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Temporal patterning of electroshock and retrograde amnesia Jamieson, John Leslie 1972

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TEMPORAL PATTERNING OF ELECTROSHOCK AND RETROGRADE AMNESIA by JOHN LESLIE JAMIESON B.A. Un i v e r s i t y of B r i t i s h Columbia, 1965 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n the Department of Psychology We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA y August, 1972 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of B r i t i s h Columbia Vancouver 8, Canada i i ABSTRACT Treatments such as e l e c t r o c o n v u l s i v e shock (ECS) i m p a i r l a t e r performance of l e a r n e d responses i f p r e s e n t e d s h o r t l y a f t e r l e a r n i n g , but not i f d e l a y e d f o r a s u f f i c i e n t time. These g r a d i e n t s are f r e -q u e n t l y termed r e t r o g r a d e amnesia and i n t e r p r e t e d as r e f l e c t i n g a memory c o n s o l i d a t i o n p r o c e s s . The p r e s e n t i n v e s t i g a t i o n was concerned w i t h the r e l a t i o n s h i p of the l e n g t h of the g r a d i e n t produced by a s i n g l e ECS to the d u r a t i o n of the memory c o n s o l i d a t i o n p r o c e s s . I n the f i r s t experiment, r a t s were t r a i n e d on a o n e - t r i a l p a s s i v e avoidance task and then presented w i t h one of t h r e e ECS t r e a t m e n t s . The treatments were f i v e ECSs of 0.5 seconds d u r a t i o n spaced e i t h e r 1 minute a p a r t , 5 seconds a p a r t , or i n one continuous 2.5 second d u r -a t i o n b u r s t . The f i v e ECSs spaced 1 minute a p a r t were found to im-p a i r performance when presented i m m e d i a t e l y , 1 hour, 24 ho u r s , and 48 hours but not 9 days a f t e r p a s s i v e avoidance t r a i n i n g . F i v e ECSs spaced 5 seconds a p a r t i m p a i r e d performance when presented immediately or 1 hour but not 24 hours a f t e r t r a i n i n g . I n c o n t r a s t , the s i n g l e 2.5 second d u r a t i o n ECS impai r e d performance when presented immedi-a t e l y but not 1 hour or lo n g e r a f t e r t r a i n i n g . The impairments pro-duced by the f i v e ECSs spaced 1 minute a p a r t a t 1 hour and 24 hours were found to be permanent over 11 days. The second experiment examined whether the long g r a d i e n t pro-duced by f i v e ECSs spaced 1 minute a p a r t was q u a l i t a t i v e l y d i f f e r e n t from s i n g l e ECS g r a d i e n t s . F i v e ECSs spaced 1 minute a p a r t were p r e -sented f o l l o w i n g p a s s i v e avoidance t r a i n i n g to r a t s a n e s t h e t i z e d w i t h e t h e r or sodium p e n t o b a r b i t a l . I n both c a s e s , the s e r i e s of ECSs s t i l l i m p a i r e d performance when pre s e n t e d 1 or 24 hours but not 9 days f o l -l o w i n g p a s s i v e avoidance t r a i n i n g . T h i s f i n d i n g does not p r o v i d e sup-p o r t f o r a d i s t i n c t i o n between the g r a d i e n t s produced by a s i n g l e ECS and a s e r i e s of ECSs. These r e s u l t s were t h e r e f o r e i n t e r p r e t e d as showing t h a t the l e n g t h of the g r a d i e n t produced by a s i n g l e ECS i n a p a s s i v e avoidance task i s not a good e s t i m a t e of the d u r a t i o n of time r e q u i r e d f o r memory c o n s o l i d a t i o n . I n t h i s p a s s i v e avoidance t a s k , c o n s o l i d a t i o n appears to c o n t i n u e f o r a p e r i o d of a t l e a s t s e v e r a l days, w h i l e the g r a d i e n t produced by a s i n g l e ECS was l e s s than 1 hour. I n the t h i r d experiment, r a t s were t r a i n e d on a o n e - t r i a l a p p e t i -t i v e taste and then presented w i t h e i t h e r f i v e ECSs spaced 1 minute a p a r t , or a s i n g l e ECS of 0.5 seconds or 2.5 seconds d u r a t i o n . I n con-t r a s t to the r e s u l t s i n the p a s s i v e avoidance t a s k , the f i v e ECSs spaced 1 minute a p a r t d i d not produce a l o n g e r g r a d i e n t than a s i n g l e ECS of e i t h e r 0.5 or 2.5 seconds d u r a t i o n . A l l t h r e e treatments im-p a i r e d performance when presented 15 seconds but not 1 hour a f t e r t r a i n i n g . S e v e r a l p o s s i b l e e x p l a n a t i o n s f o r the d i f f e r e n t e f f e c t s of the s e r i e s of ECSs i n the two t a s k s are c o n s i d e r e d , and i t i s concluded t h a t t h i s d i f f e r e n c e probably r e f l e c t s d i f f e r e n c e s between the memory c o n s o l i d a t i o n processes i n the two t a s k s . S u p e r v i s o r _ i v TABLE OF CONTENTS Page ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v i LIST OF FIGURES v i i ACKNOWLEDGEMENTS v i i i INTRODUCTION 1 Memory C o n s o l i d a t i o n Theory 1 R a t i o n a l e f o r U s i n g O n e - T r i a l L e a r n i n g Procedures to I n v e s t i g a t e Retrograde Amnesia 3 A l t e r n a t i v e s to the C o n s o l i d a t i o n I n t e r p r e t a t i o n of ECS G r a d i e n t s 9 ECS G r a d i e n t s and the D u r a t i o n of Memory C o n s o l i d a t i o n 15 Length of ECS G r a d i e n t s 18 Two P o s s i b l e R e l a t i o n s h i p s Between the Length of ECS G r a d i e n t s and the D u r a t i o n of Memory C o n s o l i d a t i o n 21 M u l t i p l e ECSs 23 Summary and R a t i o n a l e of the P r e s e n t I n v e s t i g a t i o n 26 EXPERIMENT 1: THE EFFECT OF A SERIES OF ECSS ON RETENTION OF A PASSIVE AVOIDANCE RESPONSE 30 Method. 30 S u b j e c t s 30 Surgery 30 Apparatus 31 T r a i n i n g Procedure 32 Ex p e r i m e n t a l C o n d i t i o n s 33 Behavioral Observations 41 Histology • 41 Discussion 42 EXPERIMENT 2: THE EFFECT OF PRESENTING A SERIES OF ECSS TO ANESTHETIZED ANIMALS 43 Method 44 Results 46 Behavioral Observations 46 Discussion 47 EXPERIMENT 3: EFFECT OF A SERIES OF ECSS ON AN APPETITIVE RESPONSE ACQUIRED IN A SINGLE TRIAL 51 Method 51 Results 53 Discussion 56 GENERAL DISCUSSION 58 ECS Gradients and the Duration of Memory Consolidation 58 Passive Avoidance - A p p e t i t i v e Task Differences ...61 The E f f e c t of ECS on the Consolidation Process 66 CONCLUSIONS 74 REFERENCES 75 APPENDICES 84 v i LIST OF TABLES Table Page 1 The Number of Subjects i n Each Treatment Condition i n Experiment 1 35 2 Drinking Latencies for the Groups i n Experiment 1 Which Did Not Receive ECS 38 3 Number of Licks at the Empty Water Spout on the Test Day for the Groups i n Experiment 3 54 v i i LIST OF FIGURES F i g u r e Page 1 Median D r i n k i n g L a t e n c i e s f o r the Groups R e c e i v i n g P a s s i v e Avoidance T r a i n i n g F o l l o w e d By One of the Three ECS Treatments 40 2 Median D r i n k i n g L a t e n c i e s f o r the Groups R e c e i v i n g 5 ECSs Spaced 1 Minute A p a r t Under E t h e r or Sodium P e n t o b a r b i t a l A n e s t h e s i a F o l l o w i n g P a s s i v e Avoidance 48 T r a i n i n g ACKNOWLEDGEMENTS I wish to thank Dr. David A l b e r t for his advice and assistance throughout the course of t h i s i n v e s t i g a t i o n . I would also l i k e to acknowledge the usefu l c r i t i c i s m s of Fred Madryga, Chun Mah, Len S t o r l e i n and Svavar Tryggvason i n the early stages of t h i s i n v e s t i -gation and the assistance of Dr. John P i n e l i n the preparation of the t h e s i s . This research was supported by grants to Dr. A l b e r t from the National Research Council of Canada (APA-192). Memory C o n s o l i d a t i o n Theory The p o s s i b i l i t y t h a t memories r e q u i r e a p e r i o d of time f o l l o w i n g l e a r n i n g i n order to be p r o p e r l y s t o r e d was f i r s t suggested by M u l l e r and P i l z e c k e r (1900). They observed t h a t humans l e a r n i n g a second l i s t of words s h o r t l y a f t e r a f i r s t l i s t showed i m p a i r e d r e t e n t i o n of the f i r s t l i s t . As an e x p l a n a t i o n f o r the r e t r o a c t i v e i n t e r f e r e n c e of the second l i s t , they suggested t h a t memories r e q u i r e d a p e r i o d of time f o l l o w i n g l e a r n i n g i n order to be s t o r e d i n t h e i r f i n a l , permanent form, and t h a t any d i s t u r b a n c e d u r i n g t h i s t ime might p r e v e n t the memories from becoming p r o p e r l y s t o r e d . They i n t r o d u c e d the term "memory c o n s o l i d a t i o n " to r e f e r to the i n c r e a s i n g r e s i s t a n c e of the memories t o d i s r u p t i o n over time. McDougall (1901) was the f i r s t to suggest t h a t the n o t i o n of -memory c o n s o l i d a t i o n might account f o r the phenomenon of r e t r o g r a d e amnesia f o l l o w i n g head i n j u r y i n humans. I n many cases of head i n j u r y , p a t i e n t s r e p o r t an i n a b i l i t y t o r e c a l l events which o c c u r r e d d u r i n g a p e r i o d of time immediately p r e c e d i n g the i n j u r y (see R u s s e l l & Nathan, 1946 f o r an e x t e n s i v e e x a m i n a t i o n of t h i s problem). These memory l o s s e s o f t e n depend on the c l o s e n e s s of the event to the i n j u r y ; mem-o r i e s of events which o c c u r r e d c l o s e r to the i n j u r y are more l i k e l y to be l o s t than the memories of more d i s t a n t events. McDougall ex-p l a i n e d the time-dependent c h a r a c t e r of these memory l o s s e s i n terms 1 of a memory c o n s o l i d a t i o n p r o c e s s . Presumably, memories which were l o s t were those which had been l e s s c o m p l e t e l y c o n s o l i d a t e d . P a t i e n t s r e c e i v i n g e l e c t r o c o n v u l s i v e shock (ECS) therapy have a l s o been observed to show a r e t r o g r a d e amnesia f o r antecedent events (Cronholm & O t t o s o n , 1963; W i l l i a m s , 1950; Z u b i n & B a r r e r a , 1941). I n these s t u d i e s , p a t i e n t s undergoing ECS therapy were presented w i t h a s e t of s t i m u l i a t v a r i o u s i n t e r v a l s b e f o r e ECS. I n g e n e r a l , the r e s u l t s showed t h a t r e t e n t i o n of the s t i m u l i p r e s e n t e d c l o s e s t to the ECS was most l i k e l y to be d i s r u p t e d . Retrograde amnesia has a l s o been i n v e s t i g a t e d i n more c o n t r o l l e d s e t t i n g s u s i n g e x p e r i m e n t a l a n i m a l s , u s u a l l y r a t s or mice (see L e w i s , 1969; McGaugh & Dawson, 1971; and Spevack & S u b o s k i , 1969 f o r r e c e n t r e v i e w s of t h i s work). I n these s t u d i e s , treatments such as ECS have g e n e r a l l y been found to i m p a i r l a t e r performance of a l e a r n e d response 'when presented soon a f t e r t r a i n i n g , but not when delayed f o r a s u f f i -c i e n t time. These impairments a r e u s u a l l y found t o be graded, w i t h the s h o r t e r t r a i n i n g - E C S d e l a y s producing l a r g e r impairments. Because of t h e i r s i m i l a r i t y to the memory l o s s e s found w i t h humans, these g r a d i e n t s are a l s o u s u a l l y i n t e r p r e t e d as r e f l e c t i n g r e t r o g r a d e amnesias. E x p e r i m e n t a l i n v e s t i g a t i o n s of r e t r o g r a d e amnesia have l a r g e l y been concerned w i t h two i s s u e s . F i r s t , do these g r a d i e n t s a c t u a l l y r e -f l e c t d i s t u r b a n c e s of a memory c o n s o l i d a t i o n process? Second, assuming they do r e p r e s e n t d i s t u r b a n c e s of memory c o n s o l i d a t i o n what d u r a t i o n of time i s r e q u i r e d f o r the c o n s o l i d a t i o n process to r e a c h completion? N e i t h e r of these i s s u e s i s c o m p l e t e l y r e s o l v e d . The f i r s t i s s u e has r e c e i v e d the most a t t e n t i o n , and a l t h o u g h a number of a d d i t i o n a l ex-p l a n a t i o n s have been o f f e r e d f o r these g r a d i e n t s , t h e r e i s s t i l l a s u b s t a n t i a l concensus i n f a v o r of the c o n s o l i d a t i o n i n t e r p r e t a t i o n . With r e s p e c t to the second i s s u e , i t has been a common p r a c t i c e to vie w the l e n g t h of the g r a d i e n t produced by ECS as an e s t i m a t e of the du r -a t i o n of time r e q u i r e d f o r memory c o n s o l i d a t i o n to be completed, a l -though r e c e n t f i n d i n g s suggest t h a t t h i s v i e w may not be c o r r e c t . The p r e s e n t t h e s i s i s concerned w i t h the r e l a t i o n s h i p of the l e n g t h of the amnesia g r a d i e n t produced by ECS to the d u r a t i o n of the memory c o n s o l i d a t i o n p r o c e s s . B e f o r e d i r e c t l y c o n s i d e r i n g t h i s ques-t i o n , the t r a i n i n g procedures most w i d e l y used to i n v e s t i g a t e r e t r o -grade amnesia w i l l be d e s c r i b e d , and an attempt w i l l be made to show t h a t the ECS g r a d i e n t s o b t a i n e d w i t h these procedures a r e best ex-p l a i n e d as d i s t u r b a n c e s of memory c o n s o l i d a t i o n . R a t i o n a l e For Using O n e - T r i a l L e a r n i n g Procedures to I n v e s t i g a t e R e t r o g r a d e Amnesia Duncan (1949) p r o v i d e d the f i r s t d e m o n s t r a t i o n of impai r e d performance of a l e a r n e d response which depended on the time between t r a i n i n g and ECS. He t r a i n e d r a t s i n a one-way avoidance apparatus, g i v i n g 1 t r i a l per day. F o l l o w i n g each d a i l y t r i a l , s e p a r a t e groups were g i v e n ECS e i t h e r 20 s e c , 40 s e c , 60 s e c , 4 min., 15 min., 1 h r . , 4 h r s . , or 14 h r s . l a t e r . Impaired a c q u i s i t i o n was found i n the groups g i v e n ECS a t 15 minutes or l e s s a f t e r each t r i a l . The i m p a i r -ment was graded, w i t h the s h o r t e s t t r a i n i n g - E C S d e l a y s showing the 4 slo w e s t a c q u i s i t i o n . Duncan a t t r i b u t e d t h i s ECS g r a d i e n t to a d i s -turbance of memory c o n s o l i d a t i o n . Coons and M i l l e r (1960) r e p l i c a t e d Duncan's experiment, and made the a d d i t i o n a l o b s e r v a t i o n t h a t the animals i n the s h o r t e s t t r a i n i n g - E C S c o n d i t i o n s tended t o e x h i b i t a g r e a t d e a l of e m o t i o n a l behaviour ( d e f e c a t i o n ) . On the b a s i s of t h i s o b s e r v a t i o n , they suggested t h a t ECS might have a v e r s i v e e f f e c t s which c o u l d i n t e r f e r e w i t h the a c q u i s i t i o n of the avoidance r e s p o n s e . S i n c e ECS was ad-m i n i s t e r e d f o l l o w i n g e n t r y i n t o the non-shocked s i d e , any a v e r s i v e e f f e c t s might have become c o n d i t i o n e d to t h i s s i d e , thus d e c r e a s i n g the tendency to a v o i d . I n order to t e s t the p o s s i b i l i t y t h a t ECS has a v e r s i v e e f f e c t s , they conducted a second experiment i n which r a t s were f i r s t t r a i n e d to r u n from a s t a r t box to a g o a l box to av o i d shock. A f t e r a c q u i s i t i o n of t h i s r e s p o n s e , the c o n d i t i o n s were r e v e r s e d so t h a t the animals were now shocked i n the g o a l box which p r e v i o u s l y had been " s a f e " . ECS was a d m i n i s t e r e d to s e p a r a t e groups e i t h e r 20 s e c , 60 s e c , or 1 h r . a f t e r the shock i n the g o a l box. Coons and M i l l e r found t h a t the 20-second group l e a r n e d to a v o i d the g o a l box f a s t e r than the 60-second group, and t h a t b o t h of these l e a r n e d f a s t e r than the 1-hour group. T h i s g r a d i e n t i s e x a c t l y the o p p o s i t e of t h a t which would be expected i f ECS were d i s t u r b i n g mem-ory c o n s o l i d a t i o n . They suggested t h a t ECS has a v e r s i v e e f f e c t s which may summate w i t h the a v e r s i v e e f f e c t s of the f o o t s h o c k . They argued t h a t the ECS g r a d i e n t found by Duncan pr o b a b l y r e f l e c t s a g r a d i e n t of the a v e r s i v e e f f e c t s of ECS, and not a g r a d i e n t of amnesia. I n another a t t a c k on the c o n s o l i d a t i o n i n t e r p r e t a t i o n of Duncan' f i n d i n g s , Adams and Lewis (1962) showed t h a t animals became immobile when p l a c e d i n an apparatus i n which they had r e c e i v e d a s e r i e s of ECSs. They suggested t h a t repeated ECS treatments caused " f r a c t i o n a l c o n v u l s i o n s " t o be c o n d i t i o n e d to the p l a c e where ECS was a d m i n i s t e r e d I f f r a c t i o n a l c o n v u l s i o n s were c o n d i t i o n e d to the t r a i n i n g s i t u a t i o n , they might be expected to i n h i b i t l a t e r r e s p o n d i n g , and, i n Duncan's experiment, such i n h i b i t i o n would appear as i m p a i r e d a c q u i s i t i o n . C o n v u l s i o n s would be more l i k e l y to become c o n d i t i o n e d to the appar-atus i n the groups g i v e n ECS sooner a f t e r t r a i n i n g , thereby a c c o u n t i n g f o r the graded appearance of the ECS d e f i c i t s . However, Spevack and Suboski (1969) have p o i n t e d out t h a t Adams and L e w i s ' r e s u l t s can be e x p l a i n e d s i m p l y by the a v e r s i v e e f f e c t s of a s e r i e s of ECSs. Rats o f t e n become immobile when c o n f r o n t e d w i t h s t i m u l i p r e v i o u s l y a s s o c -i a t e d w i t h a v e r s i v e s t i m u l a t i o n ( E s t e s & S k i n n e r , 1941). Moreover, t h e r e i s no d i r e c t evidence s u p p o r t i n g the c l a i m t h a t an ECS-produced c o n v u l s i o n can f u n c t i o n as an u n c o n d i t i o n e d s t i m u l u s (Kent, Hawkins, & Sharpe, 1960). To a v o i d the c r i t i c i s m s r a i s e d by Coons and M i l l e r (1960) and Adams and Lewis (1962) , experimenters began u s i n g o n e - t r i a l p a s s i v e avoidance t r a i n i n g procedures (Hudson, 1950) to i n v e s t i g a t e memory c o n s o l i d a t i o n . I n these t a s k s , animals a r e punished, u s u a l l y by f o o t s h o c k , f o r making a response such as s t e p p i n g down from a p l a t -form, or p r e s s i n g a bar. There a re two advantages of o n e - t r i a l pass-i v e avoidance t a s k s . F i r s t , s i n c e the an i m a l l e a r n s to i n h i b i t a punished response, any a v e r s i v e e f f e c t s of ECS summate w i t h the a v e r s i v e e f f e c t s of the shock to i n c r e a s e the l a t e n c y to perform the response. However, i f ECS produces a l o s s of memory f o r the f o o t s h o c k , the a n i m a l w i l l c o n t i n u e to perform the response w i t h a s h o r t l a t e n c y on l a t e r t e s t i n g . S e condly, the p a s s i v e avoidance t a s k , s i n c e i t o n l y i n v o l v e s a s i n g l e t r a i n i n g t r i a l , has an a d d i t i o n a l advantage of o n l y r e q u i r i n g the a d m i n i s t r a t i o n of a s i n g l e ECS i n c o n t r a s t to Duncan's procedure i n which ECS was a d m i n i s t e r e d f o l l o w i n g each d a i l y t r i a l . T h i s i s an advantage because a s i n g l e ECS does not produce as s t r o n g a v e r s i v e e f f e c t s as m u l t i p l e ECSs (Hudspeth, McGaugh, & Thompson, 1964). A s i n g l e ECS has g e n e r a l l y been found to produce time-dependent impairments of p a s s i v e avoidance responses (Chorover & S c h i l l e r , 1965; H e r i o t & Coleman, 1962; K i n g , 1967; Kopp, Bohdenecky, & J a r v i k , 1966; McGaugh, 1966; M i l l e r , 1968; Quartermain, P a o l i n o , & M i l l e r , 1965; and o t h e r s ) . For example, H e r i o t and Coleman (1962) t r a i n e d r a t s to p r e s s a bar f o r food. A f t e r t h i s response was a c q u i r e d , a p u n i s h i n g shock was a d m i n i s t e r e d through the bar. Separate groups of r a t s r e c e i v e d ECS e i t h e r 1, 7, 26, 60 or 180 minutes a f t e r the punishment. A con-t r o l group r e c e i v e d o n l y the p u n i s h i n g shock. Twenty-four hours l a t e r , the animals were r e t u r n e d to the bar and the number of presses i n a 10-minute s e s s i o n was recorded. The punishment impaired the bar p r e s s i n g response i n the c o n t r o l group, but t h i s impairment was a t t e n -uated by ECS i n a graded f a s h i o n , the g r e a t e s t a t t e n u a t i o n appearing w i t h the s h o r t e s t ECS d e l a y s . The groups g i v e n ECS a t 1, 7, 26, or 60 minutes a f t e r the punishment showed s i g n i f i c a n t l y l e s s impairment than 7 the c o n t r o l s . Recently, several other o n e - t r i a l learning procedures have been used to i n v e s t i g a t e retrograde amnesia. One procedure, " a p p e t i t i v e " t r a i n i n g , involves an increase i n the strength of an a p p e t i t i v e l y motivated response as the r e s u l t of a s i n g l e experience with water. For example, Tenen (1965a) allowed t h i r s t y r a t s to f i n d water i n a previously empty c u l de sac. As a r e s u l t of t h i s s i n g l e exper-ience, the r a t s showed an increased tendency to r e t u r n to the empty c u l de sac on a l a t e r t e s t session. Another procedure i s "discriminated avoidance" t r a i n i n g . In t h i s paradigm two responses are a v a i l a b l e and one of them i s followed by punishment. A s i n g l e punishment i s s u f f i -c ient to e s t a b l i s h a preference f o r the other response. For example, Pf i n g s t and King (1969) trained hungry r a t s i n a T-maze which had food a v a i l a b l e i n both arms. After the r a t s were accustomed to running the maze for food, a punishing shock was administered upon entering one arm of the maze. As a r e s u l t of t h i s s i n g l e punishment, the r a t s showed an increased preference for the other arm of the maze. Although aversive and amnesic e f f e c t s are not opposed i n these two tasks, i t i t generally possible to detect the presence of aversive e f f e c t s . Pro-v i d i n g the response baseline i s s u f f i c i e n t l y high before t r a i n i n g , presenting ECS immediately a f t e r making the response i n question should produce a decreased tendency to make t h i s response on l a t e r t e s t i n g . While t h i s c o n t r o l i s not completely s a t i s f a c t o r y , a number of experiments have observed time-dependent e f f e c t s of ECS which are not apparently due to aversive e f f e c t s of ECS with both a p p e t i t i v e ( P i n e l , 1969; S c h i l l e r & Chorover, 1967; Tenen, 1965a, 1965b) and d i s -c r i m i n a t e d avoidance procedures (Carew, 1970; P f i n g s t & K i n g , 1969). O n e - t r i a l l e a r n i n g procedures have been popular not o n l y because they permit an assessment of r e t r o g r a d e amnesia w i t h o u t the confounding f a c t o r of a v e r s i v e e f f e c t s , but a l s o because they p e r m i t a c l e a r de-t e r m i n a t i o n of the t r a i n i n g - E C S i n t e r v a l and c o n s e q u e n t l y a more p r e -c i s e e s t i m a t e of the d u r a t i o n of memory c o n s o l i d a t i o n . T h i s i s an advantage over some other procedures i n which a s e r i e s of massed t r i a l s were used (Gerbrandt, Buresova, & Bures, 1966; Thompson & Pennington, 1957). Although o n l y a s i n g l e a d m i n i s t r a t i o n of ECS was r e q u i r e d i n these t a s k s , s p e c i f i c a t i o n of the time d u r i n g t r a i n i n g at which memory c o n s o l i d a t i o n began was not p o s s i b l e s i n c e c o n s o l i d a t i o n may have s t a r t e d a t any time d u r i n g the t r a i n i n g p e r i o d . I t i s now w e l l e s t a b l i s h e d t h a t time-dependent impairments of -performance can be produced by ECS i n a v a r i e t y of t r a i n i n g s i t u a t i o n s . Many other treatments have a l s o been found to produce time-dependent d e f i c i t s . These i n c l u d e ether and p e n t o b a r b i t a l a n e s t h e s i a (Pearlman, S h a r p l e s s , & J a r v i k , 1961), CO2 ( P a o l i n o , Quartermain, & M i l l e r , 1966), c o o l i n g ( R i c c i o , Hodges, & R a n d a l l , 1968), and c o r t i c a l s p r e a d i n g d e p r e s s i o n (Bures & Buresova, 1963). These impairments are f r e q u e n t l y i n t e r p r e t e d as r e t r o g r a d e amnesia, t h e i r t e m p o r a l l y graded n a t u r e being a t t r i b u t e d to an u n d e r l y i n g memory c o n s o l i d a t i o n p r o c e s s . R e c e n t l y , a number of a l t e r n a t i v e e x p l a n a t i o n s have a l s o been o f f e r e d f o r these g r a d i e n t s . Most of these a l t e r n a t i v e e x p l a n a t i o n s are s p e c i f i c a l l y d i r e c t e d at g r a d i e n t s o b t a i n e d w i t h a s i n g l e ECS i n 9 a p a s s i v e avoidance t r a i n i n g s i t u a t i o n which i s the most popular para-digm f o r i n v e s t i g a t i n g memory c o n s o l i d a t i o n . These e x p l a n a t i o n s , however, a l s o apply i n v a r y i n g degrees to the g r a d i e n t s obtained w i t h other treatments i n other s i t u a t i o n s . A l t e r n a t i v e s to The C o n s o l i d a t i o n I n t e r p r e t a t i o n of ECS Gradients P i n e l and Cooper (1966) , w h i l e examining the s t r e n g t h of a pa s s i v e avoidance response by t e s t i n g d i f f e r e n t groups of r a t s at v a r i o u s times a f t e r t r a i n i n g , found that p a s s i v e avoidance improved over time. This improvement i n p a s s i v e avoidance over time has been r e f e r r e d to as the " i n c u b a t i o n " e f f e c t and has been found i n many (Irwin, B a n u a z i z i , K a l s n e r , & C u r t i s , 1968; McGaugh, 1966) but not a l l ( B a i l e y , Garman, & Cherkin, 1969; P i n e l , 1970) p a s s i v e avoidance t a s k s . P i n e l and Cooper (1966) noted t h a t the time course of improvement i n p a s s i v e avoidance corresponded to the le n g t h of t h e i r ECS g r a d i e n t . They suggested t h a t r a t h e r than d i s r u p t i n g a c o n s o l i d a t i o n p r o c e s s , ECS could be viewed as simply h a l t i n g the i n c u b a t i o n of the response. Spevack and Suboski (1969) have f u r t h e r e l a b o r a t e d t h i s i n c u -b a t i o n h y p o t h e s i s . They proposed that b r i e f ECS g r a d i e n t s ( l e s s than 1 minute) r e f l e c t r e t r o g r a d e amnesia, while longer periods are due to the h a l t i n g of i n c u b a t i o n . They claimed that only b r i e f g r a d i e n t s have been obtained i n the other o n e - t r i a l l e a r n i n g procedures, namely a p p e t i t i v e (Herz, 1969; P i n e l , 1969; S c h i l l e r & Chorover, 1967) and d i s c r i m i n a t e d avoidance (Carew, 1970; P f i n g s t & King, 1969), and they p o i n t out that i n c u b a t i o n does not appear i n these s i t u a t i o n s ( P i n e l , 1969; S u b o s k l , Spevack, L i t n e r , & Beaumaster, 1969). However, Spevack and Suboski's h y p o t h e s i s i s not c o n s i s t e n t w i t h a l l the a v a i l a b l e d a t a . Tenen (1965b) has r e p o r t e d an ECS g r a d i e n t of 3 hours i n an a p p e t i t i v e t a s k . I n a d d i t i o n , s e v e r a l p a s s i v e avoidance t a s k s i n which long g r a d i e n t s were found do not show i n c u b a t i o n ( B a i l e y e t a l . , 1969; P i n e l , 1970). Weiskrantz (1966) has proposed an a l t e r n a t i v e model f o r the e f f e c t s of treatments such as ECS. He suggests t h a t w h i l e v e r y s h o r t ECS g r a d -i e n t s (20 seconds) might r e f l e c t d i s t u r b a n c e s of c o n s o l i d a t i o n , l o n g e r ECS g r a d i e n t s r e f l e c t impairments of memory r e t r i e v a l . He assumes t h a t memories c o n t i n u e to i n c r e a s e i n s t r e n g t h over a p e r i o d of weeks ( i n the sense of the n e u r a l s i g n a l u n d e r l y i n g memory becoming s t r o n g e r to produce a l a r g e r " s i g n a l to n o i s e " r a t i o ) . He a l s o assumes t h a t treatments such as ECS i n t r o d u c e a d d i t i o n a l n o i s e which p r e v e n t s the »recall of weaker t r a c e s by d e c r e a s i n g the s i g n a l to n o i s e r a t i o . As -the t r a c e c o n t i n u e s to i n c r e a s e i n s t r e n g t h , i t e v e n t u a l l y stands out s u f f i c i e n t l y from the n o i s e l e v e l to be r e c a l l e d . T h i s model p r e d i c t s t h a t performance d e f i c i t s produced by ECS w i l l be temporary, d i s a p -p e a r i n g w i t h time. I n f a c t , temporary d e f i c i t s have been found by a number of i n v e s t i g a t o r s (e.g., Z i n k i n & M i l l e r , 1967). However, t h i s model a l s o p r e d i c t s t h a t the time between t r a i n i n g and t e s t i n g should be more important than the i n t e r v a l between t r a i n i n g and ECS, a f i n d i n g t h a t i s not c o n s i s t e n t w i t h the a v a i l a b l e d a t a . N i e l s o n (1968) attempted to e x p l a i n ECS e f f e c t s on performance through s u g g e s t i n g that.ECS produces b r a i n e x c i t a b i l i t y changes. These changes were thought to i m p a i r r e c a l l through a "s t a t e - d e p e n d e n t " mechanism. He suggested t h a t performance i s i m p a i r e d f o r up t o 4 days a f t e r ECS because the b r a i n i s i n a d i f f e r e n t s t a t e than i t was d u r i n g t r a i n i n g . N i e l s o n p r o v i d e d some d i r e c t e vidence f o r temporary changes i n b r a i n e x c i t a b i l i t y as a r e s u l t of ECS. He showed t h a t the i n t e n -s i t y of s u b c o r t i c a l e l e c t r i c a l s t i m u l a t i o n n e c e s s a r y to e l i c i t a c o n d i t i o n e d response i n c r e a s e d f o l l o w i n g ECS and then decreased over 4 days. N i e l s o n ' s model, l i k e ' W e i s k r a n t z ' s , p r e d i c t s t h a t the im-pairment produced by ECS would o n l y be temporary. However, N i e l s o n makes no attempt to account f o r the time-dependent n a t u r e of these impairments. P o s l u n s and Vanderwolf (1970) have suggested t h a t ECS has two e f f e c t s : a d i s r u p t i o n of c o n s o l i d a t i o n and an impairment of response i n h i b i t i o n . These two e f f e c t s a r e viewed as combining i n t a s k s r e q u i r i n g i m m o b i l i t y (such as the p a s s i v e avoidance) to produce l o n g e r g r a d i e n t s than i n t a s k s not r e q u i r i n g i m m o b i l i t y . However, i t i s not c l e a r from t h e i r model how a time-dependent e f f e c t (amnesia) can com-bi n e w i t h a non-time-dependent e f f e c t ( d i s i n h i b i t i o n ) to produce a longer time-dependent e f f e c t . I n a d d i t i o n to the t h e o r e t i c a l models which have been presented as a l t e r n a t i v e s to the c o n s o l i d a t i o n h y p o t h e s i s , there i s a l s o some r e c e n t evidence which i s d i f f i c u l t to r e c o n c i l e w i t h the memory con-s o l i d a t i o n i n t e r p r e t a t i o n , but which has not y e t g i v e n r i s e to ade-quate a l t e r n a t i v e e x p l a n a t i o n s . S e v e r a l s t u d i e s have demonstrated impairments of performance which are not dependent on the time between t r a i n i n g and ECS, but r a t h e r on the time between some other event and ECS. Schneider and Sherman (1968) p r e s e n t e d ECS to r a t s e i t h e r 0.5 seconds, 30 seconds, or 6 hours a f t e r a s i n g l e p a s s i v e avoidance t r a i n i n g t r i a l . They found t h a t performance of the p a s s i v e avoidance response was i m p a i r e d i n the 0.5 second but not 30 second or 6 hour c o n d i t i o n s . They found, however, t h a t i f an a d d i t i o n a l , n o n c o n t i n g e n t f o o t s h o c k was d e l i v e r e d 0.5 seconds b e f o r e the 30 second or 6 hour ECS, performance was a l s o i m p a i r e d . S i m i l a r f i n d i n g s were r e p o r t e d by M i s a n i n , M i l l e r , and Lewis (1968). They e s t a b l i s h e d a c o n d i t i o n e d e m o t i o n a l response (CER) t o a l i g h t by p a i r i n g i t w i t h shock, and showed t h a t i f ECS g i v e n 24 hours a f t e r t r a i n i n g was preceded by the l i g h t , performance of the CER was i m p a i r e d . I n both t h e s e c a s e s , performance impairments were r e p o r t e d which were dependent not on the time between t r a i n i n g and ECS, but r a t h e r on the time between some ot h e r event such as f o o t s h o c k or l i g h t and ECS. These f i n d i n g s can be d e s c r i b e d as r e f l e c t i n g the " r e i n s t a t e m e n t " of the a b i l i t y of ECS to d i s r u p t performance. Schneider and Sherman (1968) contended t h a t the p a i r i n g of ECS and footshock-produced a r o u s a l caused " a f t e r e f f e c t s " which i m p a i r e d the l a t e r performance of the p a s s i v e avoidance response. M i s a n i n et a l . (1968), on the other hand, suggested t h a t p r e s e n t a t i o n of the l i g h t caused the memory to be r e c a l l e d , and thus to enter a s t a t e i n which i t was more s u s c e p t i b l e to d i s r u p t i o n . N e i t h e r of these ex-p l a n a t i o n s i s v e r y e x p l i c i t , and n e i t h e r has been d i r e c t l y supported. Moreover, these phenomena are d i f f i c u l t t o r e p l i c a t e . Banker, Hunt, and Pagano (1969), Dawson and McGaugh (1969), Jamieson and A l b e r t (19.70), and Lee-Teng (1970a) have a l l f a i l e d to o b t a i n these e f f e c t s , the f i r s t two experiments b e i n g attempts a t exact r e p l i c a t i o n . How-ever, Davis and K l i n g e r (1969) have r e p o r t e d a s i m i l a r f i n d i n g u s i n g g o l d f i s h and a one-way avoidance t r a i n i n g procedure. Re-exposure to the t r a i n i n g apparatus 24 hours a f t e r t r a i n i n g was found to a l l o w a number of agents which would n o r m a l l y be i n e f f e c t i v e a t t h i s time to i m p a i r performance. D e V i e t t i and L a r s o n (1971) have a l s o r e p o r t e d a s u c c e s s f u l r e p l i c a t i o n of t h i s e f f e c t u s i n g r a t s and a CER procedure. Another f i n d i n g has r e c e n t l y been r e p o r t e d (Howard & Meyer, 1971; Robbins & Meyer, 1970) t h a t bears s u b s t a n t i a l s i m i l a r i t y to the " r e i n s t a t e m e n t e f f e c t " . I n these experiments, r a t s were t r a i n e d on t h r e e d i s c r i m i n a t i o n s , and g i v e n ECS f o l l o w i n g c r i t e r i o n on the t h i r d t a s k . The r e s u l t s i n d i c a t e d t h a t not o n l y was performance of the t h i r d d i s c r i m i n a t i o n i m p a i r e d by the ECS, but other d i s c r i m i n a t i o n s which i n v o l v e d the same type of m o t i v a t i o n as the t h i r d d i s c r i m i n a t i o n were a l s o i m p a i r e d , even when the o t h e r d i s c r i m i n a t i o n was the f i r s t l e a r n e d . ECS seemed to d i s r u p t a c l a s s of r e s p o n s e s , impairment be-i n g dependent on the n a t u r e of the m o t i v a t i o n a l s t a t e most r e c e n t l y aroused, not on the age of the memories. The i n t e r p r e t a t i o n of the r e i n s t a t e m e n t e f f e c t i s a v e r y r e a l problem. None of the e x p l a n a t i o n s so f a r o f f e r e d can adequately ex-p l a i n a l l the d a t a i n c l u d i n g the d i f f i c u l t y w i t h r e p l i c a t i o n . These f i n d i n g s are d i f f i c u l t to r e c o n c i l e w i t h the c o n s o l i d a t i o n i n t e r p r e -t a t i o n of ECS g r a d i e n t s s i n c e these g r a d i e n t s can be o b t a i n e d at 14 times when c o n s o l i d a t i o n i s presumably not o c c u r r i n g . However, i t i s important to p o i n t out t h a t t h e s e d a t a a r e not n e c e s s a r i l y i n c o n s i s t e n t w i t h the n o t i o n t h a t ECS presented s h o r t l y a f t e r t r a i n i n g n o r m a l l y d i s r u p t s a memory c o n s o l i d a t i o n p r o c e s s . I t i s p o s s i b l e , f o r example, that c o n s o l i d a t e d memories can become s u s c e p t i b l e to d i s r u p t i o n f o r some reason q u i t e d i f f e r e n t from t h a t r e s p o n s i b l e f o r most ECS g r a d i e n t s . There i s another f i n d i n g which r a i s e s some q u e s t i o n about the i n t e r p r e t a t i o n of ECS g r a d i e n t s . Chorover and DeLuca (1969) r e c e n t l y found t h a t ECS d i d not produce s e i z u r e d i s c h a r g e i n the c o r t e x i f i t f o l l o w e d w i t h i n 0.5 seconds a f t e r a f o o t s h o c k , but i t d i d produce s e i z u r e d i s c h a r g e i f delayed f o r 30 seconds or i f ECS was not p r e -ceded by f o o t s h o c k . T h i s f i n d i n g i n d i c a t e s t h a t the s e i z u r e produced by ECS i s not of a c o n s t a n t form, but can be m o d i f i e d by p r i o r pre-s e n t a t i o n of fo o t s h o c k . S i n c e f o o t s h o c k i s g e n e r a l l y used i n p a s s i v e -avoidance t r a i n i n g , t h i s f i n d i n g r a i s e s the p o s s i b i l i t y t h a t ECS g r a d i e n t s might be due to a change i n the s e i z u r e produced by ECS, r a t h e r than a change i n the u n d e r l y i n g c o n s o l i d a t i o n p r o c e s s . P r o c e s s e s other than'memory c o n s o l i d a t i o n have not been shown to adequately account f o r most ECS g r a d i e n t s , and, alt h o u g h some aspects of ECS g r a d i e n t s are not c o m p l e t e l y understood, a d i s t u r b a n c e of memory c o n s o l i d a t i o n s t i l l appears to be the b e s t e x p l a n a t i o n . While th e r e i s no d i r e c t way of dem o n s t r a t i n g t h a t these g r a d i e n t s r e f l e c t memory c o n s o l i d a t i o n , there i s i n d i r e c t support f o r the assump-t i o n t h a t they r e f l e c t memory l o s s e s r a t h e r than some ot h e r d i s t u r b a n c e . Such support comes from t h e i r s i m i l a r i t y to human r e t r o g r a d e amnesia, as w e l l as from the f a c t t h a t they a r e ob t a i n e d i n a v a r i e t y of s i t -u a t i o n s and w i t h a number of d i f f e r e n t t r e a t m e n t s . Assuming t h a t the g r a d i e n t s r e f l e c t memory l o s s , the be s t e x p l a n a t i o n f o r t h e i r tempor-a l l y graded c h a r a c t e r seems to be t h a t they r e f l e c t an u n d e r l y i n g con-s o l i d a t i o n p r o c e s s . However, because t h e r e i s s t i l l some u n c e r t a i n t y as to whether the d e f i c i t s a t r e t e s t a r e on r e t e n t i o n or performance, the term "ECS g r a d i e n t " w i l l be used i n s t e a d of the more common "amnesia g r a d i e n t " to r e f e r to an impairment of a l e a r n e d response which i s produced by ECS and which depends, i n a graded f a s h i o n , on the time between t r a i n i n g and ECS. T h i s i s done to emphasize t h a t "amnesia" i s an i n t e r p r e t a t i o n of the g r a d i e n t and not j u s t a d e s c r i p t i o n . ECS G r a d i e n t s and the D u r a t i o n of Memory C o n s o l i d a t i o n T h i s s e c t i o n w i l l f i r s t c o n s i d e r the reasons why the l e n g t h s of ECS g r a d i e n t s have been i n t e r p r e t e d as r e f l e c t i n g the d u r a t i o n of c o n s o l i d a t i o n . Recent evidence w i l l then be presented showing t h a t the l e n g t h of the g r a d i e n t produced by ECS i s not c o n s t a n t but depends to a l i m i t e d e x t e n t on ECS c u r r e n t parameters. T h i s l i m i t might r e -f l e c t the p o i n t a t which the memory not y e t c o n s o l i d a t e d i s c o m p l e t e l y d i s t u r b e d , or i t may s i m p l y r e f l e c t the f a c t t h a t a s i n g l e ECS pro-duces o n l y a l i m i t e d p h y s i o l o g i c a l d i s t u r b a n c e . As a means of ex-p l o r i n g t h i s q u e s t i o n , the p o s s i b i l i t y t h a t a s e r i e s of ECS treatments may produce a lo n g e r g r a d i e n t than a s i n g l e ECS w i l l be examined. The d u r a t i o n of time r e q u i r e d f o r memory c o n s o l i d a t i o n has f r e q u e n t l y been estimated from the l e n g t h of the ECS g r a d i e n t . The reason f o r c h o o s i n g ECS f o r t h i s purpose seems to be based, a t l e a s t i n p a r t , on the view t h a t ECS m a x i m a l l y d i s r u p t s the memory c o n s o l i d a -t i o n p r o c e s s . Such a view i s supported by two w i d e l y h e l d assumptions. F i r s t , c o n s o l i d a t i o n has been assumed to i n v o l v e p a t t e r n e d n e u r a l f i r i n g which p e r s i s t s f o r a p e r i o d of time f o l l o w i n g l e a r n i n g and which i s necessary f o r memories to be permanently s t o r e d ( G e r a r d , 1955; Hebb, 1949; John, 1967). Second, ECS has been assumed to produce a maximal d i s t u r b a n c e of n e u r a l f i r i n g p r o v i d i n g t h a t a "complete be-h a v i o r a l c o n v u l s i o n " i s produced (Toman, Swinyard, & Goodman, 1946). The most i n f l u e n t i a l statement of the p a t t e r n e d f i r i n g h y p o t h e s i s i s t h a t of Hebb (1949). Hebb suggested t h a t memory was h e l d i n i t i -t i a l l y as p a t t e r n s of n e u r a l f i r i n g r e v e r b e r a t i n g i n c l o s e d c i r c u i t s , and l a t e r i n the form of a l t e r e d s t r u c t u r a l r e l a t i o n s between the neurons i n the c i r c u i t . The r e v e r b e r a t i n g a c t i v i t y was thought to c o n t i n u e u n t i l the permanent s t r u c t u r a l changes c o n s t i t u t i n g the mem-p r y were formed and to be necessary f o r t h e i r f o r m a t i o n . S i n c e con-s o l i d a t i o n was assumed to i n v o l v e p a t t e r n s of n e u r a l f i r i n g , any treatment which produced a severe d i s r u p t i o n of n e u r a l f i r i n g would be expected t o produce a complete d i s r u p t i o n of memories not y e t c o n s o l -i d a t e d and s t i l l h e l d i n the form of r e v e r b e r a t i n g a c t i v i t y . Only those memories a l r e a d y permanently s t o r e d would remain i n t a c t . ECS, p r o v i d i n g the c u r r e n t i n t e n s i t y i s s u f f i c i e n t l y s t r o n g , t y p i c a l l y produces a p e r i o d of h i g h v o l t a g e synchronous s e i z u r e d i s -charge which appears throughout the b r a i n and which i s f o l l o w e d by a p e r i o d of d e p r e s s i o n of n e u r a l a c t i v i t y . T h i s massive d i s t u r b a n c e of n e u r a l a c t i v i t y should c o m p l e t e l y d i s r u p t any ongoing p a t t e r n s of n e u r a l f i r i n g , and t h e r e f o r e produce a complete c e s s a t i o n of the con-s o l i d a t i o n p r o c e s s . The memories s t i l l h e l d i n t h i s form sh o u l d be l o s t , w h i l e those which had a l r e a d y been permanently s t o r e d s h o u l d remain i n t a c t . A c c o r d i n g l y , i f memory c o n s o l i d a t i o n i s assumed to i n v o l v e o n l y t h i s one phase, namely the t r a n s c r i b i n g of permanent memory from a l a b i l e memory t r a c e c o n s i s t i n g of p a t t e r n e d n e u r a l f i r -i n g , the l e n g t h of the ECS g r a d i e n t should r e f l e c t the d u r a t i o n of time n o r m a l l y r e q u i r e d f o r c o n s o l i d a t i o n to r e a c h c o m p l e t i o n . The s e i z u r e d i s c h a r g e produced by ECS i s u s u a l l y accompanied by an o v e r t b e h a v i o r a l c o n v u l s i o n i n which a l l the s k e l e t a l muscles con-t r a c t . The c o n v u l s i o n produced by a s u f f i c i e n t l y s t r o n g ECS i s h i g h l y s t e r e o - t y p e d , i n v o l v i n g a b r i e f t o n i c f l e x i o n of the body f o l l o w e d by a t o n i c e x t e n s i o n . The t o n i c e x t e n s i o n spreads c a u d a l l y along the body, and h i n d l i m b t o n i c e x t e n s i o n has g e n e r a l l y been taken to i n d i -c a t e a complete b e h a v i o r a l c o n v u l s i o n . The t o n i c e x t e n s i o n phase i s f o l l o w e d by a p e r i o d of clonus and the p o s t i c t a l coma. Toman et a l . (1946) observed t h a t the form of the t o n i c c o n v u l s i o n d i d not v a r y w i t h ECS parameters, and concluded t h a t "the b r a i n i s maximally a c t i v e d u r i n g a t o n i c extensor s e i z u r e , and the d i s c h a r g e once i n i t i a t e d i s independent of the s t i m u l u s " (p. 238). L a r g e l y on the b a s i s of t h i s c o n c l u s i o n the appearance of a t o n i c b e h a v i o r a l c o n v u l s i o n has been i n c o r r e c t l y assumed to r e f l e c t a maximal n e u r a l s e i z u r e . R e c e n t l y , Chorover and DeLuca (1969) found t h a t ECS f o l l o w i n g a f o o t s h o c k can produce a t o n i c c o n v u l s i o n w i t h o u t producing c o r t i c a l s e i z u r e discharge 18 Length of ECS G r a d i e n t s The l e n g t h s of ECS g r a d i e n t s have been found to v a r y g r e a t l y ; g r a d i e n t s have been o b t a i n e d which extend f o r 10 seconds (Chorover & S c h i l l e r , 1965), 20 seconds ( P f i n g s t & K i n g , 1969), 60 seconds (Quartermain et a l . , 1965), 1 hour ( H e r i o t & Coleman, 1962), 3 hours (McGaugh, 1966), and even 6 hours (Kopp e t a l . , 1966). A c l a i m by R o b u s t e l l i , G e l l e r , and J a r v i k (1970) to have demonstrated a g r a d i e n t of 23 hours i s i n v a l i d , s i n c e t h e i r e f f e c t was not shown to be time-dependent. The l o n g e s t g r a d i e n t demonstrated w i t h a s i n g l e ECS i s 6 hours. A number of v a r i a b l e s have been found to a f f e c t the l e n g t h of the ECS g r a d i e n t . These i n c l u d e p r i o r e x p e r i e n c e w i t h the t r a i n i n g apparatus ( M i l l e r , 1970), the l e v e l of f o o t s h o c k used (Ray & B i v e n s , 1968), the natu r e of the t r a i n i n g procedure (Chorover & S c h i l l e r , 1966; Thompson & Pennington, 1957), and even the time of day (Stephens & McGaugh, 1968). The e x p l a n a t i o n s f o r the e f f e c t s of these t r e a t -ments on the l e n g t h of the ECS g r a d i e n t have not been e s t a b l i s h e d . However, one p o s s i b i l i t y i s t h a t the d u r a t i o n of time r e q u i r e d f o r c o n s o l i d a t i o n i s not c o n s t a n t but v a r i e s w i t h both the natu r e of the memory and the s t a t e of the ani m a l . Another v a r i a b l e which has been found to a f f e c t the l e n g t h of the ECS g r a d i e n t i s the nature of the ECS treatment. The d i s r u p t i v e e f f e c t s of ECS have been found to v a r y depending on the manner i n which ECS i s a d m i n i s t e r e d . Ray and B a r r e t t (1969) found t h a t ECS a-c r o s s the eyes ( v i a c o r n e a l e l e c t r o d e s ) d i s r u p t e d performance at lower i n t e n s i t i e s than c u r r e n t a c r o s s the e a r s . L i k e w i s e , K i n g (1969) found t h a t c u r r e n t passed between screw e l e c t r o d e s over the a n t e r i o r c o r t e x d i s r u p t e d performance a t lower i n t e n s i t i e s than t h a t r e q u i r e d a c r o s s e l e c t r o d e s over the p o s t e r i o r c o r t e x . I n b o t h these experiments, the amount of impairment was found to be more dependent on the mode of d e l i v e r y than on the form of the b e h a v i o r a l c o n v u l s i o n , s i n c e the lower i n t e n s i t i e s of ECS d i d not produce t o n i c c o n v u l s i o n s . I n a d d i t i o n to the importance of the l o c u s of ECS a d m i n i s t r a t i o n , a number of experiments have found t h a t the l e n g t h of the ECS g r a d i e n t depends on the c u r r e n t parameters, even when a l l parameters produce t o n i c c o n v u l s i o n s . Both c u r r e n t i n t e n s i t y and d u r a t i o n have been found to a f f e c t the l e n g t h of the g r a d i e n t . M i l l e r (1968) found t h a t i n -c r e a s i n g the i n t e n s i t y of the c u r r e n t from 35 ma to 100 ma i n c r e a s e d the l e n g t h of the g r a d i e n t from 5 minutes to 50 minutes. Most of the et h e r experiments i n v e s t i g a t i n g the e f f e c t of v a r y i n g ECS i n t e n s i t y have a l s o found g r e a t e r impairments w i t h h i g h e r i n t e n s i t i e s (Dorfman & J a r v i k , 1968; Hughes, B a r r e t t , & Ray, 1970; Lee-Teng, 1969; Pagano, Bush, M a r t i n , & Hunt, 1969). However, two s t u d i e s (Quartermain et a l . , 1965; Weissman, 1963) f a i l e d to f i n d an e f f e c t of ECS i n t e n s i t y . A p o s s i b l e reason f o r these two n e g a t i v e f i n d i n g s i s t h a t the e f f e c t of ECS i n t e n s i t y o n l y i n c r e a s e s up to an asymptote. T h i s has been shown by the two s t u d i e s which have s y s t e m a t i c a l l y examined the e f f e c t of i n c r e a s i n g ECS i n t e n s i t y (Dorfman & J a r v i k , 1968; Lee-Teng, 1969). In both experiments, the amount of d i s t u r b a n c e was found to i n c r e a s e w i t h i n t e n s i t y up to a p o i n t , beyond which f u r t h e r i n c r e a s e s i n 20 i n t e n s i t y d i d not produce g r e a t e r d i s t u r b a n c e s of performance. The e f f e c t of ECS d u r a t i o n has not been found to be as s i g n i f i -cant as i n t e n s i t y . Dorfman and J a r v i k (1968), M i l l e r (1968), and P a o l i n o , Quartermain, and Levy (1969) have a l l f a i l e d to d e t e c t any e f f e c t of v a r y i n g ECS d u r a t i o n . I n the most thorough of these s t u d i e s , Dorfman and J a r v i k (1968) found no d i f f e r e n c e s over a v e r y wide range of d u r a t i o n s (0.1 to 3.0 seconds). On the o t h e r hand, p o s i t i v e r e s u l t s have been found by A l p e r n and McGaugh (1968). They found t h a t a 0.2 second d u r a t i o n ECS i m p a i r e d performance o n l y when a d m i n i s t e r e d im-m e d i a t e l y a f t e r p a s s i v e avoidance t r a i n i n g , w h i l e l o n g e r d u r a t i o n ECSs (0.4 or 0.8 seconds) produced g r a d i e n t s of up to 3 hours. The d i f f e r -ence between these r e s u l t s may somehow be t i e d t o the f a c t t h a t A l p e r n and McGaugh (1968) s i m u l t a n e o u s l y v a r i e d both i n t e n s i t y and d u r a t i o n ( u s i n g lower i n t e n s i t i e s w i t h h i g h e r d u r a t i o n s to keep the t o t a l a-fliount of energy a p p r o x i m a t e l y e q u a l ) . The f i n d i n g s t h a t ECS g r a d i e n t s v a r y i n l e n g t h depending on c u r r e n t parameters c l e a r l y show t h a t the e a r l y view of ECS as a u n i t a r y treatment i s i n c o r r e c t . These f i n d i n g s a l s o do not support a s i m p l e h y p o t h e s i s of p a t t e r n e d n e u r a l f i r i n g , s i n c e the s e i z u r e produced by a low i n t e n s i t y ECS would be expected to d i s r u p t such a process to the same degree as the s e i z u r e produced by a h i g h i n t e n s i t y ECS. Conse-q u e n t l y these f i n d i n g s n e c e s s i t a t e a r e c o n s i d e r a t i o n of the r e l a t i o n -s h i p of the l e n g t h of ECS g r a d i e n t s to the d u r a t i o n of memory c o n s o l i -d a t i o n 21 Two P o s s i b l e R e l a t i o n s h i p s Between the Length of ECS G r a d i e n t s and the D u r a t i o n of Memory C o n s o l i d a t i o n There are two hypotheses c o n c e r n i n g the d u r a t i o n of c o n s o l i d a t i o n which f o l l o w from the f i n d i n g s of v a r i a t i o n s i n ECS g r a d i e n t s w i t h c u r -r e n t parameters. One p o s s i b i l i t y i s t h a t memory c o n s o l i d a t i o n i s not c o m p l e t e l y d i s r u p t e d by every ECS, but o n l y by those of s u f f i c i e n t l y h i g h i n t e n s i t y . Lee-Teng (1969), and Dorfman and J a r v i k (1968) both found t h a t i n c r e a s i n g ECS i n t e n s i t y o n l y i n c r e a s e d the amount of d i s -turbance of performance up to an asymptote. T h i s asymptote might r e -f l e c t the p o i n t a t which ECS d i s r u p t e d a l l the memory not y e t c o n s o l i -dated. I f t h i s p o s s i b i l i t y i s c o r r e c t , the l e n g t h of the amnesia g r a d i e n t produced by a h i g h i n t e n s i t y ECS would correspond to the d u r a t i o n of time r e q u i r e d f o r the c o n s o l i d a t i o n of memory. The other h y p o t h e s i s i s t h a t c o n s o l i d a t i o n c o n t i n u e s f o r l o n g e r -than the l e n g t h of ECS g r a d i e n t s , even those o b t a i n e d w i t h a h i g h i n -t e n s i t y ECS. Th i s i s supported by a r e c e n t f i n d i n g t h a t f l u r o t h y l , a c o n v u l s a n t vapour, produces a much longer g r a d i e n t than any which have been found w i t h ECS ( G h e r k i n , 1969). C h e r k i n , u s i n g c h i c k s , found t h a t a h i g h c o n c e n t r a t i o n of f l u r o t h y l i m p a i r e d performance of a p a s s i v e avoidance response when a d m i n i s t e r e d 24 hours but not 48 hours a f t e r t r a i n i n g . T h i s v e r y long g r a d i e n t i s of p a r t i c u l a r i n t e r e s t s i n c e i t was ob t a i n e d i n the same s i t u a t i o n i n which Lee-Teng (1970b) found an as y m p t o t i c g r a d i e n t of a p p r o x i m a t e l y one minute u s i n g ECS. The asymptote found w i t h ECS i n t e n s i t y (Dorfman & J a r v i k , 1968; Lee-Teng, 1969) i s not i n c o n s i s t e n t w i t h t h i s l a t t e r h y p o t h e s i s . Instead of r e f l e c t i n g a complete d i s t u r b a n c e of c o n s o l i d a t i o n , the asymptote may r e f l e c t some c h a r a c t e r i s t i c of the s e i z u r e produced by ECS. There i s evidence i n d i c a t i n g t h a t s e v e r a l a s p e c t s of the s e i z u r e produced by ECS i n c r e a s e w i t h ECS i n t e n s i t y up to a c e r t a i n l e v e l but beyond t h i s l e v e l f u r t h e r i n c r e a s e s i n ECS i n t e n s i t y do not produce increments i n the s e i z u r e . F o r example, Minz and Domino (1953) found t h a t the d u r a t i o n of c o r t i c a l s e i z u r e d i s c h a r g e produced by ECS i n s p i n a l c a t s i n c r e a s e d w i t h ECS i n t e n s i t y up to a p o i n t beyond which f u r t h e r i n c r e a s e s i n i n t e n s i t y d i d not r e s u l t i n l o n g e r d u r a t i o n s of d i s c h a r g e . Z o r n e t z e r and McGaugh (1970) r e c e n t l y examined the s e i z u r e d i s c h a r g e produced by ECS i n r a t s . C o n t r a r y to Minz and Domino (1953), they found t h a t the d u r a t i o n of s e i z u r e d i s c h a r g e c o n t i n u e d to i n c r e a s e w i t h i n t e n s i t y . The r e a s o n f o r t h i s d i f f e r e n c e i s u n c l e a r . Z o r n e t z e r and McGaugh d i d , however, r e p o r t t h a t the frequency of the s e i z u r e d i s c h a r g e only i n c r e a s e d up to a p o i n t . While more r e s e a r c h needs to be done on the r e l a t i o n s h i p of s e i z u r e d i s c h a r g e to ECS i n t e n s i t y , these f i n d i n g s i n d i c a t e t h a t some asp e c t s of the s e i z u r e produced by ECS may not c o n t i n u e to i n c r e a s e w i t h ECS i n t e n s i t y . On the b a s i s of the a v a i l a b l e e v i d e n c e , i t i s not p o s s i b l e to de c i d e w i t h c e r t a i n t y whether the asymptote found w i t h ECS i n t e n s i t y r e f l e c t s a maximal d i s t u r b a n c e of u n c o n s o l i d a t e d memory, or whether i t r e f l e c t s a f a i l u r e of the n e u r o n a l d i s t u r b a n c e produced by ECS to con-t i n u e to i n c r e a s e w i t h i n t e n s i t y . A p o s s i b l e way of c l a r i f y i n g t h i s i s s u e might be to examine whether i n c r e a s i n g the n e u r o n a l d i s t u r b a n c e produced by ECS w i l l r e s u l t i n f u r t h e r i n c r e a s e s i n the amount of 23 impairment. A s e r i e s of ECSs, each of which produces a s e p a r a t e s e i z u r e , should produce a g r e a t e r d i s t u r b a n c e than a s i n g l e ECS. M u l t i p l e ECSs S e v e r a l e a r l y experiments have observed time-dependent i m p a i r -ments u s i n g m u l t i p l e ECSs which were of g r e a t e r d u r a t i o n than any r e -po r t e d w i t h a s i n g l e ECS. Hunt and Brady (1951) and Brady (1952) found t h a t a s e r i e s of 21 ECSs presented t h r e e times per day i m p a i r e d the performance of a CER a c q u i r e d through e i g h t t r i a l s spaced over a 31-day p e r i o d , i f the treatments were s t a r t e d 1 or 2 days a f t e r the l a s t t r a i n i n g t r i a l . However, the e f f e c t of the ECSs was markedly reduced i f the ECSs were delayed 30 days, and o n l y s l i g h t impairment appeared i f the d e l a y was 90 days. W i l l i a m s (1961, 1963) gave e i g h t d a i l y t r a i n i n g t r i a l s on a c o n f l i c t t r a i n i n g p r o c e d u r e , i n which r a t s were t r a i n e d to c r o s s an e l e c t r i f i e d g r i d to o b t a i n water. A s e r i e s of e i g h t d a i l y ECSs were found to e l i m i n a t e g r i d h e s i t a t i o n , the measure of c o n f l i c t , when s t a r t e d 1 day but not 13 days a f t e r the l a s t t r a i n -i n g t r i a l . I n both these s e t s of experiments, the t r a i n i n g procedure i n v o l v e d many t r i a l s spaced over a p e r i o d of days, c r e a t i n g d i f f i c u l t y f o r com-p a r i n g these f i n d i n g s to those o b t a i n e d w i t h a s i n g l e ECS f o l l o w i n g one t r i a l l e a r n i n g . N e v e r t h e l e s s , these impairments a r e not g e n e r a l l y i n -t e r p r e t e d as e x t e n s i o n s of the s o r t of d e f i c i t produced by a s i n g l e ECS (Hunt, 1965; McGaugh, 1968), but r a t h e r a r e u s u a l l y d i s t i n g u i s h e d on the b a s i s of s e v e r a l supposedly apparent e m p i r i c a l d i f f e r e n c e s . There are t h r e e ways i n which the d e f i c i t s produced by s i n g l e and m u l t i p l e ECSs have been thought to d i f f e r . F i r s t , the impairment p r o -duced by m u l t i p l e ECS has been r e p o r t e d to be o n l y temporary (Brady, 1951), not a p p e a r i n g i f t e s t i n g was g i v e n 30 days a f t e r the s e r i e s of ECSs i n s t e a d of the u s u a l 4 days. On the o t h e r hand, the performance d e f i c i t s produced by a s i n g l e ECS are u s u a l l y permanent ( C h e v a l i e r , 1965; L u t t g e s & McGaugh, 1967). However, s e v e r a l s t u d i e s have shown t h a t responses d i s t u r b e d by a s i n g l e ECS may a l s o reappear s p o n t a n e o u s l y over time (e.g., Pagano et a l . , 1969) or f o l l o w i n g a "reminder" (Lewis, M i l l e r , & M i s a n i n , 1968). Moreover, the d e f i c i t observed by W i l l i a m s (1961) was a p p a r e n t l y permanent f o r a t l e a s t 52 days. Second, m u l t i p l e ECS was thought to s e l e c t i v e l y i m p a i r a CER and n o t t o d i s t u r b o t h e r responses. G e l l e r , Sidman, and Brady (1955) r e -p o r t e d t h a t m u l t i p l e ECS i m p a i r e d a CER, but not a bar p r e s s response f o r water even though the bar press response was a c q u i r e d a f t e r the CER, i . e . the CER was s e l e c t i v e l y d i s t u r b e d , not j u s t the most r e c e n t l y a c q u i r e d response. However, t h e r e i s a l s o some evidence showing t h a t a s i n g l e ECS may be more e f f e c t i v e i n d i s t u r b i n g CERs than o t h e r s o r t s of responses. Chorover and S c h i l l e r (1966) found t h a t a s i n g l e ECS produced l o n g e r g r a d i e n t s i n a CER t a s k than i n two o t h e r v a r i a n t s of p a s s i v e avoidance t r a i n i n g procedures. The t h i r d apparent d i f f e r e n c e between the e f f e c t s of s i n g l e and m u l t i p l e ECS i s the r e p o r t e d requirement of the o v e r t c o n v u l s i o n f o r the d i s t u r b a n c e produced by m u l t i p l e but not by s i n g l e ECS. Hunt, J e r n b e r g , and Lawlor (1953) found t h a t the s e r i e s of 21 ECSs d i d not produce impairment of a CER i f they were presented w h i l e the animals were a n e s t h e t i z e d w i t h e t h e r . Hunt and B eckwith (1955) found t h a t p r e s e n t i n g the ECSs under phenacemide but not d i p h e n y l h y d a n t o i n a l s o b l o c k e d the e f f e c t of ECS. Both ether and phenacemide prevented the appearance of o v e r t c o n v u l s i o n s , w h i l e d i p h e n y l h y d a n t o i n prevented the appearance of a t o n i c e x t e n s i o n but not a r u n n i n g s e i z u r e . McGaugh and A l p e r n (1966) showed t h a t the impairment produced by a s i n g l e ECS s t i l l appeared even though the ECS was g i v e n under e t h e r a n e s t h e s i a w hich b l o c k e d the o v e r t c o n v u l s i o n . The same r e s u l t was o b t a i n e d by Essman (1968) u s i n g l i d o c a i n e and 2, 4, d i c h l o r o p h e n o x y a c e t i c a c i d , and Weissman (1965) u s i n g p h e n o b a r b i t a l , d i p h e n y l h y d a n t o i n , and phena-cemide, a l l of which b l o c k e d the o v e r t c o n v u l s i o n . The g r a d i e n t s produced by s i n g l e and m u l t i p l e ECSs do not appear to d i f f e r q u a l i t a t i v e l y on the b a s i s of e i t h e r the permanence of the e f f e c t or the s e l e c t i v e d i s t u r b a n c e of CERs. On the o t h e r hand, the apparent d i f f e r e n t i a l requirement of the c o n v u l s i o n does p r o v i d e sup-p o r t f o r the p o s s i b i l i t y t h a t the g r a d i e n t s produced by s i n g l e and m u l t i p l e ECSs r e f l e c t d i f f e r e n t p r o c e s s e s . However, c l o s e r e x a m i n a t i o n of t h i s l a t t e r d i f f e r e n c e r e v e a l s s e v e r a l f a c t o r s which c r e a t e d i f f i -c u l t i e s f o r drawing a f i r m d i s t i n c t i o n . F i r s t , these data are from d i f f e r e n t experiments and i t i s i m p o s s i b l e to be c e r t a i n t h a t the treatments ( a n t i c o n v u l s a n t drug doses and ECS l e v e l s ) were comparable. T h i s i s a problem because i t i s p o s s i b l e t h a t the s e i z u r e d i s c h a r g e produced by ECS was not b l o c k e d even though the o v e r t c o n v u l s i o n was. S t i l l e and Sayers (1967) examined a number of drugs which b l o c k e d the 26 o v e r t c o n v u l s i o n ( i n c l u d i n g phenacemide, d i p h e n y l h y d a n t o i n , and pheno-b a r b i t a l ) and found t h a t the c o r t i c a l s e i z u r e d i s c h a r g e was u n a f f e c t e d by the drugs. The d i f f e r e n t i a l e f f e c t s observed between s i n g l e and m u l t i p l e ECS when the c o n v u l s i o n was b l o c k e d , may r e f l e c t the s e i z u r e b e i n g b l o c k e d i n the m u l t i p l e , but not i n the s i n g l e ECS experiments, whether or not the s e i z u r e s were b l o c k e d p r o b a b l y depends on an i n t e r -a c t i o n between the amount of drug and ECS parameters, and i s d i f f i c u l t to e v a l u a t e i n the absence of r e c o r d i n g s . Second, both s e t s of ex-periments f i n d i n g long g r a d i e n t s w i t h m u l t i p l e ECS treatments used t r a i n i n g procedures i n v o l v i n g many t r i a l s spaced over a p e r i o d of days, c r e a t i n g d i f f i c u l t y f o r comparing these f i n d i n g s to those o b t a i n e d w i t h a s i n g l e ECS f o l l o w i n g o n e - t r i a l l e a r n i n g . Summary and R a t i o n a l e of the P r e s e n t I n v e s t i g a t i o n The e a r l y view t h a t the l e n g t h of the ECS g r a d i e n t corresponded to the d u r a t i o n of c o n s o l i d a t i o n i s no lo n g e r t e n a b l e . The l e n g t h of the g r a d i e n t produced by ECS has been found to v a r y w i t h ECS parameters. S i n c e the l e n g t h of the ECS g r a d i e n t i s not c o n s t a n t , i t i s not mean-i n g f u l to i d e n t i f y the d u r a t i o n of c o n s o l i d a t i o n as the l e n g t h of the g r a d i e n t o b t a i n e d w i t h an a r b i t r a r y ECS. There remain two p o s s i b i l i -t i e s f o r the r e l a t i o n of the l e n g t h of the ECS g r a d i e n t to the d u r a t i o n of c o n s o l i d a t i o n . One p o s s i b i l i t y i s t h a t the d u r a t i o n of c o n s o l i d a -t i o n corresponds not to the l e n g t h of any a r b i t r a r y ECS g r a d i e n t , but o n l y to those o b t a i n e d w i t h an ECS of s u f f i c i e n t i n t e n s i t y , The second p o s s i b i l i t y i s t h a t memory c o n s o l i d a t i o n c o n t i n u e s f o r l o n g e r 27 than the length of even a high intensity ECS gradient. Support for the f i r s t p o s s i b i l i t y comes primarily from the f i n d -ing that ECS intensity only increases the ECS gradient to an asymptotic l e v e l . The l a t t e r p o s s i b i l i t y requires that this asymptote r e f l e c t s the limited neuronal disturbance which a single ECS i s capable of producing. There i s evidence that a l least some aspects of the seizure discharge produced by ECS reach an asymptote with increasing ECS intensity. Tentative support for the second p o s s i b i l i t y i s provided by several early studies (Brady, 1952; Williams, 1963) which have found gradients of much greater length than those obtained with a single ECS. However, inferences from these studies are complicated by the p o s s i b i l i t y that these longer gradients may r e f l e c t a d i f f e r e n t pro-cess than single ECS gradients. This p o s s i b i l i t y i s suggested p r i -marily by the apparent d i f f e r e n t i a l effects found when the convulsion was.blocked. The purpose of the present investigation i s to determine whether a series of ECSs can produce gradients which do not r e f l e c t a qualita-t i v e l y different process than gradients produced by a single ECS, but which are of greater length. If such gradients can be obtained, they should provide strong support for the p o s s i b i l i t y that memory consoli-dation continues for longer than the length of single ECS gradients. Two possible ways of investigating the effects of a series of ECSs are to vary the number of ECSs or to keep the number constant but vary the spacings between them. This l a t t e r approach was used by Brady, Hunt, and G e l l e r (1954). They found t h a t a s e r i e s of 21 ECSs produced s u b s t a n t i a l impairment of a CER when spaced 1, 8, or 24 hours a p a r t . However, when the 21 ECSs were spaced 30 minutes a p a r t , l e s s i m p a i r -ment of the CER was found and when spaced 1 second a p a r t no i m p a i r -ment was observed. The advantage of t h i s l a t t e r approach i s t h a t the e f f e c t of a s e r i e s of ECSs can be examined w i t h o u t v a r y i n g the amount of c u r r e n t a d m i n i s t e r e d to the animals i n the v a r i o u s c o n d i t i o n s . I n a d d i t i o n , t h i s l a t t e r approach appears to be b e t t e r s u i t e d f o r the purpose of the p r e s e n t i n v e s t i g a t i o n , s i n c e by p r e s e n t i n g a s e r i e s of ECSs spaced c l o s e l y t o g e t h e r an e f f e c t o n l y s l i g h t l y g r e a t e r than t h a t produced by a s i n g l e ECS may be o b t a i n e d . As the s p a c i n g s a re grad-u a l l y i n c r e a s e d , the e f f e c t of the ECS may a l s o g r a d u a l l y i n c r e a s e . The o b t a i n e d r e s u l t s may t h e r e f o r e be comparable to those o b t a i n e d w i t h a s i n g l e ECS except g r e a t e r i n magnitude. The p r e s e n t experiments are d i v i d e d i n t o t h r e e p a r t s . The f i r s t experiment i n v e s t i g a t e d the e f f e c t of a s e r i e s of ECSs on performance of a p a s s i v e avoidance response a c q u i r e d i n a s i n g l e t r i a l . The pur-pose of t h i s experiment was to determine whether the l e n g t h of the g r a d i e n t c o u l d be i n c r e a s e d as the s p a c i n g s between the ECSs were i n -creased . Since the f i r s t experiment showed t h a t a l o n g e r g r a d i e n t was produced by a s e r i e s of spaced ECSs, a second experiment was conducted to determine whether t h i s l o n g e r g r a d i e n t would be a t t e n u a t e d as a r e s u l t of b l o c k i n g the b e h a v i o r a l c o n v u l s i o n . T h i s experiment was i n c l u d e d to e v a l u a t e the p o s s i b i l i t y t h a t the s e r i e s of ECSs produced 29 a q u a l i t a t i v e l y d i f f e r e n t e f f e c t than a s i n g l e ECS. A f i n a l experiment was i n c l u d e d to determine whether the s e r i e s of ECSs would a l s o produce a prolonged g r a d i e n t f o r an a p p e t i t i v e r e -sponse a c q u i r e d i n a s i n g l e t r i a l . EXPERIMENT 1: THE EFFECT OF A SERIES OF ECSS ON RETENTION OF A PASSIVE AVOIDANCE RESPONSE The purpose of t h i s f i r s t experiment was to a s c e r t a i n whether a s e r i e s of ECSs would produce a time-dependent impairment of per-formance which i s of g r e a t e r magnitude than those produced by a s i n g l ECS. I n order to do t h i s , 5 ECSs were p r e s e n t e d , spaced 5 seconds, a p a r t or spaced 1 minute a p a r t . The performance of these two groups was compared w i t h t h a t of a group which r e c e i v e d o n l y one ECS but of f i v e times the d u r a t i o n . T h i s group served as a c o n t r o l f o r any pos-s i b l e e f f e c t of the amount of c u r r e n t per se. A p a s s i v e avoidance t a s k was used s i n c e t h i s i s the type of l e a r n i n g procedure i n which the e f f e c t s of a s i n g l e ECS have been most t h o r o u g h l y documented. Method Sub j e c t s N a i v e , male, hooded, 200-300 gm r a t s o b t a i n e d from Quebec Breeding Farm (now Canadian B r e e d i n g L a b o r a t o r i e s ) served as s u b j e c t s Surgery The animal (under sodium p e n t o b a r b i t a l a n e s t h e s i a , 45 mg/kg) was p l a c e d i n a s t e r e o t a x i c head h o l d e r and i t s s k u l l exposed. Two s m a l l h o l e s were d r i l l e d b i l a t e r a l l y to r e c e i v e the s t a i n l e s s - s t e e l screw e l e c t r o d e s (0.8 mm d i a m t e r ) . These were p o s i t i o n e d 1 mm p o s t -e r i o r to the bregma and 4 mm l a t e r a l to the s a g i t t a l s u t u r e . These screw e l e c t r o d e s , a t t a c h e d v i a c o n n e c t i n g w i r e s to p i n s , p e n e t r a t e d j u s t through the s k u l l and were i n c o n t a c t w i t h the d u r a l s u r f a c e . Two other screws were p l a c e d i n the s k u l l to p r o v i d e ad-d i t i o n a l s u p p o r t . A f t e r the s u p p o r t i n g and e l e c t r o d e screws were i n p l a c e , the s k u l l was wiped d r y and d e n t a l a c r y l i c cement was a p p l i e d to cover the screws and the wound are a i n such a way t h a t o n l y the pi n s p r o t r u d e d . Immediately f o l l o w i n g s u r g e r y , the animals were i n j e c t e d i n t r a p e r i t o n e a l l y w i t h 40 mg/kg p e n t y l e n e t e t r a z o l and i n t r a -m u s c u l a r l y w i t h 0.2 cc sodium p e n i c i l l i n ( C r y s t i c i l l i n ) . P e n i c i l l i n was a l s o r o u t i n e l y g i v e n on the day f o l l o w i n g s u r g e r y and on the second from l a s t p r e t r a i n i n g day. Apparatus The t r a i n i n g apparatus was a gray plywood a l l e y 122 cm l o n g , 11 cm wide, and 20 cm h i g h . A s t a i n l e s s s t e e l d r i n k i n g spout s i m i l a r to those used i n the home cages, but covered w i t h masking tape except f o r the t i p , p r otruded f o r 2 cm through one end w a l l . A P h y s i o l o g i c a l E l e c t r o n i c s I n c . drinkometer was connected to the water spout and the g r i d f l o o r below the spout. The tape on the d r i n k i n g spout was to prevent the drinkometer from being a c t i v a t e d except through the t i p . The g r i d f l o o r c o n s i s t e d of 3 mm diameter b r a s s rods spaced 13 mm a p a r t and which extended f o r 18 cm, the l a s t rod b e i n g j o i n e d to the hardware c l o t h which comprised the f l o o r of the r e s t of the a l l e y . The g r i d f l o o r was connected to a c o n s t a n t c u r r e n t shock source which c o u l d d e l i v e r 2.0 ma, AC f o o t s h o c k . ECS was a 60 Hz s i n e wave from an 840 v o l t t r a n s f o r m e r i n s e r i e s w i t h a 44,000 ohm r e s i s t a n c e . ECS was d e l i v e r e d from the t r a n s f o r m e r v i a f l e x i b l e w i r e s t e r m i n a t i n g i n b u t t e r f l y c l i p s w hich c o u l d be a t -tached t o the p i n e x t e n s i o n s of the screw, e l e c t r o d e s . I n order to determine the ECS c u r r e n t i n t e n s i t y , as w e l l as the impedance between the c o r t i c a l screw e l e c t r o d e s , i n a number of an-imals the v o l t a g e drop a c r o s s e i t h e r the 44,000 ohm r e s i s t a n c e or the screw e l e c t r o d e s was measured d u r i n g ECS w i t h a T e k t r o n i c s 565 Storage O s c i l l o s c o p e . The impedance between the screw e l e c t r o d e s was found to v a r y between 1,500 and 3,000 ohms, and the c u r r e n t between 17.9 and 18.4 m i l l i a m p s . T r a i n i n g Procedure The animals were housed i n group cages and m a i n t a i n e d on f r e e l y a v a i l a b l e water and P u r i n a food chunks f o r at l e a s t a week b e f o r e s u r g e r y . F o l l o w i n g s u r g e r y , the animals were housed i n d i v i d u a l l y . Food c o n t i n u e d to be f r e e l y a v a i l a b l e throughout the experiment, but crn the second day a f t e r s u r g e r y , the water b o t t l e s were removed and 23-hour water d e p r i v a t i o n was m a i n t a i n e d f o r the r e s t of the e x p e r i -ment. The animals were b r i e f l y handled on the two days f o l l o w i n g s u r g e r y . On the t h i r d day a f t e r s u r g e r y , each a n i m a l , 21 to 23 hours water d e p r i v e d , was p l a c e d i n the apparatus f o r 10 minutes. Animals were always p l a c e d a t the end o p p o s i t e the d r i n k i n g spout, f a c i n g the spout. One hour access to water was g i v e n i n the home cages f o l l o w i n g each p r e t r a i n i n g s e s s i o n . On the f o u r t h day, the animals were p l a c e d i n the apparatus f o r 5 minutes and on the f i f t h day, f o r two p e r i o d s , f i r s t f o r 3 minutes and then, 1-2 hours l a t e r , f o r 2 minutes. On the s i x t h and seventh days (the l a s t two p r e t r a i n i n g days) the animals were given 3 t r i a l s , each of 1 minute duration, separated by 30-45 min-utes. This pretraining procedure was used because preliminary exper-iments showed i t to be an e f f i c i e n t way of establishing a strong drinking response. On the la s t two days of pretraining, the drinking latency was recorded with a stopwatch. Animals not drinking during each 1 minute t r i a l were assigned a score of 60 seconds. Those with mean latencies over the three t r i a l s on the last pretraining day of greater than 23 seconds were discarded. Approximately 10 percent of the animals were excluded for this reason. On the passive avoidance training day (eighth day following surgery), the animals were placed on a stand beside the apparatus and wires for administering the ECS were attached. After 1 minute of a-daptation to the wires, a l l animals were given a single t r i a l . Upon touching the spout the animals received one of several treatments depending on the experimental condition. Experimental Conditions This experiment involved a number of stages which were run se-quentially but which w i l l be presented together for simplicity. Ani-mals were generally run in lots of 30, with each lot containing ani-mals in 3 to 5 different treatment conditions. In order to minimize differences between treatment groups due to variation in lots of animals, the animals were assigned to groups on the basis of their pretraining latencies and a l l treatment 'groups were equated on this measure. There were generally between 5 and 7 animals per treatment 34 group (see Table 1 f o r the exact number of animals i n each group). The animals r e c e i v i n g p a s s i v e avoidance t r a i n i n g were a l l g i v e n a 1.0 second, 2.0 ma f o o t s h o c k upon t o u c h i n g the spout. I n the im-mediate ECS c o n d i t i o n , ECS onset c o i n c i d e d w i t h the o f f s e t of the fo o t s h o c k and was a d m i n i s t e r e d i n the a l l e y . Delayed ECS groups were r e t u r n e d to t h e i r home cages f o l l o w i n g the f o o t s h o c k and were l a t e r g i v e n ECS on the f e e d i n g stand b e s i d e b e s i d e the a l l e y . W i t h i n t h i s framework, the e f f e c t s of t h r e e ECS treatments were examined. These were f i v e ECSs each of 0.5 seconds d u r a t i o n spaced 5 seconds a p a r t , f i v e ECSs of 0.5 seconds d u r a t i o n spaced 1 minute a p a r t , and one ECS of 2.5 seconds d u r a t i o n . The treatment c o n d i t i o n s a r e presented i n Table 1. The o r i g i n a l d e s i g n i n c l u d e d o n l y the immediate, 1 hour and 24 hour ECS d e l a y s . When i t became apparent t h a t the f i v e ECSs spaced 1 minute a p a r t i m p a i r e d performance even when pre s e n t e d 24 hours a f t e r t r a i n i n g , a d d i t i o n a l groups were added to e v a l u a t e whether t h i s impairment was time-dependent. I n a d d i t i o n to these e x p e r i m e n t a l groups, a number of c o n t r o l c o n d i t i o n s were i n c l u d e d . F i r s t , to c o n f i r m t h a t the d r i n k i n g r e -sponse e s t a b l i s h e d d u r i n g p r e t r a i n i n g was s t a b l e over the d u r a t i o n of the experiment, two groups of animals were g i v e n n e i t h e r f o o t s h o c k nor ECS on the t r a i n i n g day, but were si m p l y removed from the appar-atus upon t o u c h i n g the water spout. One group was t e s t e d 48 hours a f t e r the t r a i n i n g s e s s i o n and the ot h e r was t e s t e d a t 11 days. To show t h a t the p a s s i v e avoidance response was a l s o s t a b l e , two o t h e r groups of r a t s were g i v e n a f o o t s h o c k on the t r a i n i n g day, but no ECS. 35 Table 1 The Number of Subjects In Each Treatment Condition i n Experiment 1 Treatment Time o f a Nob FS FS-ECS Delay Testing FS Only Immed. 1 hr. 24 hr. 48 hr. 9 days No ECS 48 hrs. N=5 N=10 - - - - -No ECS 11 days N=7 N=10 - - - - -1 ECS, 2.5 sec. duration 48 hrs. N=5 - N=5 N=7 N=6 - N=7 5 ECS, 5 sec. apart 48 hrs. N=5 - N=5 N=7 N=8 5 ECS, 1 min. apart 48 hrs. N=5 - N=8 N=7 N=7 N=ll N=8 5 ECS, 1 min. apart 11 days - N=6 N=5 aFollowing ECS, or training (in the no ECS conditions) bFS = footshock (passive avoidance training) These animals were tested either 48 hours or 11 days later. Several other control conditions were included to evaluate a l -ternatives to the interpretation that the ECS treatments were pro-ducing a disturbance of memory consolidation. F i r s t , three groups were included to determine whether any aversive effects of the ECS treatments were su f f i c i e n t l y strong to affect the drinking response. These received one of the three ECS treatments instead of footshock upon touching the water spout. Second, to examine whether the impair ments produced by the five ECSs spaced 1 minute apart were permanent, two groups were given this treatment at 1 hour or 24 hours after training and tested 11 days following training. Animals i n a l l conditions received 1 hour access to water i n their home cages on each day of the experiment. On days when ECS was administered, water was given starting 1 hour after ECS. If the ani-mal received only training, water was given 1 hour after training. A l l animals were approximately 23 hours water deprived during testing Retention tests were given either 48 hours after ECS, 48 hours after training, or 11 days after training, depending on the experi-mental condition (Table 1). Testing for a l l groups took the form of three t r i a l s , 30-45 minutes apart, identical to those on the last pretraining days. Animals f a i l i n g to drink during the 60 second test were removed and assigned a score of 60 seconds for that t r i a l . The latencies of the drinking response on each of the three t r i a l s on the test day were averaged for each animal. A l l s t a t i s i c a l analyses were performed on the mean drinking 37 latency for each animal on the test day. These mean latencies did not sa t i s f y the requirements for parametric analysis, since the maximum score of 60 was obtained by a number of animals. Consequently, Halperin's (1960) extension of the Mann-Whitney test to samples cen-sored at the same fixed point was used. Results The drinking latencies for the control groups not receiving ECS are presented i n Table 2. In the groups not receiving passive avoid-ance training, the drinking latencies of animals tested 48 hours after the training day did not d i f f e r from those of animals not tested u n t i l 11 days after the training day. These groups were therefore combined. With passive avoidance training the situation was similar. The drink-ing latencies of the groups receiving passive avoidance training (footshock) did not d i f f e r between the 48 hour and 11 day testings. At both times of testing the latencies were s i g n i f i c a n t l y longer than the latencies of the corresponding groups not receiving passive avoid-ance training. This finding indicates that the passive avoidance training procedure produced s i g n i f i c a n t learning which was stable over 11 days. The groups receiving passive avoidance training were also combined. Figure 1 i l l u s t r a t e s the median drinking latencies for the groups receiving one of the ECS treatments following passive avoidance training. The drinking latency varies with both the type of ECS and the time of ECS administration. The single 2.5 second ECS s i g n i f i -cantly impaired passive avoidance performance when presented Table 2 Drinking Latencies for the Groups i n Experiment 1 Which Did Not Receive ECS Test Latency Group N (s econds) Median Rang ;e FS tes t 48 hrs. 10 60. 0 a 15.6 - 60. 0 FS test 11 days 10 60. 0 b 23.3 - 60. 0 FS Combined^ 20 60.0 C 15.6 - 60. 0 No FS test 48 hrs. 5 2.3 1.6 - 4.3 No FS test 11 days 7 2.0 2.0-4.0 No FS Combined11 12 2.0 1.6 - 4.3 a S i g n i f i c a n t l y d i f f e r e n t from No FS test 48 hours (p <.001). b S i g n i f i c a n t l y d i f f e r e n t from No FS t e s t 11 days (p< .001). c S i g n i f i c a n t l y d i f f e r e n t from Combined No FS group (p<.001). dThe difference between the 48 hour and 11 day testings i s not s i g n i f i c a n t . immediately after training (p<(.001), but not when presented 1 hour, 24 hours, or 9 days later ( a l l comparisons are to the combined foot-shock-no ECS controls, one-tailed). The f i v e ECSs spaced 5 seconds apart impaired performance when presented immediately (p< .001) or 1 hour (p< .025) after training, but not when presented at 24 hours. In contrast, the f i v e ECSs spaced 1 minute apart impaired performance when presented immediately (p<£.001), 1 hour (p<.001), 24 hours (p •(.Ol) and 48 hours (p<.02) but not 9 days after training. These results show that each ECS treatment produced an impairment of per-formance which was time-dependent. These results also show that each of the ECS treatments produced a gradient of a di f f e r e n t length. Me-dians, ranges and further s t a t i s t i c a l comparisons between these groups are presented i n Appendix A. None of the immediate ECS groups differed s i g n i f i c a n t l y from the eombined No FS control. A l l other training-ECS groups were s i g n i f i -cantly different from the No FS controls. The impairment of passive avoidance performance produced by the f i v e ECSs spaced 1 minute apart was permanent over at least 11 days appearing when testing was given 11 days rather than 48 hours after training, i n both the 1 hour (Median = 11.0, Range = 1.6 - 21.6; p <.001) and the 24 hour (Median = 40.6, Range = 9.3 - 44.0; p< .025) conditions (compared to the combined footshock-no ECS controls, one-tailed) . These groups did not d i f f e r from the corresponding groups tested at 48 hours. F i n a l l y , the three ECS treatments given to animals not receiving I M M E D . 1 H R . 2 4 H R . 4 8 H R . 9 D A Y S TIME OF ECS F i g u r e 1. M e d i a n D r i n k i n g L a t e n c i e s f o r t h e G r o u p s R e c e i v i n g P a s s i v e A v o i d a n c e T r a i n i n g F o l l o w e d by o n e o f t h e ECS T r e a t m e n t s . footshock did not produce increased latencies as compared to the com-bined no footshock-no ECS controls (2.5 second ECS: Median = 2.0; fiv e ECSs, 5 seconds apart: Median = 2.3; five ECSs, 1 minute apart: Median = 2.3), showing that none of these treatments had a direct effect on the latency of the drinking response. Behavioral Observations The 2.5 second ECS consistently evoked a f u l l tonic-clonic con-vulsion. The fi v e ECSs spaced 5 seconds apart resulted i n only one f u l l convulsion; however, each current onset was marked by a slight jerk. The five ECSs spaced 1 minute apart produced a separate re-sponse to each stimulus: to the f i r s t a tonic-clonic convulsion, to the second and third usually an i n i t i a l extension of the forelegs and opening of the mouth followed by a running seizure. The fourth and f i f t h ECSs produced similar effects, but were usually followed by more vigorous thrashing and running behavior. These were often ac-companied by vocalization. I t was frequently necessary to hold the animal by the t a i l during these seizures to prevent his running off the feeding stand. Histology Following testing, the animals were k i l l e d ; the brains were removed and fixed i n formal saline. No hemorrhages were observed on the cortex of any animal. Two brains from animals which had received the five ECSs spaced 1 minute apart were sectioned at 40 microns and every f i f t h section for 1.5 millimeters anterior and posterior to the electrodes was taken and stained with thionin. Microscopic examination 42 revealed no gross morphological damage. Discussion A l l three ECS treatments produced impairments of passive avoidance which were time-dependent. The time during which they were effective differed for each treatment; the single 2.5 second ECS produced a gra-dient of less than 1 hour, the f i v e ECSs spaced 5 seconds apart a gra-dient of between 1 and 24 hours, and the five ECSs spaced 1 minute apart a gradient of between 48 hours and 9 days. The greater impairment produced by the longer spacings i s similar to the findings reported by Brady et a l . (1954), and the present results confirm the reports of Brady (1952) and Williams (1963) that a series of ECSs can produce a long gradient. In fact, the gradient of 48 hours produced by the five ECSs spaced 1 minute apart i s far greater than the longest gradient (6 hours) which has been reported with a single ECS (Kopp et a l . , 1966). A recent study (Weiner, 1970) has also found that a series of ECSs produced a longer gradient than a single ECS. Using a multi-t r i a l shock-escape training procedure, he found that a series of four ECSs spaced 5 minutes apart impaired later performance when presented 5 or 30 minutes but not 24 hours after training. In contrast, a single ECS did not impair performance when presented at these times. However, Weiner also observed d e f i c i t s when either the series of ECSs or a single ECS were presented 7 or 14 days after training, similar to the effects found with anticholinesterase drugs (see page 69). 43 EXPERIMENT 2: THE EFFECT OF PRESENTING A SERIES OF ECSS TO ANESTHETIZED ANIMALS A d i s t i n c t i o n has been drawn between the impairments of l e a r n e d responses produced by s i n g l e and m u l t i p l e ECSs on the b a s i s of o b s e r-v a t i o n s t h a t these two treatments are d i f f e r e n t i a l l y a f f e c t e d by a n t i c o n v u l s a n t drugs ( i . e . , McGaugh, 1968). I n the case of a s i n g l e ECS, the d i s t u r b i n g e f f e c t on performance i s supposedly u n a f f e c t e d by a n t i c o n v u l s a n t s (Essman, 1968; McGaugh & A l p e r n , 1966; Weissman, 1965). I n c o n t r a s t , m u l t i p l e ECS does not appear to have any e f f e c t on p e r -formance when the c o n v u l s i o n i s b l o c k e d (Hunt et a l . , 1953; Hunt & Beckwith, 1955). However, t h i s d i s t i n c t i o n i s based on comparisons between s t u d i e s , and i t i s not p o s s i b l e to be sure t h a t the l e v e l s of -anesthesia i n the two s e t s of experiments were comparable. S p e c i f i c -a l l y , the d i f f e r e n t i a l e f f e c t s of a n t i c o n v u l s a n t s may s i m p l y have been due to the use of d i f f e r e n t drug l e v e l s i n the two s e t s of ex-periments. For example, n e u r a l s e i z u r e d i s c h a r g e may be necessary f o r both e f f e c t s , but only the drug l e v e l s used i n the m u l t i p l e ECS s t u d i e s might have been s u f f i c i e n t to b l o c k the s e i z u r e d i s c h a r g e . I t i s d i f f i c u l t to compare the drug and ECS l e v e l s used i n these ex-periments, and none of these experiments have i n c l u d e d e l e c t r i c a l r e c o r d i n g s to c o n f i r m t h a t the a n t i c o n v u l s a n t drugs b l o c k e d the s e i z u r e d i s c h a r g e as w e l l as the o v e r t c o n v u l s i o n . The p r e s e n t experiment examined the e f f e c t of b l o c k i n g the c o n v u l s i o n on the impairment of p a s s i v e avoidance performance pro-duced by f i v e ECSs spaced 1 minute a p a r t . I n order to examine the p o s s i b i l i t y t h a t the r e p o r t e d d i f f e r e n t i a l e f f e c t s of a n t i c o n v u l s a n t s might be an a r t i f a c t of d i f f e r e n t drug l e v e l s , the p r e s e n t experiment used two d r u g s , both of which b l o c k the o v e r t c o n v u s i o n , but which were found, through p r e l i m i n a r y r e c o r d i n g s , t o have q u i t e d i f f e r e n t e f f e c t s on c o r t i c a l s e i z u r e d i s c h a r g e . One d r u g , e t h e r ( d i e t h y l e t h e r ) , was found to have l i t t l e e f f e c t on s e i z u r e d i s c h a r g e , w h i l e the o t h e r d r u g , sodium p e n t o b a r b i t a l , was found to b l o c k or at l e a s t g r e a t l y a t t e n u a t e s e i z u r e d i s c h a r g e ( r e p r e s e n t a t i v e r e c o r d s are p r e -sented i n Appendix C). Me thod Seventy-seven male r a t s of the same age and s t r a i n as those i n Experiment 1 were used here. The apparatus, s u r g i c a l and t r a i n i n g procedures were i d e n t i c a l t o those used i n Experiment 1. The d e s i g n of the experiment was as f o l l o w s . Ten groups, a l l of which r e c e i v e d p a s s i v e avoidance t r a i n i n g , were t e s t e d . Three groups were g i v e n the f i v e ECSs spaced 1 minute a p a r t w h i l e anesthe-t i z e d w i t h e t h e r ( A n e s t h e t i c e t h e r , Squibb) at 1 hour (n = 6 ) , 24 hours (n = 10), or 9 days (n = 10) a f t e r t r a i n i n g . Three other groups r e c e i v e d f i v e ECSs spaced 1 minute a p a r t under sodium p e n t o b a r b i t a l a n e s t h e s i a (Nembutal, Abbott L a b o r a t o r i e s ) a t 1 hour (n = 7 ) , 24 hours (n = 9 ) , or 9 days (n = 6) . To c o n t r o l f o r e f f e c t s of e t h e r or sodium p e n t o b a r b i t a l alone on performance two groups were not g i v e n ECS but o n l y e t h e r (n = 6) or sodium p e n t o b a r b i t a l (n = 7) a n e s t h e s i a 1 hour a f t e r t r a i n i n g . Two a d d i t i o n a l groups were i n c l u d e d ; these r e c e i v e d the 2.5 second d u r -a t i o n ECS under ether (n = 8) or sodium p e n t o b a r b i t a l (n = 8) 24 hours a f t e r t r a i n i n g . These groups were i n c l u d e d s i m p l y to examine the pos-s i b i l i t y t h a t ether or sodium p e n t o b a r b i t a l might somehow augment the e f f e c t of ECS on performance. Sodium p e n t o b a r b i t a l a n e s t h e s i a was produced by i n j e c t i n g , i n t r a -p e r i t o n e a l l y , 45 mg/kg of sodium p e n t o b a r b i t a l 15 minutes p r i o r t o ECS a d m i n i s t r a t i o n . A stan d a r d method was used to a d m i n i s t e r e t h e r anes-t h e s i a . F i r s t , the animals were p l a c e d i n a 3 - l i t r e e t h e r s a t u r a t e d j a r f o r a p p r o x i m a t e l y 45 seconds ( u n t i l the r i g h t i n g r e f l e x was l o s t ) . They were then removed and the ECS c l i p s were a t t a c h e d . F i f t e e n s e-conds a f t e r b e i n g removed from the j a r e t h e r was a g a i n a d m i n i s t e r e d (a s m a l l v i a l c o n t a i n i n g e t h e r - s a t u r a t e d c o t t o n was f i t t e d over the s n o u t ) . T h i s second a d m i n i s t r a t i o n of et h e r was necessa r y to main-t a i n a n e s t h e s i a . The v i a l was o n l y kept over the snout f o r 15 seconds, and 15 seconds was always a l l o w e d to e l a p s e between a d m i n i s t r a t i o n of e t h e r and ECS. A d d i t i o n a l 15-second a d m i n i s t r a t i o n s of e t h e r were i n c l u d e d between each ECS. A l l a d m i n i s t r a t i o n s of et h e r took the same form whether ECS was a d m i n i s t e r e d or not. A l l a n a l y s e s , as i n the p r e v i o u s experiment, were performed on the mean d r i n k i n g l a t e n c i e s f o r each animal on the t e s t day, u s i n g H a l p e r i n ' s (1960) e x t e n s i o n of the Mann-Whitney t e s t . 46 Results The five ECSs spaced 1 minute apart, when presented to animals anesthetized with ether or sodium pentobarbital, produced the same impairments of passive avoidance performance as had been found i n the previous experiment using unanesthetized animals (Figure 2). The fiv e ECSs spaced 1 minute apart under ether produced s i g n i f i c a n t l y lower drinking latencies than the ether only controls when admini-stered at 1 hour (p<.02) and 24 hours (p<.02), but not at 9 days after training. Similarly, the five ECSs spaced 1 minute apart under sodium pentobarbital produced s i g n i f i c a n t l y lower.drinking latencies when administered at 1 hour (p (.01) or 24 hours (p <f.01) , but not at 9 days after training. Additional comparisons between these groups are presented i n Appendix B. There were no differences between the ether and sodium pento-barbital groups under any of the conditions. Moreover, none of these groups differed s i g n i f i c a n t l y from the corresponding groups i n Exper-iment 1. The 2.5 second ECS at 24 hours under ether (Median = 60.0, Range = 12.0 - 60.0) or sodium pentobarbital (Median = 60.0, Range = 26.6 - 60.0) did not s i g n i f i c a n t l y impair performance rel a t i v e to the groups receiving only ether or sodium pentobarbital. This find-ing suggests that anesthesia did not augment the effect of ECS on performance. Behavioral Observations Both ether and sodium pentobarbital blocked the overt convulsion I 47 to the extent that the response to ECS was only a brief jerk or s t i f -fening during current presentation. Two animals receiving ECS under ether showed evidence of a motor seizure during ECS and were discarded from the experiment. Discussion Ether and sodium pentobarbital anesthesia, both of which blocked overt signs of a seizure, did not attenuate the effect of a series of f i v e ECSs. Under both drugs, the f i v e ECSs spaced 1 minute apart im-paired performance of the passive avoidance response to the same de-gree as had been found with unanesthetized animals in the previous experiment. • The present findings are in contrast to those of Hunt, et a l . , i (1953) and Hunt and Beckwith (1955) who found that blocking the be-havioral convulsion also blocked the effect of a series of ECSs on performance. Conversely, the present findings are consistent with the results usually obtained with a single ECS (Essman, 1968; McGaugh & Alpern, 1966; Weissman, 1965). These results, therefore, do not support the hypothesis that the gradient produced by the series of . ECSs spaced 1 minute apart represents a different process than that responsible for single ECS gradients. ; McGaugh and Zornetzer (1970) have recently reported evidence which also questions the d i s t i n c t i o n between single and multiple ECS gradients. In their experiment, mice trained in a passive avoidance task were later given ECS either while anesthetized with ether or t i while unanesthetized. They found the ECS gradient was blocked i f a ') I I I 1 N O E C S 1 H R . 2 4 H R . 9 D A Y S M e d i a n D r i n k i n g L a t e n c i e s f o r t h e G r o u p s R e c e i v i n g 5 E C S ' S S p a c e d 1 M i n u t e a p a r t U n d e r E t h e r o r S o d i u m P e n t o b a r b i t a l A n e s t h e s i a F o l l o w i n g P a s s i v e A v o i d a n c e T r a i n i n g . 49 low intensity ECS and high concentration of ether were used, but not when either a high intensity ECS or low concentration of ether was used. I t now appears that both single and multiple ECS gradients may or may not be blocked by anticonvulsant drugs. The reason why anticonvulsant drugs i n some cases block the ECS gradient i s presumably because i n those cases some aspect of the neur-onal disturbance which is normally produced by ECS and which i s nec-essary to produce the ECS gradient i s blocked. McGaugh and Zornetzer (1970) reported that animals administered low intensity ECS under high concentrations of ether did not exhibit any disturbance of cort-i c a l neuronal a c t i v i t y as a result of the ECS, although c o r t i c a l seizures were observed in those animals administered either high i n -tensity ECS or low intensity ECS under low concentrations of ether. Therefore the condition i n which they observed the ECS gradient to be -blocked corresponded to the condition in which ECS did not produce a detectable neuronal disturbance. In this experiment the ECS gradient appeared under a l l condi-tions, presumably because the ECS intensity was high relative to the levels of drugs used. Nevertheless, i n the case of sodium pentobar-b i t a l anesthesia an interesting result was obtained. The level of sodium pentobarbital anesthesia used here was found to block or greatly attenuate the co r t i c a l seizure discharge normally produced by ECS suggesting that seizure discharge, at least i n the cortex, i s not necessary for the gradient produced by the series of ECSs. This result i s not inconsistent with the results of McGaugh and Zornetzer 50 (1970), since i n the present experiment other aspects of the neuronal disturbance such as the period of post-ictal depression were not blocked by the drug. More research is needed to c l a r i f y which as-pects of the disturbance produced by ECS are responsible for produc-ing the ECS gradient. 51 EXPERIMENT 3: EFFECT OF A SERIES OF ECSS ON AN APPETITIVE RESPONSE ACQUIRED IN A SINGLE TRIAL The f i r s t two experiments established that five ECSs spaced 1 minute apart produced a longer gradient i n a passive avoidance task than has been found with a single ECS. This gradient does not appear to d i f f e r except in magnitude from those produced by a single ECS. The present experiment examined the generality of this increased im-pairment by using a one-trial appetitive training procedure. This task involves a quite different response (approach) than the previous passive avoidance task (inhibition of approach). Method One hundred and thirteen rats of the same strain as in Experi-ments 1 and 2 were used i n this experiment. Of these, 40 were ex-cluded for f a i l i n g to l i c k the spout with 10 minutes on the training day, leaving only 73 subjects. The apparatus and surgical procedures were identical to those of Experiments 1 and 2.' The animals also received the same treatment as those i n the previous experiments u n t i l the f i r s t pretraining day. On this day, they were each placed i n the alley for 10 minutes with the water spout empty. The number of lick s at the empty spout was recorded on the drinkometer. For the next two days the identical procedure was followed. The animals received 1 hour of access to water in their home cages following removal from the alley. On the fourth day, appetitive training was carried out. The animals were placed i n the alley as usual, only on this day the water spout contained water. Those animals finding the water were allowed to drink for 15 seconds. They were then removed and the wires for ad-ministering ECS were attached. Three ECS treatments were used in this experiment. Two of these, five ECSs spaced 1 minute apart and one 2.5 second duration ECS were the same as those used i n the previous exper-iments. A third ECS treatment, one 0.5 second duration ECS, was also examined. Separate groups received the five ECSs spaced 1 minute apart at 15 seconds (n =5) or 1 hour (n = 7) following training. Similarly, the one ECS of 2.5 seconds duration was given at 15 seconds (n = 5) and 1 hour (n = 9) after training. The one ECS of 0.5 seconds duration was also given at 15 seconds (n = 5) and 1 hour (n = 8). The 15 second delay was required to attach the wires. ECS was always given on a feeding stand beside the alley. The 1 hour delay animals were returned to their home cages for the hour. To determine the aversiveness of the three ECS treatments, three control groups (n = 5 each) were not given water on the training day but were removed 15 seconds after f i r s t touching the spout (the time allowed the other groups for drinking) and were given one of the three ECS treatments 15 seconds later. Two groups were not given ECS: one received water (appetitive training, n = 10), the other (n = 9) did not. A l l animals were given 1 hour access to water in their home cages either 1 hour after ECS or 53 1 hour a f t e r the t r a i n i n g t r i a l . For a l l groups, t e s t i n g was g i v e n 48 hours a f t e r t r a i n i n g , and c o n s i s t e d of r e c o r d i n g the number of l i c k s a t the empty spout i n a 10 minute s e s s i o n as on p r e t r a i n i n g days. Comparisons between groups were made on the b a s i s of the number of l i c k s on the t e s t day. The data were a n a l y s e d u s i n g non-parametric t e s t s (Mann-Whitney U). R e s u l t s The a p p e t i t i v e t r a i n i n g procedure produced an i n c r e a s e i n the amount of l i c k i n g a t the empty spout on the t e s t day. The group r e -c e i v i n g water ( a p p e t i t i v e t r a i n i n g ) on the t r a i n i n g day (Median = 95, Range = 4 - 266) showed a s i g n i f i c a n t l y (U = 7, p< .001) g r e a t e r num-ber of l i c k s a t the spout on the t e s t day than the group not g i v e n water (Median = 8, Range = 1 - 24). T h i s r e s u l t demonstrates t h a t the d r i n k i n g e x p e r i e n c e on the t r a i n i n g day produced s u b s t a n t i a l l e a r n i n g of the presence of water i n the spout. R e s u l t s f o r the groups r e c e i v i n g a p p e t i t i v e t r a i n i n g f o l l o w e d by one of the ECS treatments are presented i n Table 3. No d i f f e r e n c e s were observed between the t h r e e ECS t r e a t m e n t s . Each ECS treatment produced s i g n i f i c a n t impairment of the a p p e t i t i v e response when pre-sented 15 seconds a f t e r t r a i n i n g , but not when presented 1 hour a f t e r t r a i n i n g . I n s p e c t i o n of the median number of l i c k s f o r the t h r e e groups r e c e i v i n g ECS a t 1 hour a f t e r t r a i n i n g shows t h a t these s c o r e s are somewhat lower than the median f o r the no ECS, H2O c o n t r o l . T h i s d i f f e r e n c e might suggest t h a t some impairment was s t i l l produced by 54 Table 3 Number of Licks at the Empty Water Spout on the Test Day for the Groups i n Experiment 3 Type of ECS Time of ECS N Median Range U a No ECS H20 Control 10 95 266 7*** No ECS No H20 Control 1 - 2 4 1 ECS, 0.5 sec. duration 15 sec. 1 hr. 22 53 17 42 4** 9* 22 - 254 1*** 35 1 ECS, 2.5 sec. duration 15 sec. 5 43 14 - 68 4** 10* 1 hr. 9 54 30 - 248 0*** 43 5 ECSs, 1 min. apart 15 sec. 1 hr. 39 62 11 _ 48 4** 9* 17 - 234 3** 32 aCompared to No ECS, No H20 Control bCompared to No ECS, H20 Control * p<.05 (one-tailed) ** p<.01 (one-tailed) *** p^.001 (one-tailed) the ECS treatments when administered at this time, even though the i n -dividual comparisons to the no ECS, control were not significant. However, this p o s s i b i l i t y i s not supported by the finding that even when combined, these three groups do not d i f f e r from the no ECS, H20 control (U = 110, n.s.). A l l groups receiving appetitive training followed by ECS showed sign i f i c a n t l y higher numbers of l i c k s at the empty spout than the con-t r o l group which had not received appetitive training (Table 3). These differences suggest that significant retention of the appetitive t r a i n -ing was present i n every group. The results from the control groups receiving only ECS on the training day indicate that the impaired performance found with the five ECSs spaced 1 minute apart and the 2.5 second duration ECS were not due to punishment. ECS alone did not affect the number of l i c k s (relative to the control group not receiving appetitive training) i n the five ECSs spaced 1 minute apart condition (Median = 4, Range = 0 - 76, U = 19) or the 2.5 second duration ECS condition (Median = 0, Range = 0 - 106, U = 17). If ECS was aversive, i t would be ex-pected to decrease the frequency of a response which preceded i t . Because these two treatments did not decrease the.number of l i c k s , the impairment found i n the groups given these treatments 15 seconds after appetitive training cannot be explained by punishment. On the other hand, the single 0.5 second duration ECS produced a significantly lower number of l i c k s (Median = 1, Range = 0 - 2, U = 3; p^.Ol), i n -dicating that administration of this treatment may have been aversive. Discussion In the appetitive task used here, there were no differences be-tween the lengths of the gradients produced by the three ECS treatments. The f i v e ECSs spaced 1 minute apart produced only a sl i g h t impairment of performance when presented 15 seconds after training, and no impair-ment when presented 1 hour after training. I t should be pointed out that the subjects receiving appetitive training showed considerable v a r i a b i l i t y i n the response measure used i n this task. It i s possible that this v a r i a b i l i t y masked small differences between the ECS treat-ments, although i t is quite unlikely that differences of the magnitude observed i n Experiments 1 and 2 would not have been detected. Because of the low response level i n the groups not given appeti-tive training, the adequacy of the controls for aversive effects of ECS might be questioned. Aversive effects might not have been detected because the animals were already responding at such a low rate. How-ever, i n the case of the fi v e ECSs spaced 1 minute apart and the single 2.5 second duration ECS, no aversive effects were detected i n Experi-ment 1 (or i n this experiment) and i t therefore appears safe to inter-pret the d e f i c i t s produced by these treatments in this appetitive task as amnesia. On the other hand, the single 0.5 second duration ECS, which was not examined i n Experiment 1, appeared to produce s i g n i f i c a n t aversive effects i n this appetitive task. Therefore i t is possible that the gradient produced by this treatment was due to punishment, not amnesia. The length of the gradients produced by each of the ECS treatments i n this task, between 15 seconds and 1 hour, i s shorter than the 3 hours found by Tenen (1965b) but i s somewhat comparable to those re-ported by Pinel (1969), 1 minute, and Herz (1969), 20 seconds, a l l of whom used a single ECS and appetitive tasks. However, this gradient is much shorter than the gradient found with five ECSs spaced 1 minute apart i n the passive avoidance task (Experiments 1 and 2). I t should be noted that even i f a l l three gradients are interpreted as reflecting aversive effects, the main conclusion of this experiment, namely that the series of ECSs did not produce a longer gradient than a single ECS i n this task, is unchanged. The f a i l u r e to observe v a r i a b i l i t y i n the lengths of the gradients produced by the different ECS treatments i s not inconsistent with a v a i l -able data. No study has previously examined the effects of varying ECS parameters i n a one-trial appetitive task, although a comparison of the results of Pinel (1969) and Tenen (1965b) suggests that ECS intensity may affect the length of the gradient i n an appetitive task. Pinel used 60 ma. and found a gradient of 1 minute; Tenen used 150 ma. and found a gradient of 3 hours. The present results are consistent with those of Sidman et a l . , (1955) who found that a series of ECSs impaired the performance of a CER, but not a more recently acquired appetitive response (bar press). The results of Sidman et a l . (1955) and of the present experiment sug-gest that a series of ECSs is more effective i n producing a long gra-dient when a shock-motivated inhibitory response is used than when an appetitive response is used. 58 GENERAL DISCUSSION Three i s s u e s w i l l be d i s c u s s e d h e r e : f i r s t , the p o s s i b i l i t y t h a t memory c o n s o l i d a t i o n i s r e l a t i v e l y b r i e f and i s maximally d i s t u r b e d by a s i n g l e ECS; second, p o s s i b l e e x p l a n a t i o n s f o r the d i f f e r e n t r e s u l t s o b t a i n e d i n the p a s s i v e avoidance and a p p e t i t i v e t a s k s ; and t h i r d , the e f f e c t of ECS on the c o n s o l i d a t i o n p r o c e s s . ECS G r a d i e n t s and the D u r a t i o n of Memory C o n s o l i d a t i o n The d u r a t i o n of time r e q u i r e d f o r memory c o n s o l i d a t i o n i s u s u a l l y estimated from the l e n g t h of the g r a d i e n t s produced by treatments such as ECS. Because the l e n g t h s of such g r a d i e n t s v a r y somewhat w i t h treatment parameters, i t seems pro b a b l e t h a t c o n s o l i d a t i o n c o n t i n u e s •for at l e a s t as long as the l e n g t h of the l o n g e s t g r a d i e n t which can be o b t a i n e d . However, t h e r e i s another p o s s i b i l i t y , namely t h a t mem-ory c o n s o l i d a t i o n i s maximally d i s t u r b e d by a s i n g l e ECS, and t h a t l o n g e r g r a d i e n t s o b t a i n e d w i t h other treatments r e f l e c t some other process. The view t h a t a s i n g l e ECS maximally d i s r u p t s the c o n s o l i -d a t i o n process o r i g i n a t e d from d u a l process t h e o r i e s of c o n s o l i d a t i o n ( e . g . , Hebb, 1949), i n which ECS was assumed to d i s r u p t p a t t e r n e d n e u r a l f i r i n g . While such t h e o r i e s are s e r i o u s l y questioned by the f i n d i n g of v a r i a b i l i t y i n ECS g r a d i e n t s w i t h ECS parameters, the view t h a t s i n g l e ECS g r a d i e n t s r e f l e c t a maximal d i s t u r b a n c e of con-s o l i d a t i o n has l i n g e r e d on. C o n s o l i d a t i o n i s g e n e r a l l y assumed to 59 be complete w i t h i n a few minutes or a t l o n g e s t a few hours a f t e r t r a i n -i n g , c o r r e s p o n d i n g to the l e n g t h of ECS g r a d i e n t s . The p r e s e n t i n v e s t i g a t i o n attempted to show t h a t g r a d i e n t s c o u l d be produced w i t h a s e r i e s of ECSs which were l o n g e r than s i n g l e ECS g r a d i e n t s but not o t h e r w i s e d i f f e r e n t . Such a f i n d i n g would be i n c o n -s i s t e n t w i t h the p o s i t i o n t h a t s i n g l e ECS g r a d i e n t s r e f l e c t a maximal d i s r u p t i o n of memory c o n s o l i d a t i o n , and would i n s t e a d suggest t h a t memory c o n s o l i d a t i o n c o n t i n u e s f o r a l o n g e r p e r i o d than i s e s t i m a t e d from the l e n g t h of s i n g l e ECS g r a d i e n t s . I n Experiment 1, i n which a p a s s i v e avoidance t r a i n i n g procedure was used, a s e r i e s of f i v e ECSs spaced 1 minute a p a r t produced a gra d -i e n t of 48 ho u r s , s u b s t a n t i a l l y l o n g e r than the g r a d i e n t ( l e s s than 1 hour) produced by a s i n g l e ECS. T h i s g r a d i e n t i s a l s o of g r e a t e r l e n g t h than the l o n g e s t g r a d i e n t (6 hours) which has p r e v i o u s l y been r e p o r t e d w i t h a s i n g l e ECS (Kopp et a l . , 1966). While the g r a d i e n t of 48 hours found i n Experiment 1 i s c o n s i d -e r a b l y l o n g e r than the d u r a t i o n of time that memory c o n s o l i d a t i o n i s g e n e r a l l y assumed to c o n t i n u e f o r , i t i s comparable i n l e n g t h to the g r a d i e n t s found i n two other r e c e n t s t u d i e s . Buresova and Bures (1971) found t h a t KC1 a p p l i e d to the c o r t e x of r a t s f o r a prolonged p e r i o d i m p a i r e d l a t e r performance of a shock-motivated p a t t e r n d i s c r i m i n a t i o n when a d m i n i s t e r e d 24 hours but not 14 days f o l l o w i n g t r a i n i n g . Sim-i l a r l y , C h e r k i n (1969) showed t h a t h i g h c o n c e n t r a t i o n s of f l u r o t h y l i m p a i r e d p a s s i v e avoidance b e h a v i o r i n c h i c k s when presented 24 hours but not 48 hours a f t e r t r a i n i n g . Experiment 2 examined whether the long gradient found with the series of ECSs in Experiment 1 was qu a l i t a t i v e l y different from single ECS gradients. The primary support for a d i s t i n c t i o n between single and multiple ECS gradients comes from studies showing that anticon-vulsant drugs blocked the gradients produced by multiple ECSs (Hunt et a l . , 1953; Hunt & Beckwith, 1955) but not single ECSs (Essman, 1968; McGaugh & Alpern, 1966; Weissman, 1965). In Experiment 2 a series of f i v e ECSs spaced 1 minute apart were s t i l l found to produce a long gradient when presented under ether or sodium pentobarbital anesthesia, both of which blocked overt signs of a convulsion. This finding i s opposite to the results previously reported with multiple ECSs, but similar to those found with single ECSs. Therefore i t is probable that the differences previously found between the effects of ant i -convulsant drugs on single and multiple ECS gradients were due to .different drug levels or ECS parameters i n the different experiments, and not due to a qualitative difference between the gradients pro-duced by single and multiple ECSs. The results of a recent study by McGaugh and Zornetzer (1970) also indicate that the differences reported earlier between single and multiple ECS gradients are probably i n v a l i d . They found that single ECS gradients could be blocked by ether anesthesia i f a low intensity ECS and a high concentration of ether were used, but not i f either a high intensity ECS or low concentration of ether were used. The findings of McGaugh and Zornetzer (1970) together with the results of Experiment 2 suggest that a d i s t i n c t i o n between 61 s i n g l e and m u l t i p l e ECS gradients on the basis of supposed d i f f e r e n t i a l e f f e c t s of anticonvulsant drugs i s i n c o r r e c t . A q u a l i t a t i v e d i s t i n c t i o n between s i n g l e and m u l t i p l e ECS grad-ients i s not supported by the e f f e c t s of anticonvulsant drugs, nor by any other evidence. The longer gradients produced by a series of ECSs l i k e l y r e f l e c t a greater disturbance of the same underlying process which i s disturbed by a s i n g l e ECS. Assuming that ECS gradients r e -f l e c t the disturbance of memory co n s o l i d a t i o n , the conclusion follows from the r e s u l t s of Experiments 1 and 2 that the cons o l i d a t i o n pro-cess f or t h i s passive avoidance response continues for at l e a s t 48 hours. While a series of ECSs produced a long gradient i n the passive avoidance task, i t did not produce a longer gradient than a s i n g l e ECS (of 0.5 or 2.5 seconds duration) i n a one t r i a l a p p e t i t i v e task. A l l three treatments produced only a s l i g h t impairment at 15 seconds, and none at 1 hour. This f i n d i n g has a number of possible i m p l i c a -tions which w i l l be considered i n the next section. Passive Avoidance - Ap p e t i t i v e Task Differences The f i n d i n g that a series of ECSs spaced 1 minute apart pro-duced gradients of quite d i f f e r e n t lengths i n the passive avoidance and a p p e t i t i v e tasks i s not predicted by consolidation theory, but i s from two other positions (Posluns & Vanderwolf, 1970; Spevack & Suboski, 1969) both of which do not view ECS gradients i n passive avoidance tasks as evidence for memory consolidation. Nevertheless, this finding i s not inconsistent with consolidation theory, and can b explained from a consolidation position i n two ways. These four view points w i l l be considered here. Incubation theory, as presented by Spevack and Suboski (1969), holds that ECS gradients i n passive avoidance tasks reflect the halt-ing of an incubation process, not interference with memory consoli-dation. The strength of the learned response is assumed to increase (incubate) following training, and ECS is assumed to halt this incu-bation process. On the other hand, brief ECS gradients (less than 1 minute) which have been found i n appetitive and discriminated a-voidance tasks were assumed to refl e c t a true interference with con-solidation since the learned responses i n these tasks do not appear to incubate. According to their theory, a short gradient would be predicted in the appetitive task since responses i n such tasks pre-' sumably do not incubate. The passive avoidance task might be ex-pected to yield a longer gradient since the learned response might undergo a long incubation period. However, there i s some direct evidence against Spevack and Suboski's incubation hypothesis. Tenen (1966b) found a long grad-ient (3 hours) in a one t r i a l appetitive task. In. addition, Bailey et a l . (1970) and Pinel (1970) found no evidence for incubation i n passive avoidance tasks which yielded long gradients. Incubation theory has one other serious flaw; because ECS is assumed to halt the incubation process the theory is incapable of explaining v a r i -a b i l i t y in ECS gradients with current parameters. Therefore, while 63 incubation theory predicts d i f f e r e n t length gradients i n passive a-voidance and appetitive situations, as presently formulated i t i s inadequate to account for the present findings. Posluns and Vanderwolf (1970) suggested that ECS has two ef-fects : f i r s t , i t impairs i n h i b i t i o n of responding; and second, i f presented within a few seconds of training i t can disrupt memory consolidation. They suggest that ECS produces long gradients i n tasks where response i n h i b i t i o n f a c i l i t a t e s the learned response, such as the passive avoidance, but not i n tasks where response i n -h i b i t i o n i s incompatible with the learned response, such as appeti-tive tasks. However, their theory evades the c r i t i c a l question of how a time-dependent effect (amnesia) combines with the non-time-dependent effect (impairment of response inhibition) to produce a longer gradient. Therefore this theory i s not able to account for the time dependence of the long gradient found here with a series of ECSs. I t should be pointed out the theory of Posluns and Vanderwolf offers an interesting explanation for the f a i l u r e of the series of ECSs to produce a longer gradient than a single ECS i n the appetitive task. They have shown that a series of ECSs produces greater impair-ment of response i n h i b i t i o n than a single ECS (Posluns & Vanderwolf, 1970). If a series of ECSs also produces a greater disturbance of memory consolidation than a single ECS, these two effects could have cancelled one another so that both treatments produced gradients of similar length. From a co n s o l i d a t i o n point of view, the most l i k e l y explanation f o r the d i f f e r e n t length gradients produced by a s e r i e s of ECSs i n the two tasks i s that the c o n s o l i d a t i o n processes require d i f f e r e n t times to reach completion. Several studies have shown that the length of the gradient produced by ECS depends on a number of v a r i a b l e s which do not l i k e l y a f f e c t the neural disturbance produced by ECS, but which may exert t h e i r e f f e c t through "speeding up" the consolidation process. These v a r i a b l e s include p r i o r experience with the t r a i n i n g apparatus ( M i l l e r , 1970), the l e v e l of footshock used (Ray & Bivens, 1968), and the nature of the t r a i n i n g procedure (Chorover & S c h i l l e r , 1966). Some c h a r a c t e r i s t i c s of the a p p e t i t i v e t r a i n i n g used here may have been more conducive to rapid c o n s o l i d a t i o n than the c h a r a c t e r i s t i c s of the passive avoidance t r a i n i n g procedure. There i s a second explanation for the passive avoidance-appetitive ' difference which i s also consistent with c o n s o l i d a t i o n theory. Rather than r e f l e c t i n g differences i n the duration of the two consolidation processes, the d i f f e r e n t length gradients might r e f l e c t differences i n the s u s c e p t i b i l i t y of the two consolidation processes to d i s r u p t i o n . A series of ECSs might produce a more pronounced disturbance of the consolidating passive avoidance memory than of the consolidating appet-i t i v e memory, even though the two processes might require s i m i l a r times to reach completion. This could happen for example i f the two memories were being stored i n d i f f e r e n t areas of the b r a i n , which were d i f f e n -t i a l l y . affected by ECS. There i s evidence that limbic structures may be involved i n the consolidation of passive avoidance responses (Barcik, 1969; Kesner & Doty, 1968) and limbic areas are known to be highly susceptible to seizures. Unfortunately the brain structures involved i n the storage of appetitive responses have not as yet been investigated. The f a i l u r e of the series of ECSs spaced 1 minute apart to pro-duce a longer gradient than a single ECS i n the one t r i a l appetitive task suggests that the process being disturbed i n this task differs from that responsible for the long gradient i n the passive avoidance task. While the nature of the differences between these processes i s s t i l l unclear, i t should be emphasized that this finding does not im-ply that ECS gradients i n the passive avoidance task do not reflect memory consolidation. On the contrary, the explanation for the grad-ient i n the passive avoidance task which i s consistent with the larg-est amount of data i s that of a disruption of memory consolidation. The different findings obtained with a series of ECSs i n the passive avoidance and appetitive tasks may indicate either that the consoli-dation processes i n the two tasks require different times to reach completion or that somewhat different changes are involved i n consol-idation of the two memories. The gradient of 48 hours found i n Experiment 1 does not appear to be qualitatively different from shorter gradients produced by a single ECS, nor does i t appear to be due to some process other than a disturbance of memory consolidation. Instead, this long gradient seems to be best explained by the assumption that memory consolidation continues for at least 48 hours after training i n this passive avoidance task. Although 48 hours i s considerably longer than consol-i d a t i o n has been generally assumed to continue f o r , i t appears neces-sary to conclude that the conso l i d a t i o n process may i n some cases con-tinue for at l e a s t t h i s length of time. However, i t i s s t i l l necessary to explain why even though co n s o l i d a t i o n continues for t h i s long, a s i n g l e ECS may s t i l l produce only a b r i e f gradient. In order to c l a r -i f y the mechanism responsible for v a r i a t i o n s i n ECS gradients with ECS parameters, the next section examines the nature of the e f f e c t of ECS on the consolidation process. The E f f e c t of ECS on the Consolidation Process The e a r l y view of memory conso l i d a t i o n was a process by which information was transformed from a l a b i l e memory trace to a stable permanent memory (for example, Hebb, 1949). The i n i t i a l l a b i l e trace was assumed to involve patterned neural f i r i n g , the continuation of which was necessary for the permanent memory to be established. Con-sequently, ECS was assumed to stop the consolidation process, since by d i s r u p t i n g the patterned f i r i n g further memory was prevented from entering the stable state. Accordingly, the amount of memory a v a i l -able to the animal at the time of testing corresponded to the amount which had entered the permanent state at the time ECS was administered. However, the early dual trace theory of consolidation cannot adequately e x p l a i n why, for example, the d i f f e r e n t i n t e n s i t i e s of ECS produce d i f f e r e n t length gradients. C l e a r l y both i n t e n s i t i e s cannot be viewed as stopping the consolidation process. An a l t e r n a t i v e formulation of the e f f e c t of ECS on the consolidation process i s re-quired to account for t h i s v a r i a b i l i t y i n the ECS gradient with ECS parameters. A second f i n d i n g which i s also d i f f i c u l t to r e c o n c i l e with the early dual process model i s that the gradients produced by ECS are occasionally only temporary and i f the time of t e s t i n g i s delayed the d e f i c i t disappears (e.g., Pagano et a l . , 1969). I f ECS had stopped the consolidation process through d i s t u r b i n g patterned f i r i n g , the strength of the permanent memory should have remained constant over time. Therefore t h i s f i n d i n g also necessitates the formulation of an a l t e r n a t i v e view of the e f f e c t of ECS on the consolidation process. Two approaches to t h i s problem w i l l be considered here. One approach which has been taken to account f o r these two findings i s to postulate that the memory trace continues to change ' over a long period and that ECS produces a disturbance which i n t e r -feres with r e c a l l of the memory (Deutsch, 1971; Weiskrantz, 1966). Weiskrantz (1966) assumes that memory increases over a prolonged period of time, i n the sense of achieving a greater s i g n a l to noise r a t i o ( t h i s time-dependent change i n the memory might be termed con-s o l i d a t i o n although Weiskrantz does not r e f e r to i t as such). He suggests that ECS does not disrupt t h i s process (except when admin-is t e r e d w i t h i n a few seconds of t r a i n i n g ) , but rather adds more noise to the system. This noise impairs the r e c a l l of recent memories but not older memories which have a greater s i g n a l to noise r a t i o . Weiskrantz's model can explain the d i f f e r e n t gradients produced by different intensities of ECS through assuming that the high intensity ECS produces more noise. His model also predicts that ECS gradients would only be temporary, since the signal to noise ratio continues to increase even after ECS is administered, so that when the signal be-comes su f f i c i e n t l y strong, retention appears. There i s one major inadequacy of Weiskrantz's model. I t implies that the c r i t i c a l variable determining whether ECS w i l l impair per-formance is the time between training and testing, and not the time between training and ECS. This follows because the two processes, noise produced by ECS and increasing strength of the memory signal, are assumed to be independent. In other words, ECS i s not assumed to directly affect the consolidation process at the time of administra-tion; rather this process continues at i t s normal rate after ECS. Since the strength of the memory signal i s assumed to only depend on the time between training and testing, and since the noise produced by ECS is independent of the time of ECS administration, presenting ECS between training and testing should have the same effect regard-less of how long after training It is administered, so long as the time between training and testing i s held constant. However, con-trary to this prediction, the time between training and ECS has been found to be much more important than the time between training and testing; i n fact, most experiments demonstrating ECS gradients keep the training-testing interval roughly constant. For example, in Ex-periment 1 the series of ECSs impaired performance when administered at 1 or 24 hours but not 9 days after training even when the training-69 testing interval was held constant at 11 days. Deutsch (1971) has proposed a similar model to Weiskrantz's although i t i s not simply intended to explain ECS gradients, but rather i s also concerned with the nature of memory storage. Deutsch assumes that memory is stored i n the form of decreased synaptic re-sistance i n some cholinergic synaptic pathways. He assumes the re-sistance continues to decrease for a number of days after training (again, this time-dependent change i n the memory i s not sp e c i f i c a l l y referred to as consolidation by Deutsch). As evidence for this change in resistance, he has shown that anticholinesterase drugs impair per-formance of several tasks when administered 5 or more days after train-ing, but not when administered 1 or 3 days after training. Deutsch assumes that since the anticholinesterase drugs decrease the rate of breakdown of acetylcholine they w i l l f a c i l i t a t e synaptic transmission. ' Since synaptic resistance i s assumed to be high 1 or 3 days after training, the synaptic f a c i l i t a t i o n w i l l f a c i l i t a t e (or at least not impair) r e c a l l . However, at 5 or more days after training, synaptic resistance is lower, and the synaptic f a c i l i t a t i o n produced by the drug w i l l produce too great a f a c i l i t a t i o n of synaptic transmission resulting i n a blockage of r e c a l l . As additional support for his theory Deutsch has shown that anticholinergic drugs which impair syn-aptic transmission through blocking the effect of acetylcholine pro-duce the opposite effects of anticholinesterase drugs, namely an im-pairment of performance when administered at 1 or 3 days and no effect when administered at 5 or more days. In Deutsch's experiments the drugs are assumed to produce a temporary impairment of r e c a l l , and the treatment-testing interval i s kept constant at 24 hours, a time when acetylcholine or cholinesterase ac t i v i t y is presumably s t i l l being affected by the injected substance. While Deutsch's data support the notion that memory continues to change over a period of days following training, and also suggest that a change i n cholinergic synapses is involved i n the memory, his model does not directly bear on the interpretation of gradients produced by other treatments such ECS. If an attempt i s made to extend Deutsch's model to other gradients, i t w i l l f a i l to adequately explain the find-ings, because Deutsch's model, l i k e Weiskrantz's, involves two inde-pendent processes; the drug is not assumed to affect the change i n synaptic resistance at the time of administration. The second approach which has been taken to explain findings such as temporary gradients as well as v a r i a b i l i t y i n the ECS gradient with ECS parameters is to assume that ECS directly affects the consol-idation process at the time of administration, and that the effect of ECS i s not necessarily to stop consolidation, but simply to slow i t s rate. While several versions of this slowing hypothesis have been presented (Albert, 1966; Cherkin, 1969; McGaugh & Dawson, 1971) a l l basically assume that consolidation may continue after ECS and that the degree to which consolidation continues depends on the ECS para-meters. The slowing hypothesis can be seen most clearly by contrast-ing i t with the early view that ECS stopped consolidation. When ECS is assumed to stop consolidation, the amount of memory present at 71 t e s t i n g would j u s t correspond to the amount already consolidated when ECS was administered. According to the slowing hypothesis, some mem-ory would also be consolidated a f t e r ECS administration. Therefore, at t e s t i n g the animal would have a v a i l a b l e the amount of memory con-solid a t e d before ECS as w e l l as the amount of memory consolidated a f t e r ECS. A slowing hypothesis can explain temporary gradients since i n some cases s u f f i c i e n t consolidation may continue following ECS to produce increased retention when tested at longer times a f t e r t r a i n i n g than when tested soon a f t e r t r a i n i n g . I t can also explain the v a r i -a b i l i t y i n the length of ECS gradients with ECS parameters since a weaker ECS treatment might only s l i g h t l y retard consolidation so that a s u b s t a n t i a l amount of memory would be consolidated a f t e r ECS. A stronger ECS treatment on the other hand would slow consolidation to ' a greater degree, so that l i t t l e memory would be consolidated a f t e r 'ECS and consequently, retention would be poorer. Mah, A l b e r t , and Jamieson (1972) have recently provided support for a slowing hypothesis. They found that a s i n g l e ECS given 5 min-utes a f t e r passive avoidance t r a i n i n g produced only a s l i g h t impair-ment. However, when a second ECS was presented at 1 or 2 but not: 3 hours a f t e r a f i r s t ECS at 5 minutes an a d d i t i o n a l d e f i c i t was ob-served. The time-dependent effect of the second ECS appears to r e f l e c t a disturbance of con s o l i d a t i o n , i n d i c a t i n g that consolidation was con-tinuing following the f i r s t ECS. The slowing hypothesis does not suffer from the problem of models 72 such as Weiskrantz's (1966), since the effect of ECS is assumed to be directly on the consolidation process. Because ECS i s assumed to af-fect consolidation at the time of administration, the training-ECS interval should be a more important determinant of the effect of ECS than the training-testing interval, a prediction consistent with most available evidence. One slight, d i f f i c u l t y with the slowing hypothesis is that some authors (e.g., McGaugh & Dawson, 1971) interpret i t as predicting that consolidation would eventually reach completion i n a l l groups regardless of the training-ECS interval. While this prediction does not necessarily follow (for example, i f slowed su f f i c i e n t l y no further consolidation might take place), several modifications of the slowing hypothesis can eliminate this interpretation. For example, McGaugh and Dawson (1971) postulate that ECS affects a short term memory stage, and the amount of short term memory determines the level that long term memory eventually reaches. Another modification which eliminates this interpretation would be to assume that ECS blocked some of the memory outright, and that only part of i t continued to consolidate. Nevertheless, some form of a slowing hypothesis appears to be the best explanation for the effects of ECS on the consolidation process. Clearly, a revised view of the consolidation process is required. Rather than simply involving the formation of a permanent memory from neural f i r i n g patterns, consolidation must involve a gradual change in the stored representation of the memory which may continue for at least several days after training. Instead of being stopped by ECS, this process may be slowed to varying degrees by d i f f e r e n t ECS treatments. However, two major questions are s t i l l unanswered. F i r s t , does con-s o l i d a t i o n i n at l e a s t some cases continue i n d e f i n i t e l y , so that the memory never reaches a permanent state? Second, i s cons o l i d a t i o n i n some cases completed more quickly (within a few minutes or hours) than i n other cases, as i s suggested by the r e s u l t s of Experiment 3? Fur-ther research should provide answers to these questions as w e l l as the more basic question of the nature of the mechanism which underly the storage of information i n the b r a i n . 74 CONCLUSIONS A series of five ECSs produced greater impairment of a learned passive avoidance response when spaced 1 minute apart than when spaced 5 seconds apart or when presented i n one continuous burst. In a l l three cases the impairment was time-dependent; the length of the grad-ient varying from less than 1 hour (single ECS) to between 2 and 9 days (five ECSs spaced 1 minute apart). The impairment produced by the five ECSs spaced 1 minute apart was permanent over 11 days, and was not attenuated when the ECSs were presented while the animals were anesthetized with ether or sodium pentobarbital, both of which blocked the convulsion normally produced by ECS. This long gradient does not appear to be qualitatively different from those found with a single ECS, and because of i t s greater length, probably reflects a greater disturbance of the same process response for single ECS gradients. The most l i k e l y explanation for this process i s a time-dependent change i n the memory (consolidation). Therefore, in this passive a-voidance task the memory consolidation process appears to continue for at least several days. In a one t r i a l appetitive task, the five ECSs spaced 1 minute apart did not produce a longer gradient than a single ECS. 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Amnesia and b r a i n seizure a c t i v i t y i n mice: e f f e c t s of d i e t h y l ether anesthesia p r i o r to e l e c t r o -shock sti m u l a t i o n . Communications i n Behavioral Biology, 1970, 5, 243-248. M i l l e r , A. J. Va r i a t i o n s i n retrograde amnesia with parameters of electroconvulsive shock and time of t e s t i n g . Journal of Com-parative and P h y s i o l o g i c a l Psychology, 1968, _66, 40-47. M i l l e r , R. R. E f f e c t s of environmental complexity on amnesia induced by electroconvulsive shock i n r a t s . Journal of Comparative and P h y s i o l o g i c a l Psychology, 1970, 7JL, 267-275. Minz, B., & Domino, E. F. Eff e c t s of epinephrine and norepinephrine on e l e c t r i c a l l y induced seizures. Journal of Pharmacology and Experimental Therapeutics, 1953, 107, 204-218. Misanin, J. R., M i l l e r , R. R., & Lewis, D. J . Retrograde amnesia produced by electroconvulsive shock a f t e r r e a c t i v a t i o n of a consolidated memory trace. Science, 1968, 160, 554-555. Muller , G. E., & P i l z e c k e r , A. Experimentelle beitrage zur lehre von gedachtnis. Z. Psychologie, 1900, Suppl. No. 1. Cited by Glickman, S. E. Perseverative neural processes and consol-i d a t i o n of the memory trace. Psychological B u l l e t i n , 1961, 58, 218-233. "Nielson, H. C. Evidence that electroconvulsive shock a l t e r s memory r e t r i e v a l rather than memory consolidation. Experimental Neurology, 1968, 20, 3-30. Pagano, R. R. , Bush, D. F. , Martin, C , & Hunt, E. B. Duration of retrograde amnesia as a function of electroconvulsive shock i n t e n s i t y . Physiology and Behavior, 1969, 4-, 19-21. Paolino, R. M., Quartermain, D., & Levy, H. M. Ef f e c t s of e l e c t r o -convulsive shock duration on the gradient of retrograde amnesia. Physiology and Behavior, 1969, 147-149. Paolino, R. M., Quartermain, D., & M i l l e r , N. E. Dif f e r e n t temporal gradients of retrograde amnesia produced by carbon dioxide anesthesia and electroconvulsive shock. Journal of Comparative and P h y s i o l o g i c a l Psychology, 1969, 69., 141-149. Pearlman, C. A. J r . , Sharpless, S. K., & J a r v i k , M. E. Retrograde amnesia produced by anestheic and convulsant agents. Journal of Comparative and P h y s i o l o g i c a l Psychology, 1961, _54, 109-112. 81 Pfingst, B. E., & King, R. A. Effects of posttraining electro-convulsive shock on retention-test performance involving choice. Journal of Comparative and Physiological Psychology, 1969, 68, 645-649. Pinel, J. P. J. A short gradient of ECS-produced amnesia i n a one-t r i a l appetitive learning situation. Journal of Comparative and Physiological Psychology, 1969, .68, 650-655. Pinel, J. P. J. Two types of ECS-produced disruption of one-trial training i n the rat. 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Proceedings of the Society for Experimental Biology and Medicine, 1941, 48, 596- 597. 84 APPENDICES Appendix Page A A d d i t i o n a l S t a t i s t i c a l Analyses on Data from Experiment 1 85 B A d d i t i o n a l S t a t i s t i c a l Analyses on Data from Experiment 2 88 C E l e c t r i c a l Recordings Under Ether and Sodium Pentobarbital Anesthesia 90 85 APPENDIX A A d d i t i o n a l S t a t i s t i c a l A n a l y s e s on Data From Experiment 1 1. Data f o r e x p e r i m e n t a l groups Type of ECS Time of ECS N Median Range 5 ECSs spaced immed. 8 2.2 1 .6 - 3. 0 1 minute a p a r t 1 h r . 7 21.3 2 .3 - 23. 6 24 h r s . 7 28.3 4 .0 - 60. 0 48 h r s . 11 36.0 9 .0 - 60. 0 9 days 8 59.3 31 .6 - 60. 0 5 ECSs spaced immed. 5 2.3 2 .0 - 2. 6 5 sec. a p a r t 1 h r . 7 39.6 19 .0 - 60. 0 24 h r s . 8 60.0 33 .6 - 60. 0 1 ECS, 2.5 sec. immed. 5 3.3 2 .3 - 3. 6 d u r a t i o n 1 h r . 7 51.3 2 .0 - 60. 0 24 h r s . 6 57.8 31 .6 - 60. 0 9 days 7 60.0 42 .3 - 60. 0 Appendix A (continued). 2. Comparison between ECS delays for each ECS condition. A l l analyses are done with Halperin's (1960) extension of the Mann-Whitney t e s t . P r o b a b i l i t i e s are one-tailed since the longer ECS delays were not expected to produce greater im-pairments than the shorter delays. 5 ECSs 1 minute apart Immed. 1 hr. 24 hrs, 1 hr. .01 24 hrs. .001 n. s. 48 hrs. .001 .05 n. s. 9 days .001 .001 .02 5 ECSs 5 seconds apart Immed. 1 hr. 1 hr. .001 24 hrs. .001 .02 1 ECS, 2. 5 seconds duration Immed. 1 hr. 24 hrs 1 hr. .001 24 hrs. .001 n. s. 9 days .001 n. s. n.s. 87 Appendix A (continued). 3. Comparisons between ECS treatments for each ECS delay. A l l analyses are done with Halperin's (1960) extension of the Mann-Whitney t e s t . P r o b a b i l i t i e s are one-tailed since the greater spacings were expected to produce greater impairments. Immediate ECS 1 ECS, 2.5 sec. duration 5 ECSs 5 sec. apart 5 ECSs 5 sec. apart .01 5 ECSs 1 min. apart .02 n.s. 1 hour ECS 1 ECS, 2.5 sec. duration 5 ECSs 5 sec. apart 5 ECSs 5 sec. apart .025 5 ECSs 1 min. apart .001 .02 24 hour ECS 1 ECS, 2.5 sec. duration 5 ECSs 5 sec. apart 5 ECSs 5 sec. apart n.s. 5 ECSs 1 min. apatt .03 .01 9 day ECS 1 ECS, 2.5 sec. duration 5 ECSs 1 min. apart n.s. APPENDIX B A d d i t i o n a l S t a t i s t i c a l Analyses on Data from Experiment 2 Data for groups re c e i v i n g 5 ECSs spaced 1 Drug Time of ECS N Median Ether 1 hr. 6 11.5 24 hrs. 10 21.6 9 days 10 60.0 Sodium 1 hr. 7 3.3 Pentobarbital 24 hrs. 9 11.3 9 days 6 54.8 Range 1.6 - 60,0 5.3 - 60.0 42.6 - 60.0 2.0 - 15.6 1.6 - 60.0 25.6 - 60.0 Appendix B (continued). 2. Comparisons between ECS delays for each drug condition. A l l analyses are done with Halperin's (1960) extension of the Mann-Whitney t e s t . P r o b a b i l i t i e s are one-tailed since the longer ECS delays were not expected to produce greater im-pairments than the shorter delays. 5 ECSs 1 minute apart under ether 1 hour 24 hours 24 hours n.s. 9 days .01 .01 5 ECSs 1 minute apart under sodium pentobarbital 1 hour 24 hours 24 hours n.s. 9 days .001 .05 90 APPENDIX C E l e c t r i c a l Recordings Under Ether and Sodium Pentobarbital Anesthesia The recordings presented here were obtained i n a preliminary i n v e s t i g a t i o n ; these animals did not undergo t r a i n i n g . Levels of anesthesia are the same as those used i n Experiment 2. The recordings were taken from a b i p o l a r electrode c o n s i s t i n g of twisted s t a i n l e s s s t e e l wires, insulated except for 0.5 mm from the t i p , w i t h a 1.0 mm t i p separation. The electrode was aimed at the cortex 2.0 mm ant e r i o r to bregma, 2.0 mm l a t e r a l to the s a g g i t a l suture and 1.0 mm below the dur a l surface, and was implanted along with ECS screw electrodes i d e n t i c a l to those used i n Experiments 1, 2, and 3. A l l the recordings presented here are from animals i n which the electrodes were confirmed h i s t o l o g i c a l l y , to be i n the cortex. Recordings were taken about a week a f t e r surgery. Seizure d i s -charge was recorded on an EEG channel of a Grass Model 7 polygraph. During passage of the ECS current, the polygraph leads were shorted to ground, and immediately a f t e r current o f f s e t were switched back to the animal. Two to three seconds were l o s t to "blocking". Recordings were taken with a time constant of 0.3, chart speed of 2.5 mm per second, and s e n s i t i v i t y of 150 microvolts per cm. In both Figure 1 and Figure 2 the recordings from 10 d i f f e r e n t 91 Appendix C (continued). animals are presented. The f i r s t segment s t a r t s with the onset of the current while the animal i s unanesthetized. The f i r s t few seconds of the records contain stimulus a r t i f a c t s i n d i c a t i n g ECS onset and o f f -set (the f i r s t two spikes) and the switching of the recording leads back to the animal from ground ( t h i r d spike). The second segment i s a recording taken 3 minutes a f t e r the ECS. The t h i r d segment s t a r t s with onset of an ECS given the fo l l o w i n g day while the animal was anesthetized with sodium pentobarbital (Figure 1) or ether (Figure 2). Again the three stimulus a r t i f a c t s can be seen at the beginning of each record. The l a s t segment i s taken s h o r t l y (usually 10-30 seconds) before ECS, i . e . , while the animal i s anesthetized. The unanesthetized (normal) seizure discharge was t y p i c a l l y of high amplitude (300-500 microvolts) and lasted between 15 and 18 seconds. The frequency was highly v a r i a b l e between animals, although i t t y p i c a l l y slowed toward the end of the seizure to 2 or 3 per se-cond. In some cases a few high amplitude spikes appeared a f t e r the seizure discharge had ended (animals 1, 2, 6, 7, 15). These may have been movement a r t i f a c t s . In some records, the post seizure depression i s masked by r e s p i r a t i o n a r t i f a c t (1, 2, 3, 5, 10, 11, 12, 13, 15, 16, 19, 20). The seizure discharge under sodium pentobarbital anesthesia was greatly attenuated or absent. In no case did the seizure discharge continue for longer than 12 seconds, nor was the amplitude higher than 75 microvolts (the large spike i n record 8 was probably an a r t i f a c t ) . Appendix C (continued). The post ECS depression i s very marked (the lowered i n t e n s i t y of res-p i r a t i o n caused by the anesthesia decreases the magnitude of a r t i f a c t ) , The depression i s not an e f f e c t of the anesthesia i t s e l f since the pre ECS record ( l a s t column Figure 1) t y p i c a l l y shows high amplitude a c t i -v i t y . I t seems clear that the concentration of sodium pentobarbital used here greatly attenuates seizure discharge, although the period of post seizure depression i s s t i l l present. The recordings under ether anesthesia (Figure 2) are not as consistent. Two animals (11, 16) showed almost no seizure discharge; two animals (12, 19) showed attenuated seizure discharge, and the other s i x seemed to show a b r i e f e r period of high frequency a c t i v i t y than normal, followed by a long series of low frequency spikes (usually about 1 1/2 per s e c ) . This period of low frequency s p i k i n g i s not seen i n any of the unanesthetized recordings (although 3 approximates i t ) , and i n some cases (11, 14, 15) continues for longer than unan-esthetized seizure discharge. Two conclusions can be drawn about the e f f e c t of ether anesthesia on seizure discharge: f i r s t , i n most cases the seizure discharge i s not blocked, and second, the pattern of seizure discharge under ether anesthesia i s d i f f e r e n t from the unan-esthetized pattern. Figure 1. Seizure Discharge for 10 Rats Receiving ECS While Unanesthetized and Later Under Sodium Pentobarbital Anesthesia. Figure 2. Seizure Discharge for 10 Rats Receiving ECS While Unanesthetized and Later Under Ether Anesthesia. 

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