e n c i e s to the  msec.  Cholinergic tested  a  The  spontaneously,  seemed r e l a t i v e l y  1-2  of  sometimes  decerebrate  with  recording  complex wave r e s p o n s e n o t e d  trough  though with were  before  CM  i s shown i n F i g u r e  cortex  was  of  superimposed.  msec, w h i l e  bursts  p r e c r u c i a t e c o r t e x .while  w a v e , u s u a l l y on  latencies 9-15  part  evoked  spikes  of  No  found.  involvement  i n the  e x p e r i m e n t s by  intravenous change  comparing  injections  i n the  cortex-CM  evoked  of  the  response responses  atropine  spikes  or  i n -doses  complex  of  122 ENTOPEDUNCULAR NUCLEUS  Some e x p e r i m e n t s w e r e d e s i g n e d pallido-thalamic the  entopeduncular  of  either  EN.  In  tested  CM  or  a  t o t a l ' of  These numbers both  action VL  at  VL  a  conditioning  a  1-2  of  up  stimulated, required  by  was  the  part  of  the  also  i n the  several  One  VL  to  one  stimulus  of  stimulation  these of  cell  longer  the  stimulating  electrode  CM-Pf c o m p l e x  Of  the  activated  s h o w e d ;an  nuclei  An  were was  example  of.  47.  e f f i c a c y of i n the  1.5  at  after  interval  i n the mm  a pair  CM-Pf  EN  l e a s t one  of  complex  lateral  medial  twenty-five by  However,  other,  situated other  or  followed  electrode  the  CM  second.  both.  relative  CM-Pf c o m p l e x , a n d  which were a n t i d r o m i c a l l y  either  that  sites,  i n Figure  t i p was  .  to  interstimulus to  stimulation  found  When b o t h  responded  experiments  the  were  were  by  per  in  stimulation.  i t was  hundred  i s reproduced  concentric  tested.  every  second response.  these experiments two  cells,  cells  stimuli  found which  e l e v e n by  latter  considerably  before  In  to  stimulus  the  and  followed  msec, d e l a y  occlusion  CM  were  CM  of  stimulation  a c t i v a t i o n of and  the  from c e l l s  that  s i x which were evoked  In, t h e  frequencies  found  antidromic  cells  e v o k e d by  nuclei.  I t was  i n w h i c h b o t h VL  thirty  potentials  bipolar  caused  include  t e s t whether  actually originates  nucleus.  experiments  antidromically  of  pathway  to  to i t ,  cells of  these  i 123  WW**  50 MSEC Microelectrode recording i n lateral part of .CM*-Pf''' c o m p l e x a f t e r '-. s i f t g l ^ , ^ r ^ q r | a ' c i a t e c o r t e x stimulus at-arrow. '•  F i g u r e 46.  v  A  m  B *  200  _l : 2  V  10 MSEC  C S D *  Figure  47.  Superimposed traces showing antidromic activat i o n , o f E N n e u r o n e b y - CM and. V L s t i m u l a t i o n . A • each':.of t w o s t i m u l i w i t h 1.5 m s e c i n t e r s t i m u l u s i n t e r v a l evokes antidromic a c t i o n p o t e n t i a l . .response; B. s a m e f o r t w o V L s t i m u l i ; C. CM, "then VL' s t i m u l a t i o n o n l e f t — 1 . 5 ' m s e c i n t e r v a l ; o n ' . r i g h t — 2 . 4 msec i n t e r s t i m u l u s i n t e r v a l i s r e q u i r e d before- s p i k e . p o t e n t i a l i s r e l i a b l y e v o k e d b y V L stimulus;,. ' D. V L , t h e n CM s t i m u l u s ..--on l e f t — 1 . 5 m s e c i n t e r v a l ; on r i g h t — 1 . 9 msec i n t e r s t i m u l u s i n t e r v a l i s r e q u i r e d b e f o r e s p i k e p o t e n t i a l i s r e l i a b l y e v o k e d b y CM s t i m u l a t i o n . •.;••'••  124 electrodes, electrode  twenty-two were  and s i x by t h e more m e d i a l  evoked by both. was  1.6  activated  msec  stimulation  'The a v e r a g e  -following o f VL.  CM  latency  by t h e more one, three  cells  of response  stimulation  a n d 1.7  lateral  i n EN  msec  being cells  after  CHAPTER  IV  DISCUSSION  The  spontaneous  in  VL  seen  by  Andersen  cently  by  in this and  Andersen  et or  concept  glycine  blocking  accepted,  that  i s very  [1968] f o r t h e  or  a principal [Curtis,  would  found  pattern.  that  of  i n thalamic as  y-amino b u t y r i c a c i d  Johnston,  1970],  function  as  could  the  be  izations  specific (GABA)  inhibitory  agent which with  observations  post-stimulus  that  more  i s not  IPSPs  of  the however,  inhibitory  B i c u c u l l i n e has the  been action  Duggan, F e l i x  therefore  that  activity  and  GABA  may  thalamus  rhythmic  s t i m u l a t i o n of  EN  i n VL  a  the  [1971] h a v e ,  of  and  hyperpolaractivity.  did cells  on  the  1969]  spontaneous b u r s t i n g  bursting  If  Johnston,  glycine the  administered  as  l e a s t some  the  re-  strychnine  t r a n s m i t t e r i n the  the  and  apparent e f f e c t  antagonist  generates  described  depression.  [Curtis,  It i s possible  associated The  generate  an  at  relay nuclei.  a relatively  no  McLennan,  b i c u c u l l i n e does b l o c k  phenomena proposed  Duggan and  activity  Strychnine  Duggan and  generates  that  VBC,  a c t i o n of  indicate that  bursting  to  f o r VL.  post-stimulus  inhibitory, transmitter which bursting  similar  s y s t e m a t i c a l l y had  agent  this  stimulus-induced  a l . [19 69]  bursting activity  current  is  study  Andersson  iontophoretically the  and  not and  126 that  the post  weaker  than  (Figures  stimulus  that  d e p r e s s i o n was e i t h e r  produced  by, c o r t i c a l  o r BC  2 1 , 22) i s i n a g r e e m e n t w i t h  Desiraju  and Purpura  following  [1969]  that  appear  to contradict  the findings  some E P S P s o f V L  of cell  back mechanism. indicated small  could  by t h e r e s u l t s o f t h i s  proportions  activated with (3/11  i s not influenced That t h i s  than  addition,  this  nucleus  stimulation would  of other  be t h a t  excitatory lation,  could  influence  were by  the r e s u l t i n g i n h i b i t i o n ,  than  with  i s difficult  o f t h e model  [1966]  In  stimulation than  A third  appears  explanation  t o have a  cortical  o r BC  lesser  stimu-  which by t h e model i s should  also  be  t o be w e a k e r . It  part  relatively  the proposed i n h i b i t o r y  dependent on p r i o r e x c i t a t i o n o f neurones, expected  be  stimulation.  systems.  on VL c e l l s  feed-  cerebellar  produce d i f f e r e n t e f f e c t s afferent  on a  also  inhibition,  b e c a u s e EN s t i m u l a t i o n  influence  i n which  cells  (3/28 c e l l s )  i f EN f i b r e s a l s o  part  by t h e i n h i b i t o r y  study  i n t e r n e u r o n e s , . e . g . , by p r e s y n a p t i c of  i n large  10 m s e c l a t e n c y  c e l l s ) -or , c o r t i c a l  I t i s possible  be t h e c a s e m i g h t  o f t h e EN e v o k e d  less  cells  IPSPs.  [1962].  t h e EN p a t h w a y t e r m i n a t e s which  of  the collateral-inhibitory  feedback model o f Andersen and E c c l e s however, t h a t  o r much  stimulation  EN s t i m u l a t i o n w e r e n o t s u c c e e d e d b y  These data  type  absent  that  i n face  the post  cortical  t o argue  of the evidence  stimulus  stimulation  against  depression  t h e axon  collateral  of Sakata e t a l . i s s t i l l  after degeneration'of  present thalamo-  127 cortical  fibres.  to  t h e model  VL  from  However,  ( p . 22)  i n t e r p o s i t u s nucleus depression  positive  evidence w i l l  validity.  has been  I t should  which  could  found  [Uno, e t a l . , ,  be n e c e s s a r y  be p o i n t e d  o n t h e VBC.,  The  out that  possible therefore  the  sensory  appearance  relay muclei  The  that  s e e n on VL  reported  by  the e a r l y burst i n VL  [19 6 8 a ] .  A  by these latency  cells  other  to the  more  on from  model,.however,  f i n d i n g s i n VL.  depression)  I t  activity  are s i m i l a r could  response has n o t been  e x c e p t by McLennan,  similar  burst  workers spikes  by  Huffman  phenomenon was  in  in be  caused  responses could  are very  to optic tract  stimulus  to-synaptic activation  They  BC  similar exception  previously and  observed  a l s o be c o n v e r t e d  increased  the  Marshall  by C u r t i s and  geniculate nucleus  were  suggestion  study  investigators, with  a p p l i c a t i o n o f ACh.  Their  1970]  the evidence  of e l e c t r i c a l  i n this  phoretic due  on  and VL w h i c h  [1963] i n t h e l a t e r a l The  post-  mechanisms.  reported  Davis  a  e x c i t a t o r y e f f e c t s o f c e r e b e l l a r n u c l e i and  stimulation those  types  (e.g.,post-stimulus  by d i f f e r e n t  to  that  cause  b a s e d was; g a t h e r e d  objections  have almost e x c l u s i v e l y been based is  also  on  t o determine i t s  t h e A n d e r s e n - E c c l e s m o d e l was  experiments  objections  and b e c a u s e an i n h i b i t o r y . i n f l u e n c e  stimulus  which  because of the other  (LGN).  s t i m u l a t i o n seen •  to single,  intensity proposed  short-  o r by  that  ionto-  the  bursts  at about the t h r e s h o l d  i s a p l a u s i b l e one, b u t i f t h i s  i s the  level. sole  128 explanation, spike  the replacement of the burst with  i s difficult Because  anesthetized, animals, spike  this  type  but only  o f r e s p o n s e was f o u n d  i n place  and  chloralose preparations,  has been  anesthesia  The i d e a  after  The  ability  frequently i n both  spike  produced  due  might  BC e v o k e d  spikes  that  short  indicate  were c o n v e r t e d  temporally The  the  synchronously  under c e r t a i n a n e s t h e t i c  out  a long  could  dispersed  threshold with  membrane a b o u t t h r e s h o l d  early  short s t i l l  after  burst  an  that  EPSPs  afferent  c o n d i t i o n s be  explain the early burst EPSPs might reach  a longer level  latency  they  EPSPs o r t o  possibility  could  time  to a  Intracellular  dispersed  stimulus  potential  to  (ACh a n d t h e amino  generation.  whether  mechanism.  temporally  i n one  of the a f f e r e n t systems, but that  occur  Such  that  l a t e n c y EPSPs a r e  which normally  over  release  t h e p h e n o m e n o n may b e r e l a t e d t o  f o r spike  t o reduced, other  As•  barbiturate  membrane o r t r a n s m i t t e r  o f d e p o l a r i z i n g drugs  by a c t i v a t i o n  recording  agents.  I.V. p e n t o b a r b i t a l .  suggests  subthreshold  single  i t may b e r e l a t e d t o a n o n - s p e c i f i c  r e v e r s i b l y t o change t h e e a r l y b u r s t s  latency  some  latency  by t h e o b s e r v a t i o n  latency  bursts  acids)  that  i s strengthened  single short  early  seen  of the post-synaptic  mechanisms.  is  of a short  decerebrate  may. b e r e l a t e d t o t h e e f f e c t s o f a n e s t h e t i c  early burst  are  frequently i n  once i n a l a r g e s e r i e s o f  i t s appearance  depression  a single  to understand.  the  case  only  response.  the action  and m a i n t a i n  f o r a longer  spread  time  than  the would  129 a  synchronous barrage  certain  anesthetics  duction  rate The  were  responses to  Sakata  exception  of  EN cells.  only  presynaptic  short  cells  results  cells  10  msec.  was  done on  basis  is  difficult  the  of  compared  response during  is  similar  by  cortical  stimulation  to that or  BC  with  stimulation.  they  into  t o be  judged i t  two  groups—  l a t e n c i e s as  short  latencies to burst  re-  analysis in this  study  The  i n latency  on  also  sample of t h i r t e e n  mean l a t e n c i e s , s o  observed  of  Their  divisible  and  the  cells  and  3-4  that with  comparison mean l a t e n c i e s  msec,  number o f  latency.  spikes  i o n t o p h o r e t i c a p p l i c a t i o n of  appeared  however,.since  i s that  response  however, s e v e r a l of  reduction  the  VL  field  msec, o c c a s i o n a l l y were evoked w i t h The  in  These workers  responses with  ten  than  with  of.the pallido-thalamic  be  r e s p o n s e s was  and  responses  [1969].  i n nature.  giving burst  msec,  authors  a l . , 1970], a g a i n  study may  Albe-Fessard  spike  stimulation  several other  et  extracellular  sponses greater  the  Uno,  latency negative  post-synaptic  5-9  by  cortical  result.  bursts.  to which these  to  2.5-3  to  that  a c t i o n p o t e n t i a l con-  s t i m u l a t i o n gave a v a r i e t y of  a  as  described  early  found  three  cells  e t a l . , 1966;  D o r m o n t , Ohye and  be  reduce • the  o f VL  those  the  The  pathway  could  I t i s conceivable  i n afferent terminals, giving this  similar  [e.g.,  of EPSPs.  ACh  early bursting cells The  unaffected  burst by  were encountered w i t h  of or  DLH  evoked  responses  to  EN  chloralose- anesthesia about equal  fre-  130 quency  i n c h l o r a l o s e and d e c e r e b r a t e p r e p a r a t i o n s .  similarity evoked or  of underlying  by. EN  i f they  could  mechanism  i s possible  stimulation achieve only  are temporally  i f the EPSPs  peri-threshold  dispersed.  The b u r s t  a l s o be r e l a t e d t o t h e absence  A  of IPSPs  levels,  response  following  activation  by p a l l i d o - t h a l a m i c pathway s t i m u l a t i o n which  been noted  by D e s i r a j u and P u r p u r a  thalamic whether are  activation.  I t would  the early bursts  [1969]  after  be n e c e s s a r y  evoked  by. BC  isms  by a n e s t h e t i c  agents.  that  t h e s h o r t - l a t e n c y EPSPs which  pallido-  then  to  or c o r t i c a l  related to a l t e r a t i o n s i n the inhibitory  consider  stimulation  feedback  D e s i r a j u and P u r p u r a ' s  mechanobservation  do n o t g e n e r a t e  an  (10-20 msec.)  could  action  potential  have a p r o l o n g e d  the basis  f o r f u r t h e r s p e c u l a t i o n on t h e mechanism o f t h e  burst  is  Desiraju  studies  the.range  Purpura This cells  Both  Frigyesi  corresponds be  iontophoretic  here  o f t h e EN  pathway  [Frigyesi,  - VL  1969; F r i g y e s i  have n o t mentioned  l a t e n c i e s observed  with  induced  and Machek,  EPSPs w i t h  burst  i n those  and D e s i r a j u  with  2-3  msec,  responses. studies  and  that  2-3  msec.  several  latency  a p p l i c a t i o n o f an e x c i t a t o r y agent.  1970];  responses  l a t e n c i e s o f about  the present observations to fire  with  and Machek,  the latencies of e x t r a c e l l u l a r  have r e p o r t e d  could  reported  reports  o f EPSP  consistent with  observed.  of the results  and P u r p u r a ,  p o s s i b l e as t h e s e  However is  comparison  intracellular  1969;  form  response. Little  the  duration  has  during  The  131 presence of  the  presynaptic  latency  the  confirmatory  and  activation that  the  of  cells  direct-EN  activation required would  EN  about  is  the  of  two  of  1.6  Purpura"s  Only could  that  the  of of  this  spike.  the  very  I t m u s t be  EN to  only  a  EN  such  of  EN  about  few  16) a  mm.  If  on. t h e  wave  i n more  activity,  then  extensively  fine calibre  is Desiraju  activity  seen  activity—a  f r o m VL  latency  and  latencies after  minimum l a t e n c y  cells  short  the  slow conduction v e l o c i t y .  electrical  The  by  axons branch very  proposal  be. r e l a t e d t o  of  ventral part  increase  by  0.7-0.9 m s e c ,  o n c e was  generation  i n latency  presynaptic  a relatively  time  (1.5-2.0 msec, F i g u r e to  i s that  The  spike  signal recorded  giving rise  a c t i v a t i o n of than  appears  terminal  msec.  parts  represents  thus  observation  msec l a t e n c y  longer  2-3  for  suggests  by  p o t e n t i a l s superimposed  explanation  difficulty  study which  antidromic  latency  s t i l l  VL,  and  difference  more d o r s a l  evidence  having  stimulation.  of  msec,  stimulation.  response between the  the  most, l i k e l y  A  latency  msec,  stimulation  pathway- i s r e p r e s e n t e d  large  unitary  regions  Purpura.  mean l a t e n c y  i n locations separated  as  collaterals  is  and  absence of accepted  EN  as  upon e n t e r i n g  1.8  0.8-2  m s e c a f t e r EN  relatively  puzzling,  dorsal  - VL  result in a total  (0.8-1.0 msec)  the  of  after thalamic  1.5-2  presynaptic-type  factor  activity  for monosynaptic transmission  The  is  type  was  EPSPs of  questioned whether  their  in  pallidal, this  single  observed  for  1.1  which  msec,  Desiraju  and  findings  were  132 due, to  e.g.  to  EN.  a c t i v a t i o n of  The  explained  later  by  burst  some o f  the  suggestions  e v o k e d by  due  additional activation at  pathways.  The  thought to  or  cortical  anatomical  e x i s t i n the  substrates  Frigyesi,  [19 6 9 ] .  of  VL  and  of  CM,  been observed  and  by  dichotomized  at  antidromically invaded  by  collision  that the  40%  of  thalamic  identified  b o t h CM  VL  EN  thought to  have a c t i v a t e d neurones  concentric sphere 1.5  of  of  influence  with  of  mm.•in d i a m e t e r .  electrode  located  proportion  of  because  the  of  the  i n CM  1.5  20%  as  the  within  s i z e of  also  fibres  of  the were that  the  stimuli  are  a small  volume.  e x c i t a t i o n by, p a i r s  was  not  expected  more t h a n  that  such  fibres coursing this  of  indicate that  activate a relatively  pallido-thalamic  by  These  study  separation  I t m i g h t be  more compact  have  suggests  only  are  stimulation  [196 8 ] .  in this  each e l e c t r o d e  would  n e u r o n e s by  That  higher,  mm  pathways  pallido-thalamic  non-overlapping  electrodes  EN  stimulation  considerably  be  pallido-nigro-VL  Rispal  cells  may  observations  f o r such  level.  proportion  The  be  and  the  early  could  demonstrated  Ohye, Dormont and  workers estimated  made f o r  have been proposed  a c t i v a t i o n of  the  be  latencies via indirect  pallido-CM-VL or  Even more i n d i r e c t r o u t e s  antidromic  already  longer  close  seen could  s t i m u l a t i o n , or  systems.  The  pathways  responses normally  bursts to  BC  cortico-thalamic  nucleus.  the  about,  an  high to i t , Stimulation  133 of  VL on t h e o t h e r  of  pallido-VL  larger  area.  collaterals the  the of  f i b r e s because Estimates  admittedly  o f the percentage  it-is  thought that  collaterals The and  understood.  If basal  accepted to  a basis  EN-CM i n f l u e n c e s  ganglia  figure, axons  send  t o VL  pathway  Nauta and W h i t l o c k , 1954] Scarff  and McMurtry, action  I t i s possible  presented  influence  potentials  pathways  T h e CM-VL  f o ra double  on VL by t h e  of course  that  t o VL and t h a t  i n the Introduction,  motor  i ti s s u r p r i s i n g t h a t  field  f i b r e s t o VL  they  o f VL.  VL d o e s n o t seem t o e x e r t  Large  cells, s i x  i s a minimum  are not transmitted  independent the idea  [e.g.,  [Purpura,  o f EN n e u r o n e s .  have a r o l e  the  provide  basis  nuclei.  electrophysiologists  same g r o u p the  sending  significance of the collateral  would  on  which are  On t h i s  most o r a l l o f t h e E N - t h a l a m i c  t o these  send  b y CM s t i m u l a t i o n , s u g g e s t s  suggested b o t h by a n a t o m i s t s  1965]  be b a s e d  e v o k e d EN c e l l s  Because t h i s  CM i s n o t p r e s e n t l y  and  therefore  a minimum-^of 5 0 % o f t h e E N c e l l s  h a v e c o l l a t e r a l s t o CM.  a  o f axons which  sample o f e l e v e n VL evoked  activated  proportion  project-to  e v o k e d b y CM s t i m u l a t i o n .  small  w h i c h were a l s o  a small  probably  o f VL a n t i d r o m i c a l l y  antidromically  that  they  only  t o b o t h V L a n d CM s h o u l d  proportion  also  h a n d may e x c i t e  function  t h e i r major  a strong  t h r o u g h VL i s output  influence  s i m i l a r t o those  i.e.,./.that  pathway there.  s e e n a f t e r BC o r  134 cortical  s t i m u l a t i o n a r e n o t found with  [ D o r m o n t , Ohye a n d A l b e - F e s s a r d , attributed stimuli the  i n part  than  1965] a l s o  nature  that  the cerebello-thalamic  one.  this  transmission  i n VL was s e e n  study.  The c o m p l e t e  lack  the neuronal  thalamic  pathway  and gross  this  c h o l i n e r g i c component.  the cortico-medial  agents  p o t e n t i a l s were c l e a r l y  stimulation, The by  only  s i n g l e EN e v o k e d  pathway which  I t i s possible  atropine  i n a  obtained  i n this  distinguished responses  that  non-specific case.  atropine  this  cell  latency negative  are taken  Tebecis As no  synaptic  could  be  was a l s o  tested. depressed  depressed by  m a n n e r a s n o DLH c o n t r o l w a s  induced  as r e p r e s e n t i n g  results with  contrasted  f o l l o w i n g EN  I n no t e s t was t h e r e  I f the cells  o r " DH3E  was d e p r e s s e d b y  EN r e s p o n s e s a f t e r a d m i n i s t r a t i o n  atropine.  i n this  i s t o be  r e s p o n s e w h i c h was p a r t i a l l y  iontophoretically applied  ACh.  the  single cell  with  evoked.by c o r t i c o -  [1970] h a s s u g g e s t e d may b e p a r t l y c h o l i n e r g i c . field  powerful  pathway h a s no  This  geniculate  evidence  i s less  by a t r o p i n e  response  be  part of  infrequently  of blocking  activation indicates that  significant with  firing  could  o f EN, so t h a t  by c h o l i n e r g i c b l o c k i n g  synaptic  of  This  However,.anatomical  suggests  Interference  stimulation  do n o t a c t i v a t e a l a r g e  p a l l i d o - t h a l a m i c pathway.  [Szabo,  1969].  to the dispersed  i n any one r e g i o n  EN  o f DH3E  to fire  were  o r I.V.  with  the direct  I.V. a t r o p i n e  any change o f  about  3 msec  pathway,  found  i n a l l cases.  135  The  negative  indicate  effects of atropine  that  probably  a n d DH3E o n o t h e r  responses  no - components o f t h e d i r e c t o r  postulated  i n d i r e c t pathways a r e c h o l i n e r g i c a l l y mediated.  conclusion  i s supported by t h e o b s e r v a t i o n  Parent,  Simard  pathway  i s devoid: o f The  and P o i r i e r  [1968]  that  of Olivier,  the pallido-thalamic  cholinesterase.  effects of cholinergic blockers  on t h e pathway  from t h e c e r e b e l l a r n u c l e i t o VL a r e p a r a d o x i c a l . -  With  the  o f BC  one.exception  evoked  tested  f o r DH3E  o r DH3E.  were n o t blocked  /atropine.  location  (Figure  excitability  early burst  blocking  was i n d i c a t e d evoked  field  (Figure  That the iontophoretic  surprising.  EPSPs observed 1970],  1967] on  that  by t h e r e t a i n e d  tial.  As t h i s  should  pathway,  [ E c c l e s , I t o and  a very  [Uno, e t a l . ,  Szentagothai,  ten synaptic  t o generate  f i g u r e may r e p r e s e n t  n o t , perhaps  size of the unitary  after activation of this  may b e s u f f i c i e n t  DLH  application of blocking  a c t i v a t i o n o f fewer than  a VL c e l l  of the field  33).  Because o f t h e large  " i t has been estimated  reduced by  r e s p o n s e s a t t h e same  a g e n t s d i d n o t a f f e c t t h e BC-VL r e s p o n s e s be  case,  i n two cases by t h e l a c k  3 4 ) and i n t h e t h i r d  of the cells  responses  I n each  responses were markedly  That t h e atropine  e f f e c t on c o r t i c a l  iontophoretic  by I.V.-atropine.  field  r e s p o n s e s was s p e c i f i c of  3 2 ) , no b l o c k i n g  T h e t w o BC e v o k e d  however, BC-evoked I.V.  (Figure  a c t i o n p o t e n t i a l s was s e e n w i t h  atropine  This  terminals  an a c t i o n small  poten-  proportion  136 of  the  total  of  the  BC  affecting the  number o f  s y n a p s e s on  neurones uniform  a VL  postsynaptic  microelectrode (4-6  spike  of  fluid,  with  at  the  membrane c l o s e , t o  to  block  trations  result  ACh  and  adequate  been  seen  regarded  as  Intravenous overall  The evoked  of  without  of  a very  i n the  electrode  BC  relay  perineuronal of  t i p could  the  the  Davis,  atropine be  sufficient  before  concen-  are  evoked  achieved  spike  sufficient  b l o c k i n g by  suggested  I.V.  be the by  has  has  been  excitability.  presumably  to block  depressing  of  1966], but  o f membrane  atropine  of  non-  transmission  of  size  amino a c i d e x c i t a b i l i t y  r e s p o n s e s may  previously  achieves  almost a l l  membrane atropine  excitability. on  two  BC  a t t r i b u t a b l e to only  a  cerebello-thalamic McCance, P h i l l i s  and  b]. of  partly  could  to  many  small  concentrations  [e.g.,  synapses without  [196 8  least  synapses  of  administration of  Because at  drug  synaptic  c h o l i n e r g i c mediation  Westerman  lead  non-specific depression  absence  p a t h w a y , as  is  will  the  studies  early burst  partial  that  Blockade  depression  concentrations  cholinergic  compared w i t h  the  to block  i n other  blocked The  ejected  that  be  amino a c i d s e n s i t i v i t y  a t more d i s t a n t s i t e s . coincident with  could  generation.  2 5 - 3 0 y)  concentration  the  cell  assembly  y vs.  the  endings,,it i s possible that  be  the  indication  that  c h o l i n e r g i c , the proposed  as  the  BC  basis  the - VL  BC  - VL  pathway-  cholinergic  for action of  anti-  137 cholinergic reported  i n Parkinson's disease.  t h a t neurones  discharge of  drugs  rate  o f N.. i n t e r p o s i t u s  o f 50-100/sec.  t h e u n i t a r y • E P S P s evoked  Because  [Uno, e t a l . ,  1970], s u c h a h i g h  should  have a s t r o n g  tonically  A partial  depolarization so t h a t  cells The  cells  effects  effect;  anesthetized  appear  an e x c i t a t i o n  enough  There  i n VL  appears  of the indicated  t o be  i n chloralose  interference  drug, and a d e p r e s s i o n which i s o r a t l e a s t more  and a t r o p i n e .  refractory  The d e p r e s s i o n d i dn o t sensitive to  t h a n was t h e e x c i t a t i o n . depression observed here  seen by C u r t i s  produces  on VL  mediated  responses  w h i c h was n o t s e e n  animals because  by c h l o r a l o s e  The  authors  influence  t o tremor g e n e r a t i n g mechanisms.  t o b e b l o c k e d b y DH3E a n d w a s l e s s  atropine  and R y a l l  proposed  a type of cholinergic  In this  EN-VL b l o c k i n g m i g h t  be r e l a t e d  receptor  be e x p l a i n e d evokes  t h a n BC o r c o r t i c a l  to that  These  which  b e common t o m a n y . t y p e s  case, the apparent s p e c i f i c i t y  t h e EN s t i m u l a t i o n  excitation  could  [1966] i n R e n s h a w c e l l s .  d e p r e s s i o n and which might  of neurone.  because  depolarizing  to explain.  by t h i s  stimu-  resting discharge  of cholinergically  independent of the e x c i t a t i o n to block  by c e r e b e l l a r  o f A C h o n EN e v o k e d  difficult  w i t h ACh e x c i t a t i o n  resting  l o w e r t h e membrane p o t e n t i a l  do n o t respond  are also  a dual  might  removal  have a  o f t h e magnitude  i n VL c e l l s  lation  neurones.  I t o [1969] h a s  of  s i m p l y by s u g g e s t i n g t h a t a less  powerful  stimulation,  synaptic  t h e EN-VL  response  is  d e p r e s s e d more e a s i l y Because  stimulation evoked  than the  synaptic  a c t i v a t i o n by  were n o t d e p r e s s e d by  responses  seems t o h a v e  specificity  could  receiving  EN  a f f e r e n t s , but  were seen  in cells  systems lie  As  a third  terminals  ation  of  responses  indicate  not also  provide The  specific 1963].  ganglion cells  terminals  neurone,  ACh  might  could  could  proposed  also  for  selectively  reduce  the  responses  afferent  specifity  can be  EN  affect  Depolariz-  t h e amount  of  s i z e of the EPSPs  to  level.  However, the d e p r e s s a n t e f f e c t s  i n almost  the t o t a l  amino a c i d s  Soeda and  of barium  that  range  have been on  t h e ACh  depression recording  suggested  t o have  [ C u r t i s and  i s might  nonWatkins,  [1965], however,.found  glutamate d i d not depolarize  t o have  not  problems.  neurones  Koketsu  would  r e s p o n s e s do  Intracellular  to these  of the frog •  are thought not  latency  the d i f f e r e n t latency  the answer  cells  The  thus reducing  e x c i t a t o r y actions  perfusions  of  The  of the p a l l i d o - t h a l a m i c pathway.  t o EN-VL f i b r e s .  Nishi,  the depression  a c t i v a t e d by. o t h e r  d i f f e r e n t pathways or  specific  cortical  some o f t h e d e p r e s s e d EN  possibility,  either that  represent  and  of the type of  b u t no m e c h a n i s m  released  sub-threshold  BC  some s p e c i f i c i t y .  a property  which were  these nerve  transmitter  o n EN  ACh,  w i t h o u t d e p r e s s i o n - b y ACh.  nerve  a  be  at the synapse,  this.  others.  spinal  I t i s interesting that synaptic  endings  on  that  these-  them.  139 Findings  of differential  different confirm level  cell  sensitivity  populations  the idea  that  presented  specificities  have been p r e s e n t e d Briggs  and Dray  neurones which 5-HT,  Excitations  a n d V.  in  the excitations  I t appears  with  NMA  those  i n brain  by  stem  amino a c i d  a t depths  e x c i t a t i o n by differences  cortex.  iontophoretic to neighbouring  induced  corresponding  that  by, t h e s e  indicate  there  less potency, while  to  layers  are differences  i f two, r a t h e r  e x c i t a t i o n mechanisms a r e neurones  The  depths,  two amino a c i d s .  that  RF  applied  has i n d i c a t e d  induced  data  Bradley,  l e v e l s o f DLH e x c i t a t i o n .  i n t h e same w a y  t h e e f f e c t s o f NMA  The than  postulated,  as LG, resemble  though closely  o f DLH. Though t h e s e n s i t i v i t y  cell  that  time by s t i m u l i  therefore  a n d DG  affects thalamic  with  Boakes,  s e e n w e r e n o t t h e same a t a l l c o r t i c a l  w e r e more p r o n o u n c e d  multiple  Supporting  i n the cerebral  neurones  than were comparable  studies  b] .  (LSD) b l o c k s  [1970]  f o r a longer  II  DG  McLennan  tend t o  acids  by i o n t o p h o r e t i c a l l y  diethylamide  of cortical  differences  1968  reports.  same a m i n o a c i d s  were d e p r e s s e d  cortex  i n recent  are excited  b u t n o t b y DLH.  but  study  exist at the neuronal  [1969] h a v e r e p o r t e d  lysergic acid  between these  LG  i n this  f o r d i f f e r e n t groups o f excitatory,amino  [McLennan,.Huffman and M a r s h a l l ,  LG  t o amino a c i d s i n  groups  studied  difference  d i d n o t seem as g r e a t  between t h e two f o r DG  as f o r LG  140 (Figure  29],  includes  the  a number o f  110  nA  for  purposes  for  DG  the  differences  or  to  level..  may  of  or  An  glutamate  c a l c u l a t i o n , the smaller  are  nuclear  specific  than  the  a non-specific  the  similarity  the  two  of  the  enzyme and proposal  drug  of  acid  has  above  indications that  shown t h a t  amino a c i d s  A as  find  Huffman,  be  and  was  the  1971].  VL  more  do  to  of  on  specificity  objection  to  transmitter  in the  [Krnjevic:,:  action.  e x i s t between  be  but  DG  found  remove t h i s  can  receptor  exist,  lack  The the  objection.  agent  have  attributed  N-methyl glutamate  an  dorsal  a glutamate  a glutamate blocking  not-to  this  system i n  n o n - s p e c i f i c i t y of  properties  at  of  generally  conceptual  help  mechanisms  presence  the  indicate a  i s not  used  Whether  i t s stereoisomer  a synaptic  should  some b l o c k i n g  and  nA  decided  that  specificities  a=methyl glutamate, but Marshall  LG  that  i t s proposed  to  the  particularly  amino a c i d r e c e p t o r  receptors.  Attempts  at  different.cell  could  postulate  seem t o  receptor  of  membrane u p t a k e  e f f e c t s of  glutamic  been  110  be.  same d e g r e e : - . i n  diacidic  1970]  excitatory  to  group would  glutamate  should  c a n n o t be  latter  enzyme o r  present to  and  of  differences,  they  regions  I t i s tempting  cell  excited  DG  a t t r i b u t e d to d i f f e r e n t receptor  example of  i s not  nuclei.  the  which were not  presently.unknown properties  stage.  of  cells  category-particularly for  Because, however,.a c e i l i n g  appear  populations  which  non-evoked  to  [McLennan,  141 The a  two forms o f a n t a g o n i s m  possibly similar  in  this  study  atropine. as  found w i t h  variability  during  o f a c t i o n has been  a p p l i c a t i o n was  has been b l o c k e d ,  returned  w i t h i n a few minutes."  atropine  a p p l i c a t i o n often blocked  long The  periods  o f time  blocking  excitation necessary the  b y DLH  Interactions of  Bloom, effects  ACh,  cell  of interest,  probelms  [Phillis  firing  and c o u l d  independent.  Bloom e t a l .  during  that  caudate nucleus  again  compared  with  i s obviously  of the b r a i n t o determine applicability.  are i n progress. agents  and e f f e c t s  particularly  and T e b e c i s ,  observation.  i . e . , an e x c i t a t i o n  partially  the  More work  and i t s g e n e r a l  and S a l m o i r a g h i ,  i s a novel  spontaneous is  parts  when  when c o m p a r e d  1965]. The  o f sodium t h i o p e n t a l i n d e l a y i n g  excitation  usually  prolonged  specific  between a n e s t h e t i c  previously  Costa  t h e ACh r e s p o n s e  was v e r y  i o n t o p h o r e t i c a l l y applied drugs,  been noted  as. s o o n  t h e ACh s e n s i t i v i t y f o r  or aspartic acid.  on these  stopped  However, a  but less specific  of the antagonism  studies  observed  cessation of atropine delivery.  i n VL and i n o t h e r  nature  Further  after  o f LG e x c i t a t i o n  t o ACh e x c i t a t i o n ,  are puzzling but  the iontophoretic application of  I f the atropine  ACh s e n s i t i v i t y  aMG  ACh, have  1967; selective  t h e o n s e t o f ACh  The d e p r e s s i o n  the latent period reflect  a dual  and a d e p r e s s i o n  which  (Figure  cells  are at least of  a r e found i n  of chloralose anesthetized  42)  action of  In spite of the observation  fewer ACh-sensitive  of  than of  142 decerebrate seen  c a t s , the  in this  examination  study of  validity  excited  VL  originally  an  lateral  part  anatomical  successful to  other  of  this  because of  of  the  observation  that the  times and  because  latency  than  represent perhaps nuclei  finer  notable  the  a post  similar  absence of  electrophysiologically  the  The  the  the  attempt  responses  the  than  f o r the basis  trough spike  of  of  fibres  the  of  previous  from the long  CM  latency  that described  [ A n d e r s e n and  Andersson,  in cells  1968],  of  of  the  somecortex,  longer  that  the  to  of  was  from the  i t i s thought  of  field  firing  cells  are  cortex  p o s i t i v e wave of  evoked  [1968]  e x c i t a t o r y h y p e r p o l a r i z a t i o n of to  anatomical  probably  p o s i t i v e wave was  responses,  electro-  cortex-CM pathway  a" d e p r e s s i o n  the  the  Rinvik's  relatively of  useful  characteristics  of  are  on  appears  be  further  results  cortex. of  outlined  r e s p o n s e may  to define  spike  as  ACh  pathway were  [1966],  that  diameter  neural  of  undertaken  following activation the  specific  cortico-CM  fibres  i s unknown, b u t  found  one  preparations.  Mehler  from  n u c l e i accounts  response  Though o n l y  chloralose anesthetized  findings with  The  effect  The. p o s i t i v e c o r r e l a t i o n  pathway  response.  the  i n attempts  by. a d i r e c t  relay  the  C M - P f c o m p l e x w h i c h was  i n d i c a t e that, the  considerably  of  made i t i s t h o u g h t t o b e  a t t e m p t to; d e f i n e  nucleus.  physiological  the  i t i s hoped  workers  studies  i n the  b a s i s by  and  specificity  surprising.  studies of i n an  and  e f f e c t was  neurones  The  the  was  this  general  potency  CM  i t  may  cells,  relay  143 The ported  abundance  i n the last  unanswered. understanding analysis ship  o f VL w h i c h have  two y e a r s  have  s t i l l  I t i s suggested  that  a prerequisite  of the roles  of the types  o f each type  an a n a l y s i s  of studies  of this  of cells  to afferent  has n o t y e t been  within  and e f f e r e n t reported,  activate  t h e same g r o u p s o f V L n e u r o n e s  do  exist.  differences,  questions to the be a  careful  VL and t h e r e l a t i o n -  observation  systematic  that  many  nucleus w i l l  Machek s 1  left  been r e -  pathways.  Such  b u t F r i g y e s i and  E N a n d SN s t i m u l a t i o n  d i dnot  indicates  at.least of afferent  that  some  connections-  144 SUMMARY AND Spontaneous ing  a n d BC a n d c o r t i c a l - e v o k e d  activity  activity  CONCLUSIONS  was f o u n d  i n VL.  nor depression  rhythmic  Neither  the bursting  o f drug-induced  s t i m u l a t i o n was a f f e c t e d  burst-  firing  by i o n t o p h o r e t i c  or  b y BC intravenous  strychnine. In  addition to the short-latency  activity burst  evoked  i n V L b y BC a n d c o r t i c a l  responses  o f neurones  mulation  were  cortical  s t i m u l a t i o n were  but  those  found.  The b u r s t  responses  found  found  atropine,  BC-evoked  responses  The r e s u l t s i n d i c a t e t h a t  such  responses  is  cholinergic at least i n part  of  iontophoretically applied  to  the high  synaptic  by  blocking  efficiency  t h e two o c c a s i o n s  tested.  pathways do n o t appear  one  t h e BC-VL p a t h w a y  a g e n t s may b e d u e  of this  o r I.V. a t r o p i n e  I . V . DHBE d i d n o t a l t e r  on only  and t h e i n e f f e c t i v e n e s s  and EN-evoked responses  iontophoretic  tion.  i n decerebrate  b u t n o t by i o n t o p h o r e t i c a l l y a p p l i e d  occasion.  on  animals,  i n VL were b l o c k e d  DHBE b l o c k e d  DHgE.  sti-  t o BC a n d  i n anesthetized  atropine.  by  a n d EN  also.  Short-latency  Cortical  stimulation,  t o BC, c o r t i c a l  t o EN s t i m u l a t i o n w e r e  preparations  I.V.  and l a t e - b u r s t i n g  system.  i n VL were n o t b l o c k e d n o r by  EN-evoked  iontophoretic cell  The c o r t i c o - V L  responses a n d EN-VL  t o depend on c h o l i n e r g i c media-  145 The  burst  r e s p o n s e s o f VL n e u r o n e s  have a wide  latency  range, which  t o s t i m u l a t i o n o f EN  could  activation  of these c e l l s  by d i r e c t  pathways.  The c o n v e r s i o n  of a burst  2-3 m s e c  latency  the  presence  the  direct  spike  indirect  response  to a single reflect  from a c t i v a t i o n  of  pathway. a p p l i e d ACh sometimes  responses  o f VL n e u r o n e s  n o t t o BC o r c o r t i c a l postsynaptic  o f weaker  t o more s p e c i f i c  depressed  t o EN s t i m u l a t i o n b u t  stimulation.  depression which  responses only due  as w e l l as  b y e x c i t a t o r y a g e n t s may  o f 2-3 E P S P s r e s u l t i n g  Iontophoretically synaptic  be due i n p a r t t o  This  may  a  affects the synaptic  a f f e r e n t systems  actions  reflect  or could  o f ACh o n EN-VL  be  trans-  mission. L G a n d DLH w e r e their NMA  ability  was  similar could at  i n pattern  t o LG.  These  two groups found  of thalamic  not block  i n two groups  neurones.  DG a n d A C h  with  neurones  were which  e x c i t a t o r y mechanisms f o r acids.  considerable  specificity  the  i n d u c e d b y LG; b u t i t d i d  the short-latency excitation  BC s t i m u l a t i o n .  of  findings indicate differences  o f amino  to block  patterns i n  t o DLH w h i l e  be r e l a t e d t o d i f f e r e n t  aMG w a s  by  t o induce f i r i n g  similar  least  firing  found t o have d i f f e r e n t  o f VL  neurones  146 9.  Thiopental,  pentobarbital  systemically induce fects 10.  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