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Memory storage : evidence that consolidation continues following electroconvulsive shock Mah, Chun Jew 1972

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MEMORY STORAGE: EVIDENCE THAT CONSOLIDATION CONTINUES FOLLOWING ELECTROCONVULSIVE SHOCK b y CHUN JEW MAH B.A., University of British Columbia, 1970 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS in the Department of Psychology We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA APRIL, 1972 I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and. s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by t h e Head o f my Depar tment o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Depar tment The U n i v e r s i t y o f B r i t i s h C o l u m b i a V a n c o u v e r 8 , Canada ABSTRACT Recent experimental evidence indicates that the effectiveness of posttraining electroconvulsive shock in disturbing retention i s not constant but highly variable. One factor which appears to contribute to this variation is the strength of the electroshock current. Currents of higher intensity or of longer duration have generally been found to be more effective in disturbing retention. Indirectly, this evidence suggests that an electroshock treatment does not invariably stop memory consolidation. It appears that following a weak electroshock treatment, the interference with consolidation is not complete and that consolidation may continue afterwards. This pos s i b i l i t y was directly examined in the present experiment with a one-trial passive avoidance task. The results showed that rats given one electroconvulsive shock 5 min after the passive avoidance training suffered only a slight loss of retention. However, when a second electroconvulsive shock was given at 1 hr after training, there was a significantly greater retention loss than that following one electroconvulsive shock at 5 min or at 1 hr. Additional results indicate \ that the disruptiveness of the second electroconvulsive shock i s time-dependent and that the retention de f i c i t does not appear to be due to punishing or disinhibitory effects of the electroconvulsive shocks. These findings are interpreted as indicating that memory consolidation can continue after electroconvulsive shock. TABLE OF CONTENTS A b s t r a c t . . . T a b l e o f C o n t e n t s L i s t o f F i g u r e s Acknowledgment . I n t r o d u c t i o n Method S u b j e c t s S u r g i c a l P r o c e d u r e s A p p a r a t u s E x p e r i m e n t a l P r o c e d u r e s S t a t i s t i c s R e s u l t s D i s c u s s i o n . . . C o n c l u s i o n R e f e r e n c e s . . . . i i i L I S T OF FIGURES Page F i g u r e 1. Median a p p r o a c h l a t e n c i e s f o r each e x p e r i m e n t a l group on t h e r e t e n t i o n t e s t 18 F i g u r e 2. The e f f e c t o f an ECS a t 5 ir.in f o l l o w i n g f o o t s h o c k on t h e l e n g t h o f t i m e a f t e r w a r d when a s e c o n d ECS can be g i v e n and i m p a i r r e t e n t i o n I 21 i v ACKNOWLEDGMENT The author would like to express his gratitude to Dr. D.J. Albert whose supervision, financial support and inspiration made this research project a very enriching and f u l f i l l i n g experience. The author i s also very pleased to be indebted to Dr. Roderick Wong for many helpful discussions and for his c r i t i c a l commentary on the writing of the thesis. C o n s o l i d a t i o n t h e o r y , w h i c h p o s t u l a t e s t h a t memory i s s u s c e p t i b l e t o d i s r u p t i o n s h o r t l y b u t n o t l o n g a f t e r l e a r n i n g , has g e n e r a l l y been th e most s u c c e s s f u l way o f a c c o u n t i n g f o r t h e d i s t u r b a n c e s o f r e t e n t i o n f o und when e l e c t r o c o n v u l s i v e s h o c k (ECS) i s g i v e n a f t e r t r a i n i n g . The r e c e n t a c c u m u l a t i o n o f e v i d e n c e t h a t t h e e f f e c t i v e n e s s o f ECS (and o t h e r amnesic a g e n t s as w e l l ) i n d i s r u p t i n g r e t e n t i o n i s n o t c o n s t a n t b u t h i g h l y v a r i a b l e ( C h o r o v e r and S c h i l l e r , 1965; O u a r t e r m a i n , P a o l i n o , and M i l l e r , 1965; Carew, 1970; Kopp, Bohdanecky, and J a r v i k , 1966; McGaugh, 1966; R o b u s t e l l i , G e l l e r , and J a r v i k , 1969) s u g g e s t s t h a t t h e t i m e -dependent p r o c e s s e s i n v o l v e d i n c o n s o l i d a t i o n may be i n ' f l u e n c e d by many v a r i a b l e s . T h i s e v i d e n c e has p r o v i d e d f r u i t f u l g round f o r a f u r t h e r e l a b o r a t i o n o f c o n s o l i d a t i o n t h e o r y t o a c c o u n t f o r t h i s v a r i a b i l i t y and has a l s o l e d t o t h e development o f a l t e r n a t i v e s t o t h e c o n s o l i d a t i o n h y p o t h e s i s as a b a s i s f o r e x p l a n a t i o n . A r e v i e w o f t h e e x p e r i m e n t a l l i t e r a t u r e i n d i c a t e s t h r e e s o u r c e s o f e v i d e n c e w h i c h appear t o p r o v i d e t h e b e s t e x p l a n a t i o n s f o r t h e appa-r e n t v a r i a t i o n i n t h e l e n g t h o f E C S - i n d u c e d amnesia g r a d i e n t s . The f i r s t o f t h e s e s u g g e s t s t h a t t h e v a r i a t i o n i s due t o d i f f e r e n c e s t o w h i c h c o n s o l i d a t i o n i s d i s t u r b e d and t o w h i c h a n o t h e r p r o c e s s , " i n c u b a t i o n " o f a c o n d i t i o n e d e m o t i o n a l r e s p o n s e ( C E R ) , i s i n t e r r u p t e d . The second h y p o t h e s i s s u g g e s t s t h a t t h e v a r i a t i o n i s r e a l l y due t o changes i n t h e s u s c e p t i b i l i t y o f t h e c o n s o l i d a t i o n p r o c e s s t o d i s r u p t i o n as a c o n s e -quence of v a r i a t i o n s i n what i s l e a r n e d and how i t i s l e a r n e d . The t h i r d h y p o t h e s i s s u g g e s t s t h a t t h e v a r i a t i o n i n amnesia g r a d i e n t s i s due s u b s t a n t i a l l y t o v a r i a t i o n s i n the s e v e r i t y o f t h e amnesic a g e n t . The e v i d e n c e f o r each o f t h e s e e x p l a n a t i o n s w i l l now be p r e s e n t e d and e v a l u a t e d . 2 The Incubation Hypothesis The f i r s t hypothesis is an alternative to a simple consolidation theory in that i t postulates that two time-dependent processes rather than only one are interfered with by a disturbance of brain activity which occurs following acquisition (Spevack and Suboski, 1969). One of these i s the well-known consolidation process but this i s considered to be very brief (less than 1 minute). The other and longer process is incubation which can take several hours (Pinel and Cooper, 1966a). Descriptively, incubation is the gradual increase in the strength of a conditioned emotional response that takes place over time following the training t r i a l s . The variation in the length of ECS-induced amnesia gradients, according to this hypothesis, i s due to differences in the extent to which response incubation is involved in the tasks studied. If no incubation is involved, the amnesia gradient w i l l reflect only the short-duration consolidation process, while i f incubation i s present, the amnesia gradient w i l l be much longer since the longer time-course incubation process w i l l be interfered with. This point of view is known as the incubation hypothesis and i s derived mainly from the following evidence. In certain instances of passive avoidance learning (Pinel and Cooper, 1966a) , there appears to be a period following training when a newly acquired passive avoid-ance response appears to spontaneously increase in strength (the incubation effect). When this gradient of incubation is compared to the gradient obtained by giving ECS at various times following passive avoidance training, the incubation and ECS-induced amnesia gradients are found to be practically identical. On the basis of these results, 3 P i n e l and Cooper (1966b) and P i n e l (1968)have s u g g e s t e d t h a t i n e x p e r i m e n t s where ECS i s g i v e n a f t e r t r a i n i n g as t h e i n t e r r u p t i n g a g e n t , the p e r f o r m a n c e d e f i c i t o b s e r v e d upon r e t e s t i n g c o u l d be due t o t h e i n t e r f e r e n c e w i t h i n c u b a t i o n r a t h e r t h a n to an i m p a i r m e n t of memory. The p o s s i b i l i t y t h a t the E C S - i n d u c e d p e r f o r m a n c e d e f i c i t i n t h e p a s s i v e a v o i d a n c e t a s k i s due t o a d i s t u r b a n c e of i n c u b a t i o n was s u b s e q u e n t l y s t r o n g l y s u p p o r t e d by C h o r o v e r and S c h i l l e r ' s (1966) f i n d i n g . t h a t i f the development of a c o n d i t i o n e d e m o t i o n a l r e s p o n s e w h i c h o c c u r s d u r i n g p a s s i v e a v o i d a n c e l e a r n i n g i s p r e v e n t e d , a l a r g e p a r t o f t h e d i s r u p t i v e e f f e c t of ECS upon r e t e s t p e r f o r m a n c e i s e l i m i n a t e d . More r e c e n t l y , Spevack and S u b o s k i (1969) have p o i n t e d o u t t h a t i n i n s t a n c e s o f a p p e t i t i v e o r d i s c r i m i n a t i o n l e a r n i n g where l i t t l e o r no i n c u b a t i o n o c c u r s , ECS g r a d i e n t s a r e i n v a r i a b l y s h o r t . The f o r e g o i n g summary i n d i c a t e s t h a t the i n c u b a t i o n h y p o t h e s i s c a n a s s i m i l a t e i n t o i t s framework a s u b s t a n t i a l p a r t o f the e v i d e n c e on t i m e -dependent d i s t u r b a n c e s of memory ca u s e d by ECS. However, t h e r e i s a l s o a c o n s i d e r a b l e volume of e q u a l l y r e l i a b l e e v i d e n c e i n the c o n s o l i d a t i o n l i t e r a t u r e w h i c h i s c o m p l e t e l y i n c o n s i s t e n t w i t h the i n c u b a t i o n h y p o t h e s i s . T h i s c o n f l i c t i n g e v i d e n c e c o n c e r n s t h e v e r y h e a r t of the h y p o t h e s i s , t h e p r o p o s i t i o n t h a t any l o n g amnesia g r a d i e n t s o b t a i n e d w i t h ECS a r e due t o the i n t e r f e r e n c e w i t h i n c u b a t i o n and n o t c o n s o l i d a t i o n . F o r example, G h e r k i n (1970) found t h a t r e s p o n s e i n c u b a t i o n does n o t o c c u r i n h i s a v o i d a n c e t a s k and y e t l o n g g r a d i e n t s o f amnesia can s t i l l be f o u n d . S i m i l a r l y , McGaugh (1966) r e p o r t e d r e s u l t s i n d i c a t i n g an amnesia g r a d i e n t w h i c h i s l o n g e r t h a n the i n c u b a t i o n g r a d i e n t f o r h i s t a s k . I n a r e c e n t e x p e r i m e n t w i t h d i s c r i m i n a t e d a v o i d a n c e l e a r n i n g , B a r r e t t , Hughes, and 4 Ray (1971) also found a long amnesia gradient that did not paral l e l the incubation curve. Tenen (1965a, b) using a one-trial appetitive task with no punishing experience to induce CER incubation reported a long amnesia gradient of 3 hours. These results on ECS-induced retention deficits with long time gradients cannot be accounted for by an incubation interpretation. Thus, although the incubation hy-pothesis has been useful in emphasizing the possibility that confounding variables ( i . e . , incubation) may be involved in the amnesia gradients : obtained with ECS in some tasks, in general, the variation in the length of the amnesia gradients found with ECS does not seem a t t r i -butable to the presence or absence of an incubation process. Task Variation and Amnesia Gradients The second way of accounting for the variation in ECS-induced amnesia gradients is not a formally elaborated hypothesis but a col-lection of evidence suggesting that the variation in amnesia gradients is systematically related to certain task and treatment variables. This evidence suggests that differences in the complexity of different tasks and in the strength of the reinforcer used during training are related to the length of the amnesia gradient. We w i l l f i r s t examine this evidence and then suggest how i t can be incorporated into con-solidation theory. With respect to task complexity, the following evidence has been reported. Chorover and Schiller (1966) have reported some results which indicate that passive avoidance learning involving the inhibition of - stepping off a pedestal i s less susceptible to disruption by ECS than passive avoidance of stepping through a hole into a dark chamber. 5 S i m i l a r r e s u l t s were a l s o f o u n d by Carew ( 1 9 7 0 ) . R e c e n t l y , t h e f i n d i n g s o f L e w i s , M i l l e r , and M i s a n i n (1968) and o f M i l l e r (1970) s u g g e s t t h a t t h e s e t a s k - a s s o c i a t e d d i f f e r e n c e s i n s u s c e p t i b i l i t y t o ECS i n t e r f e r e n c e may be r e l a t e d t o t h e manner i n w h i c h t h e r e l e v a n t i n f o r m a t i o n about the l e a r n i n g t a s k i s a c q u i r e d . B o t h L e w i s e t a l and M i l l e r f o u n d t h a t i n c r e a s i n g the a n i m a l ' s f a m i l i a r i t y w i t h t h e t r a i n i n g a p p a r a t u s p r i o r t o t r a i n i n g s i g n i f i c a n t l y d e c r e a s e d t h e d i s -r u p t i v e e f f e c t o f ECS g i v e n f o l l o w i n g l e a r n i n g . M i l l e r went on t o show t h a t as t h e c o m p l e x i t y o f t h e t r a i n i n g e n v i r o n m e n t i s i n c r e a s e d , a much g r e a t e r amount o f f a m i l i a r i t y w i t h the t r a i n i n g a p p a r a t u s i s needed t o o f f s e t t h e d i s r u p t i v e e f f e c t s o f ECS. C o n s i s t e n t w i t h t h i s e v i d e n c e a r e the e a r l y r e s u l t s o f R u s s e l l (1949) who f o u n d t h a t t h e r e t e n t i o n of more d i f f i c u l t maze l e a r n i n g was s i g n i f i c a n t l y more s u s -c e p t i b l e t o i n t e r f e r e n c e by ECS. From t h e s e r e s u l t s , i t a p p e a r s c l e a r t h a t v a r i a t i o n i n l e a r n i n g t a s k s i s one cause of t h e v a r i a t i o n i n a m n e s i a g r a d i e n t s . However, whether one can a t t r i b u t e s p e c i f i c a l l y the c a use of t h e v a r i a t i o n i n amnesia g r a d i e n t s t o t h e c o m p l e x i t y o f t h e t r a i n i n g e n -v i r o n m e n t a t the t i m e of r e s p o n s e a c q u i s i t i o n w i l l have t o be v e r i f i e d by a d d i t i o n a l e v i d e n c e v a r y i n g c o m p l e x i t y a c r o s s a g r e a t e r v a r i e t y o f t r a i n i n g c o n d i t i o n s . The o t h e r c h a r a c t e r i s t i c of t a s k s t h a t has been r e l a t e d t o t h e s u s c e p t i b i l i t y t o d i s t u r b a n c e by ECS i s t h e amount of r e i n f o r c e m e n t used d u r i n g t r a i n i n g . Ray and B i v e n s (1968) r e p o r t e d t h a t when h i g h e r f o o t -s hock i n t e n s i t i e s were used d u r i n g t r a i n i n g , ECS i s l e s s d i s r u p t i v e o f r e t e n t i o n . R o b u s t e l l i , G e l l e r , A r o n , and J a r v i k (1969) v a r i e d t h e d e l a y between the s t e p - t h r o u g h r e s p o n s e and t h e p u n i s h i n g s t i m u l u s d u r i n g 6 passive avoidance training and found the responses acquired with the longer delays of punishment more susceptible to the amnesic effects of ECS. These results also suggest that there is a relation between training conditions and the length of amnesia gradients. However, at the very least these experiments w i l l have to be done using positive reinforcers before differences in reinforcement per se can be seriously inferred to be the c r i t i c a l variable. Overall, these experiments on task differences do indicate that the variation in amnesia gradients found with ECS is' at least partly due to the variation in training conditions and in the response being acquired. The experimenters who have produced these results have avoided speculating on how these task differences affect the consolida-tion process. Lewis (1969) has come close to such speculation with his proposal that the way in which information is "registered" and "inte-grated into an existing cognitive complex" is directly affected by conditions present during training. However, in terms of consolidation, the most straightforward interpretation of this evidence would seem to be that the rate or speed of consolidation is affected by the learning conditions and the actual response learned. Thus, for example, simple response learning in familiar situations may be both assimilated faster (as Lewis suggests) and consolidated faster and therefore is less sus-ceptible to interference by an amnesic agent after acquisition. The suggestion that the rate of the consolidation process may d i f -fer between tasks is supported by a substantial number of experiments whose results tend to indicate that the rate of consolidation can be experimentally manipulated. Gerard (1955), for instance, has provided 7 some e v i d e n c e t h a t c o n s o l i d a t i o n may be p r o l o n g e d by a p e r i o d o f hypo-t h e r m i a g i v e n s h o r t l y a f t e r t r a i n i n g . I f h a m s t e r s were made h y p o t h e r m i c s h o r t l y a f t e r t r a i n i n g , t h e p e r i o d f o l l o w i n g t r a i n i n g when an ECS c o u l d e f f e c t i v e l y d i s r u p t r e t e n t i o n was s i g n i f i c a n t l y i n c r e a s e d . D a v i s , B r i g h t , and A g r a n o f f (1965) have s u b s e q u e n t l y made t h e same o b s e r v a t i o n i n g o l d f i s h . U s i n g a s i m i l a r e x p e r i m e n t a l d e s i g n , A l b e r t (1966a) f o u n d t h a t i f a b r i e f p e r i o d o f 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 was g i v e n t o r a t s s h o r t l y a f t e r t r a i n i n g , t h e p e r i o d f o l l o w i n g t r a i n i n g when a s e c o n d t r e a t m e n t o f s p r e a d i n g d e p r e s s i o n c o u l d d i s r u p t r e t e n t i o n was s i m i l a r l y g r e a t l y i n c r e a s e d . One way o f i n t e r p r e t i n g t h e s e f i n d i n g s ( A l b e r t , 1966a) i s t h a t c o n s o l i d a t i o n i s s l o w e d s u c h t h a t t h e p r o c e s s e s w h i c h u n d e r l i e c o n s o l i d a t i o n p r o g r e s s a t a s l o w e r pace and t h e r e f o r e , a r e s u s c e p t i b l e t o i n t e r f e r e n c e f o r a l o n g e r p e r i o d a f t e r t r a i n i n g . There i s a l s o some e v i d e n c e w h i c h s u g g e s t s t h a t c o n s o l i d a t i o n c a n be speeded up. A l b e r t (1966b) has r e p o r t e d t h a t a s h o r t p e r i o d o f a n o d a l p o l a r i z a t i o n o f t h e c o r t e x f o l l o w i n g t r a i n i n g s h o r t e n e d t h e t i m e f o l l o w i n g t r a i n i n g when a t r e a t m e n t o f 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 c o u l d n o r m a l l y d i s r u p t r e t e n t i o n . More r e c e n t l y , B l o c h , Deweer, and Henn e v i n (19 70) f o u n d t h a t low l e v e l s t i m u l a t i o n o f t h e r e t i c u l a r f o r -m a t i o n i m m e d i a t e l y f o l l o w i n g t r a i n i n g a l s o a t t e n u a t e d t h e am n e s i c e f -f e c t s o f a n o r m a l l y d i s r u p t i v e t r e a t m e n t o f f l u r o t h a n e a n a e s t h e s i a g i v e n 1 m i n u t e a f t e r t r a i n i n g . S i m i l a r l y , a t t e n u a t i n g e f f e c t s upon t h e d i s r u p t i o n c a u s e d by ECS have a l s o been f o u n d w i t h I n j e c t i o n s o f s t i m u l a n t d r u g s . Weissman (1967) a d m i n i s t e r e d s t r y c h n i n e s u l p h a t e o r p e n t y l e n e t e t r a z o l t o r a t s j u s t a f t e r t r a i n i n g and b e f o r e an ECS t r e a t -ment and f o u n d some a t t e n u a t i o n o f r e t r o g r a d e amnesia upon r e t e s t t h e 8 n e x t day. B i v e n s and Ray (1966, c i t e d i n McGaugh, 1968) a d m i n i s t e r e d s t r y c h n i n e s u l p h a t e t o mice 10 m i n u t e s b e f o r e 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 ECS w i t h i n 30 seconds and a l s o f ound an a t t e n u a t i o n o f r e t r o g r a d e amnesia on a r e t e s t 24 h o u r s l a t e r . McGaugh and H a r t ( c i t e d i n McGaugh, 1968) i n a s i m i l a r e x p e r i m e n t a l s o f o u n d t h a t an i n j e c t i o n o f s t r y c h n i n e s u l p h a t e 10 m i n u t e s b e f o r e t r a i n i n g d e c r e a s e d the amnesic e f f e c t s o f an ECS a d m i n i s t e r e d 18 seconds o r 1 minute f o l -l o w i n g o n e - t r i a l i n h i b i t o r y a v o i d a n c e t r a i n i n g . R e c e n t l y , Essman (1966) and Essman and G o l o d (1968) f o u n d t h e i n j e c t i o n o f t r i c y a n o a m i n o p r o p e n e and Essman, S t e i n b e r g , and C o l o d (1968) f o u n d t h e i n j e c t i o n o f n i c o t i n e b e f o r e p a s s i v e a v o i d a n c e t r a i n i n g a l s o r e d u c e d t h e amnesic e f f e c t o f ECS i n m i c e . Because t r i c y a n o a m i n o p r o p e n e and n i c o t i n e a r e f o u n d r e s p e c t i v e l y t o i n c r e a s e s i g n i f i c a n t l y t h e r i b o n u c l e i c a c i d c o n t e n t o f the b r a i n and t o a l t e r t h e b i o g e n i c amine changes c a u s e d by an ECS, t h e s e i n v e s t i g a t o r s s u g g e s t e d t h a t changes i n t h e c o n t e n t o f b r a i n r i b o n u c l e i c a c i d and i n b i o g e n i c a m i n e ' ( i . e . , s e r o t o n i n ) a c t i v i t y may be two f a c t o r s w h i c h a r e i n v o l v e d i n a n t a g o n i z i n g t h e amnesic e f f e c t s o f ECS. The a t t e n u a t i o n o f amnesia f o u n d i n a l l o f t h e s e e x p e r i m e n t s i s s u g g e s t i v e o f the p o s s i b i l i t y t h a t memory s t o r a g e p r o c e s s e s ( i . e . , c o n s o l i d a t i o n ) are f a c i l i t a t e d o r a c c e l e r a t e d by t h e s e v a r i o u s e x p e r i -m e n t a l m a n i p u l a t i o n s . C o n s i d e r e d t o g e t h e r , t h i s e v i d e n c e s u g g e s t s , t h a t the r a t e o f c o n s o l i d a t i o n i s v a r i a b l e and t h a t i t m i g h t , t h e r e f o r e , be a f f e c t e d by the c o n d i t i o n s o f t r a i n i n g and r e i n f o r c e m e n t . E l e c t r o c o n v u l s i v e Shock P a r a m e t e r s The t h i r d h y p o t h e s i s a c c o u n t i n g f o r t h e v a r i a t i o n i n t h e l e n g t h 9 of E C S - i n d u c e d amnesia g r a d i e n t s s u g g e s t s t h a t the amount o f r e t e n t i o n i m p a i r m e n t o b s e r v e d i n any e x p e r i m e n t i s d i r e c t l y r e l a t e d t o the s e v e r i t y o f the amnesic t r e a t m e n t ( A l p e r n and McGaugh, 1968; M i l l e r , 1 9 6 8 ) . T h i s h y p o t h e s i s a r o s e from e x p e r i m e n t a l e v i d e n c e i n d i c a t i n g t h a t t h e d i s t u r b a n c e o f r e t e n t i o n f o l l o w i n g an a mnesic t r e a t m e n t was g e n e r a l l y p a r t i a l and r e l a t e d t o the s e v e r i t y o f the a mnesic t r e a t m e n t . The more s e v e r e the amnesic t r e a t m e n t , t h e h i g h e r was the p r o b a b i l i t y t h a t the d i s t u r b a n c e w o u l d be s u f f i c i e n t t o i m p a i r r e t e n t i o n . A s u r v e y o f the l i t e r a t u r e i n d i c a t e s s u b s t a n t i a l e v i d e n c e s u p p o r t i n g t h i s p r o p o s a l . Of t h e e x p e r i m e n t s u s i n g ECS as a d i s t u r b i n g a g e n t , Weissman ( 1 9 6 5 ) , M i l l e r ( 1 9 6 8 ) , Pagano, Bush, M a r t i n and Hunt ( 1 9 6 9 ) , • Ray and B a r r e t t ( 1 9 6 9 ) , J a r v i k and Kopp ( 1 9 6 7 ) , Dorfman and J a r v i k (1968) and Lee-Teng (1969) have a l l f o u n d t h a t w i t h i n c r e a s e s i n the i n t e n s i t y o f t h e e l e c t r o s h o c k c u r r e n t t h e r e i s a c o r r e s p o n d i n g i n c r e a s e i n the amount o f i n t e r f e r e n c e w i t h r e t e n t i o n . The o n l y e x c e p t i o n t o t h i s g e n e r a l p a t t e r n o f r e s u l t s i s an e a r l i e r e x p e r i m e n t o f Weissman (1963) w h i c h d i d n o t o b s e r v e an i n c r e a s e i n r e t r o g r a d e a mnesia f o l l o w i n g l a r g e i n c r e a s e s i n t h e ECS c u r r e n t i n t e n s i t y . I n e x p e r i m e n t s where t h e d u r a t i o n i n s t e a d of t h e i n t e n s i t y o f the e l e c t r o s h o c k i s v a r i e d , t h e e v i d e n c e i s s u b s t a n t i a l l y l e s s c l e a r . A l p e r n and McGaugh (1968) have f o u n d s i g n i f i c a n t l y more r e t r o g r a d e amnesia f o l l o w i n g l o n g e r d u r a t i o n ECS c u r r e n t s . However, a s u b s e q u e n t e x p e r i m e n t by P a o l i n o , Q u a r t e r m a i n , and Levy ( 1 9 6 9 ) , w h i c h a l s o v a r i e d the d u r a t i o n o f t h e ECS c u r r e n t , d i d n o t f i n d any a p p a r e n t change i n t h e amount of amnesia f o l l o w i n g a f o u r -f o l d i n c r e a s e i n the d u r a t i o n of the ECS. B e s i d e s the e v i d e n c e w i t h e l e c t r o s h o c k e x p e r i m e n t s , t h e r e i s a 10 s u b s t a n t i a l body o f f i n d i n g s f r o m e x p e r i m e n t s u s i n g o t h e r a mnesic a g e n t s w h i c h a l s o t e n d s t o s u p p o r t t h e h y p o t h e s i s t h a t t h e amount o f r e t e n t i o n i n t e r f e r e n c e i s d i r e c t l y r e l a t e d t o t h e s e v e r i t y o f t h e amnesic t r e a t -ment. A l b e r t (1966a) and Bure"sdva and Bure"s (1971) have found g r e a t e r i n t e r f e r e n c e w i t h i n c r e a s e d d u r a t i o n s o f s p r e a d i n g d e p r e s s i o n . C h e r k i n (1969) i n c r e a s e d b o t h t h e d u r a t i o n and t h e c o n c e n t r a t i o n o f t h e c o n v u l -s a n t f l u r o t h y l and f o u n d much g r e a t e r r e t e n t i o n i n t e r f e r e n c e . A l p e r n and K i m b l e (1967) f o u n d t h a t t h e d i s r u p t i v e n e s s o f d i e t h y l e t h e r was r e l a t e d t o i t s t e m p e r a t u r e . O u i n t o n (1966) and B e i t e l and P o r t e r (1968) r e s p e c t i v e l y f ound t h a t i n c r e a s i n g t h e t i m e o f e x p o s u r e t o c a r b o n d i o x i d e o r t o h y p o t h e r m i a f o l l o w i n g t r a i n i n g c o r r e s p o n d i n g l y i n c r e a s e d t h e amount o f r e t e n t i o n i n t e r f e r e n c e . F l e x n e r , F l e x n e r , and S t e l l a r (1965) have r e p o r t e d t h a t as t h e c o n c e n t r a t i o n o f t h e a n t i -b i o t i c p u r o m y c i n was i n c r e a s e d , i t s d i s t u r b a n c e o f memory became p r o -g r e s s i v e l y more e f f e c t i v e . I n summary, a l t h o u g h t h e e v i d e n c e i s n o t unanimous, t h e b u l k o f i t , b o t h w i t h ECS and o t h e r amnesic a g e n t s , seems t o f a v o r t h e c o n c l u -s i o n t h a t t h e r e i s a d i r e c t r e l a t i o n s h i p between t h e s e v e r i t y o f t h e amnesic t r e a t m e n t and t h e amount o f r e t e n t i o n i n t e r f e r e n c e . T h i s e v i -dence seems t o v e r i f y t h e s u g g e s t i o n t h a t t h e d i s t u r b a n c e o f c o n s o l i d a -t i o n by an amnesic agent i s n o t an a l l o r none phenomenon. R a t h e r i t a p p e a r s t h a t t h e amount o f d i s r u p t i o n o f c o n s o l i d a t i o n i s a f u n c t i o n o f t h e magnitude o f t h e d i s r u p t i v e e f f e c t s i n d u c e d by t h e amnesic a g e n t . I t i s i m p o r t a n t t h a t t h e e x p e r i m e n t s w h i c h have shown a d i r e c t r e -l a t i o n s h i p between t h e i n t e n s i t y o r t h e d u r a t i o n o f t h e am n e s i c t r e a t m e n t and t h e amount o f r e t r o g r a d e amnesia have n o t u s u a l l y p r e s e n t e d 11 e v i d e n c e i n d i c a t i n g t h a t the more i n t e n s e o r l o n g e r d u r a t i o n a mnesic t r e a t m e n t c r e a t e d more s e v e r e d i s t u r b a n c e s o f n e u r a l a c t i v i t y . Of t h e e x p e r i m e n t s c i t e d above, o n l y t h e F l e x n e r e t a l . ( 1 9 6 5 ) s t u d y p r o v i d e d some e v i d e n c e t h a t t h e i n c r e a s e i n t h e d i s r u p t i v e n e s s o f t h e a m n e s i c . a g e n t , p u r o m y c i n i n t h i s c a s e , upon memory was c o r r e l a t e d w i t h c o r r e s -p o n d i n g l y g r e a t e r b i o l o g i c a l d i s t u r b a n c e s ( i . e . , t h e e l e v a t i o n i n t h e d egree and t h e d u r a t i o n o f c e r e b r a l p r o t e i n s y n t h e s i s i n h i b i t i o n f o l -l o w i n g i n j e c t i o n s o f more c o n c e n t r a t e d p u r o m y c i n s o l u t i o n s ) . I n terms o f c o n s o l i d a t i o n t h e o r y , s u c h e v i d e n c e seems t o be e s s e n t i a l i n o r d e r t o show t h a t t h e r e i s an a c t u a l p h y s i o l o g i c a l b a s i s f o r t h e g r e a t e r d i s t u r b a n c e o f r e t e n t i o n f o l l o w i n g more s e v e r e a mnesic t r e a t m e n t s . T h e r e i s i n t h e l i t e r a t u r e some i n d e p e n d e n t e x p e r i m e n t s w h i c h do i n d i -c a t e s u c h a r e l a t i o n f o r s e v e r a l a mnesic a g e n t s . I l i n z and Domino (1953) , f o r example, have f o u n d t h a t e l e c t r o c o r t i c a l s e i z u r e s o f i n -c r e a s i n g s t r e n g t h and d u r a t i o n were i n d u c e d by more i n t e n s e as w e l l as by l o n g e r d u r a t i o n s o f e l e c t r i c a l s t i m u l a t i o n o f t h e b r a i n . Z o r n e t z e r and McGaugh (1970) have f o u n d t h a t i n c r e a s i n g e l e c t r o s h o c k i n t e n s i t y p r o d u c e d a more s e v e r e d i s t u r b a n c e o f b r a i n a c t i v i t y i n terms o f i n c r e a s e d s e i z u r e d i s c h a r g e s and h e i g h t e n e d f r e q u e n c y o f s p i k e a c -t i v i t i e s . The l o n g e r d u r a t i o n s o f 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 a r e f o u n d t o be a s s o c i a t e d w i t h a l o n g e r p e r i o d o f d e p r e s s i o n o f n e u r a l a c t i v i t y (Bure"s, 1 9 5 9 ) . H i g h e r c o n c e n t r a t i o n s o f f l u r o t h y l have been found t o p r o d u c e h i g h e r f r e q u e n c y o f s p i k e d i s c h a r g e s ( K e r z , S p o o n e r , and C h e r k i n , 1 9 7 0 ) . S e v e r e h y p o t h e r m i a i s found t o p r o d u c e a g r e a t e r f l a t t e n i n g o f t h e EEG i n d i c a t i n g an absence o r l a r g e d e c r e a s e i n n e u r a l a c t i v i t y ( H o r s t e n , 1 9 4 9 ) . 12 A clear indication of the way in which more severe amnesic treat-ments cause more memory deficits i s not yet available, but several authors have suggested some interesting p o s s i b i l i t i e s . Albert (1966a) and Cherkin (1969) have proposed that the reason there i s more reten-tion following a weak amnesic treatment is that these weak treatments slow but do not stop consolidation. Post-treatment consolidation thus can be the cause of the subsequently observed retention. As more direct evidence for the possibility that consolidation does continue following an amnesic treatment, Albert (1966a) has provided some result showing that a brief period of cortical spreading depression, which was not in i t s e l f sufficient to impair retention, enabled a later period of spreading depression to produce a loss of retention at a time when the second spreading depression treatment by i t s e l f would normally be i n -effective. Albert suggested that while the f i r s t period of spreading depression was not sufficient to impair retention, i t did disturb con-solidation in a latent way which allowed the second period of spread-ing depression to actually stop the consolidation process and prevent retention. Alpern and McGaugh (1968), Miller (1968),and Ray and Barrett (1969) have each suggested that the differences in effectiveness found with ECS treatments of various parameters are due to the variation in . the amount of current which passes through the brain. They suggest that this results in varying degrees of disturbance of neural activity. In a somewhat more precise elaboration of this general line of thinking Ray and Barrett (1969) have reasoned that retention circuits may be in areas of the brain which are not, or are only slightly, affected 13 by low l e v e l s o f ECS c u r r e n t a p p l i e d t o t h e e n t i r e b r a i n . W i t h h i g h e r c u r r e n t s , t h e s e a r e a s o f t h e b r a i n a r e p r e s u m a b l y a l s o d i s t u r b e d and t h i s c o u l d be one f a c t o r w h i c h c o n t r i b u t e s t o t h e d i f f e r e n c e s i n a mnesia i n d u c e d by ECS o f v a r y i n g p a r a m e t e r s . A l t e r n a t i v e l y , i t i s a l s o p o s s i b l e t h a t , w i t h more i n t e n s e o r l o n g e r d u r a t i o n e l e c t r o s h o c k c u r r e n t s , t h e t o t a l amount o f p h y s i o l o g i c a l d i s t u r b a n c e c r e a t e d w i t h i n t h e same b r a i n s t r u c t u r e s i s g r e a t e r so t h a t t h e c o n s e q u e n t amount o f r e t e n t i o n i n t e r -f e r e n c e i n d u c e d i s a l s o l a r g e r . The P r e s e n t E x p e r i m e n t Of t h e t h r e e e x p l a n a t i o n s e xamined, t h e l a s t two, v a r i a t i o n s i n t a s k v a r i a b l e s and i n d i s t u r b i n g - a g e n t p a r a m e t e r s , a p p e a r t o p r o v i d e t h e most s u b s t a n t i a l b a s i s f o r e x p l a i n i n g t h e o b t a i n e d v a r i a t i o n i n E C S - i n d u c e d amnesia g r a d i e n t s . The e f f e c t s o f b o t h t h e s e v a r i a b l e s seem t o make se n s e i n terms o f t h e c o n s o l i d a t i o n h y p o t h e s i s . D i f f e r -ences i n tasks m i ght w e l l be e x p e c t e d t o have some e f f e c t upon t h e ease w i t h w h i c h i n f o r m a t i o n i s a s s i m i l a t e d and c o n s o l i d a t e d f o l l o w i n g a c q u i s i t i o n . D i f f e r e n c e s i n t h e s e v e r i t y w i t h w h i c h an a m n e s i c a g e n t d i s t u r b s some a s p e c t o f n e u r a l p r o c e s s e s seem t o f o l l o w t h e p a t t e r n t h a t w o u l d be e x p e c t e d i f t h e n e u r a l s u b s t r a t e o f memory s t o r a g e p r o -c e s s e s i s b e i n g i n t e r r u p t e d . The i n t e n t o f t h e p r e s e n t e x p e r i m e n t i s t o l o o k more c l o s e l y a t t h e q u e s t i o n o f how more s e v e r e d i s t u r b a n c e s o f n e u r a l p r o c e s s e s c a use c o r r e s p o n d i n g l y more s e v e r e d i s t u r b a n c e s o f c o n s o l i d a t i o n . The above e v i d e n c e on v a r i a t i o n i n a mnesic agent p a r a m e t e r s and t h e amount o f r e t r o g r a d e amnesia i s a l l i n agreement w i t h t h e g e n e r a l c o n c l u s i o n t h a t weaker d i s t u r b a n c e s o f n e u r a l a c t i v i t y a r e l e s s e f f e c t i v e i n 14 d i s r u p t i n g r e t e n t i o n because t h e y do n o t i n v a r i a b l y s t o p t h e 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 e x p e r i m e n t i n v e s t i g a t e s t h e 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 c o n t i n u e s f o l l o w i n g a s i n g l e ECS. The method f o r e x a m i n i n g t h i s p o s s i b i l i t y was t o a d m i n i s t e r an ECS a t a t r a i n i n g -ECS i n t e r v a l where o n l y a s m a l l r e t e n t i o n l o s s o c c u r s , and t h e n a s e c o n d ECS a t a l o n g e r p o s t - t r a i n i n g i n t e r v a l . I t was r e a s o n e d t h a t i f c o n s o -l i d a t i o n i s o n l y p a r t i a l l y d i s t u r b e d by t h e f i r s t ECS, t h e a d d i t i o n a l i n t e r f e r e n c e p r o d u c e d by a second ECS m i g h t be s u f f i c i e n t t o a c t u a l l y s t o p t h e p r o c e s s and p r e v e n t r e t e n t i o n . Method S u b j e c t s The s u b j e c t s were 128 n a i v e , m a l e , b l a c k hooded r a t s (200-300 grams) p u r c h a s e d from t h e Quebec B r e e d i n g Farm. They were housed i n i n d i v i d u a l cages and m a i n t a i n e d on a 23-hr w a t e r d e p r i v a t i o n s c h e d u l e t h r o u g h o u t t h e e x p e r i m e n t . S u r g i c a l P r o c e d u r e s T h r e e days b e f o r e a p p r o a c h t r a i n i n g i n t h e a l l e y , ECS s c r e w e l e c t r o d e s were i m p l a n t e d i n t h e a n i m a l s ' s k u l l s . A screw e l e c t r o d e c o n s i s t e d o f a 2 cm l o n g s t e e l p i n c o n n e c t e d by a t h i n , s t a i n l e s s s t e e l w i r e t o a j e w e l l e r ' s s crew. W h i l e t h e r a t was a n a e s t h e t i z e d w i t h sodium p e n t o b a r b i t a l ( Nembutal, 40 mg/kg), i t s s k u l l was e x p o s e d , and b i l a t e r a l s c r e w e l e c t r o d e s were t h r e a d e d j u s t t h r o u g h t h e s k u l l a t 3 mm l a t e r a l and 1 mm p o s t e r i o r t o bregma. Two s u p p o r t i n g s c r e w s v/ere s i m i l a r l y t u r n e d i n t o t h e s k u l l j u s t a n t e r i o r t o t h e c o r o n a l s u t u r e . D e n t a l a c r y l i c was t h e n a p p l i e d t o c o v e r c o m p l e t e l y t h e s u p p o r t i n g and e l e c t r o d e s c r e w s , and t h e w h o l e wound a r e a . 15 A p p a r a t u s The p a s s i v e a v o i d a n c e a p p a r a t u s c o n s i s t e d o f a wooden a l l e y (104 crc by 14 err. by 20 cm h i g h ) w i t h a mesh runway l e a d i n g t o a g r i d d e d g o a l a r e a ( l a s t 19 cm of t h e a l l e y ) where a w a t e r s p o u t p r o t r u d e d from t h e end w a l l . F o o t s h o c k (2 ma a c , 1 s e c ) was d e l i v e r e d by e l e c t r i f y i n g t h e g r i d d e d g o a l a r e a w i t h a power t r a n s f o r m e r s u p p l y i n g 420 V. E l e c -t r o c o n v u l s i v e s h o c k (25 ma, 0.4 s e c ) was g e n e r a t e d through a 60 Hz, 820 V s o u r c e w h i c h was c o n n e c t e d i n s e r i e s t o a 33,000-ohm r e s i s t o r and t h e screw e l e c t r o d e s i m p l a n t e d i n t h e a n i m a l ' s s k u l l . ECS d e l i v e r e d i n t h i s manner r e l i a b l y p r o d u c e d t o n i c - c l o n i c s e i z u r e s . E x p e r i m e n t a l P r o c e d u r e s F o r t y - e i g h t h r a f t e r s u r g e r y , t h e a n i m a l s were p l a c e d on a 2 3 - h r w a t e r d e p r i v a t i o n s c h e d u l e w h i c h c o n t i n u e d f o r t h e r e m a i n d e r o f t h e e x p e r i m e n t . Twenty-one h r l a t e r (Day 1 ) , t h e a n i m a l s began a p p r o a c h t r a i n i n g i n t h e a l l e y . On Day 1, t h e y were g i v e n a 5-min h a b i t u a t i o n t r i a l . Then from Day 2 t o Day 6, each a n i m a l was p l a c e d i n t o one end o f t h e a l l e y f a c i n g t h e g o a l and l e f t f o r 1 min. The l a t e n c y f o l l o w i n g t h e r e l e a s e o f t h e a n i m a l u n t i l i t s t a r t e d d r i n k i n g a t t h e g o a l was r e c o r d e d w i t h a s t o p w a t c h . A n i m a l s w h i c h d i d n o t d r i n k were a s s i g n e d a s c o r e o f 60 s e c . Three such t r i a l s , each s e p a r a t e d by about 20 m i n , were g i y e n d a i l y . On t h e b a s i s o f t h e mean l a t e n c i e s t o d r i n k from Day 2 t o Day 6, t h e a n i m a l s were d i v i d e d i n t o matched g r o u p s . On Day 7, t h e a n i m a l s were " t r e a t e d " . P r i o r t o t h e i r b e i n g p l a c e d i n t o t h e a l l e y on Day 7, a l l a n i m a l s had w i r e l e a d s a t t a c h e d t o t h e i r s k u l l e l e c t r o d e s ( t h i s d i d n o t p r e v e n t t h e a n i m a l s from a p p r o a c h i n g t h e w a t e r s p o u t p r o m p t l y ) . E v e r y a n i m a l w h i c h r e c e i v e d p a s s i v e a v o i d a n c e 16 training was permitted to approach the goal area as previously. Three sec after the animal crossed into the goal area, i t received a footshock (FS) via the grid floor. Fifteen sec after the F S , the animal was taken from the alley and returned to i t s cage. The wire leads on the animal's skull electrodes were not removed u n t i l after the f i r s t E C S or sham ECS treatment 5 min after the training. Animals not treated at 5 min had their wire leads removed during the transfer back to their cages (see Figure 1 for a description of the experimental paradigm). The footshock control group (FS-only) received a sham ECS (no current passed) 5 min following the FS. Group 5-min-ECS was given an ECS 5 min after the FS. The purpose of this group i s to show that a single ECS administered at a f a i r l y short training-ECS interval does not produce a substantial interference with retention. To examine the pos s i b i l i t y that memory consolidation is not suppressed completely by the single ECS at 5 min after training, group 5-min-l-hr-ECSs received a second ECS 1 hr after the FS. To see i f the effect of the second ECS was time-dependent, group 5-min-24-hr-ECSs was given the second ECS 24 hr after the FS. Finally, three other groups were included. Group 1-hr-ECS was given a single ECS 1 hr after the passive avoidance training to assess the disruptive effect of a single ECS at 1 hr after training. Group 24-hr-25-hr-ECSs was administered two ECSs separated by one hr, 24 hr after training, to control for possible disinhibitory effects of two closely paired ECSs. The last group, No-FS-5-min-l-hr-ECSs, was a control for any aversive effects of the paired ECSs alone. Animals 17 in this group were not footshocked, but were removed from the alley 3 sec after they crossed into the goal. ECS was administered 5 min and 1 hr later. Forty-eight hr (Day 9) after training, the animals of each group with the exception of those belonging to group 24-hr-25-hr-ECSs were returned to the alley for three 60-sec test t r i a l s . The mean approach latency on the three test t r i a l s was scored for each animal as a measure of retention. Group 24-hr-25-hr-ECSs was retested 72 hr (Day 10) after training in order to maintain an ECS-retest interval approximately equal to that of the other groups. Statistics. S t a t i s t i c a l analyses were performed using two-tailed Mann-Whitney U tests. Results The results are summarized in Figure 1. A single ECS at 5 min after the training (5-min-ECS group.) did not significantly reduce the retest approach latencies below those of the FS-only group (p < 0.10). However, a second ECS at 1 hr after the FS (5-min-l-hr-ECSs group) s i g -nificantly increased the disruptive effects of the ECS treatment. The retest score for the 5-min-l-hr-ECSs group was significantly lower than that of the 5-min-ECS group as well as that of the FS-only group (both p < 0.002). That the disruptive effect of the second ECS is time-dependent is shown by the performance of the 5-min-24-hr-ECSs group, which received the second ECS 24 hr after the training. The approach latencies for the 5-min-24-hr-ECSs group were not significantly different from those of group 5-min-ECS. 18 Figure 1. Median approach latencies for each experimental group on the retention test. A l l groups (except group 7) were given a FS in the passive avoidance apparatus followed by ECS or sham. ECS treatments. These treatments w^re as follows: Group 1, ECS at 5 min and 1 hr after the FS; Group 2, ECS at 5 min and 24 hr after the FS; Group 3, ECS at 5 min after the FS; Group 4, ECS at 1 hr after the FS; Group 5, ECS at 24 hr and 2 5 hr after the FS, and Group 6, a sham ECS at 5 min after the FS. Group 7 did not receive a FS but was given an ECS 5 min and 1 hr after the removal from the avoidance apparatus. 19 GROUPS (n) 1. 5-min - 1 -hr - ECSs (16) i 2. 5-min -24-hr -ECSs (16) * 3. 5-min - E C S (14) I 4. I- hr - ECS (9) 5. 24-hr -25-hr - E C S s (9) 6. FS - only (8) 7. No-FS-5 -min - l -h r -ECSs (12) MEDIAN APPROACH LATENCIES (sec. ) 20 The p o s s i b i l i t y t h a t t h e second ECS f o r t h e 5-min ECS g r o u p s was a f f e c t i n g .a time-dependent p r o c e s s i s s u p p o r t e d by t h e f i n d i n g t h a t t h e r e t e s t a p p r o a c h l a t e n c i e s o f t h e 24-hr-25-hr-ECSs g r o u p , w h i c h r e c e i v e d t h e p a i r e d ECSs 24 h r a f t e r t r a i n i n g , were n o t s i g n i f i c a n t l y d i f f e r e n t f r o m t h o s e o f the F S - o n l y c o n t r o l . T h i s f i n d i n g s u g g e s t s t h a t t h e p o o r r e t e s t p e r f o r m a n c e f o r the group 5 - m i n - l - h r - E C S s i s n o t due t o p o s s i b l e d i s i n h i b i t o r y e f f e c t s o f t h e ECSs ( P o s l u n s and V a n d e r w o l f , 1970). I n agreement w i t h t h e r e c e n t f i n d i n g s by K e s n e r , G i b s o n , and L e C l a i r (1970) t h e p a i r e d ECSs a l o n e (group No-FS-5-min-1-hr-ECSs) d i d n o t appear t o have any e f f e c t upon t h e a p p r o a c h r e s p o n s e w h i c h c o u l d be a t t r i b u t e d t o i n h i b i t o r y o r a v e r s i v e e f f e c t s o f ECS. F i g u r e 1 a l s o shows t h a t a s i n g l e ECS by i t s e l f a t 1 h r a f t e r t r a i n i n g o n l y s l i g h t l y i n t e r f e r e d w i t h r e t e n t i o n (1-hr-ECS v s F S - o n l y , p < 0.10). However, t h e d i s r u p t i v e e f f e c t o f an ECS a t 1 h r a f t e r t r a i n i n g was s i g n i f i c a n t l y i n c r e a s e d when i t was p r e c e d e d by a n o t h e r ECS a t 5 min a f t e r t r a i n i n g (1-hr-ECS v s 5 - m i n - l - h r - E C S s , p < 0.05). T h i s i n d i c a t e s t h a t a l t h o u g h t h e ECS a d m i n i s t e r e d a t 5 min a f t e r t r a i n i n g d i d n o t g r e a t l y d i s r u p t r e t e n t i o n , i t d i d i n some way i n c r e a s e t h e e f f e c t i v e n e s s o f a second ECS g i v e n a t 1 h r . T h i s enhancement o f the e f f e c t i v e n e s s o f a second ECS i n d i s r u p t i n g r e t e n t i o n seems t o l a s t a t l e a s t 1 h r b u t l e s s t h a n 24 h r . I n o r d e r t o d e l i m i t more p r e c i s e l y t h e d u r a t i o n o f t h e i n c r e a s e d s u s c e p t i b i l i t y t o d i s r u p t i o n i n d u c e d by t h e f i r s t ECS a t 5 min a f t e r t r a i n i n g , s e v e r a l a d d i t i o n a l groups o f r a t s were r u n i n t h e way d e s -c r i b e d p r e v i o u s l y and were g i v e n an ECS 5 min a f t e r t h e p a s s i v e a v o i d -ance t r a i n i n g . A second ECS was t h e n a d m i n i s t e r e d a t v a r y i n g t i m e s 21 Figure 2. The effect of an ECS at 5 min following footshock on the length of time afterward when a second ECS can be given and impair retention (dash l i n e ) . The horizontal line represents the maximum retention expected of the two ECS groups as estimated from the effect of a single ECS at 5 min. The curve (solid line) showing the effect of a single ECS given at varying times following learning i s presented to show how much the administration of two ECSs rather than one i n -creased the time following footshock when a treatment could be given and s t i l l impair retention. To complete the one ECS curve, a group (n=9) which received a single ECS at 2 sec following footshock has been added. 22 23 a f t e r t h e f i r s t ECS. The r e s u l t s a r e p r e s e n t e d i n F i g u r e 2. T h e r e was a s i g n i f i c a n t i n t e r f e r e n c e w i t h r e t e n t i o n when t h e second ECS was a d m i n i s t e r e d a t 2 h r ( n = l l ) (5-min-ECS v s 5-min-2-hr-ECSs, p < 0.002) a f t e r t r a i n i n g , b u t a t 3 h r (n=12) o r 6 hr'(n=12) t h e e f f e c t i v e n e s s o f t h e se c o n d ECS had d i s s i p a t e d . F i g u r e 2 a l s o summarizes t h e r e s u l t s o f t h e p r e s e n t e x p e r i m e n t s . I t i l l u s t r a t e s how much t h e a d m i n i s t r a t i o n o f two ECSs, r a t h e r t h a n one, i n c r e a s e d t h e t i m e f o l l o w i n g t h e FS when an ECS t r e a t m e n t c o u l d be g i v e n and s t i l l d i s t u r b r e t e s t p e r f o r m a n c e . D i s c u s s i o n Memory c o n s o l i d a t i o n a p p e a r s t o c o n t i n u e f o l l o w i n g a s i n g l e ECS g i v e n a t 5 m i n u t e s a f t e r p a s s i v e a v o i d a n c e t r a i n i n g . The e v i d e n c e f o r t h i s i s t h a t w h i l e a s i n g l e ECS a t 5 m i n u t e s a f t e r t r a i n i n g does n o t g r e a t l y d i s r u p t r e t e n t i o n , a second ECS g i v e n some t i m e a f t e r t h e f i r s t ECS d r a s t i c a l l y i n c r e a s e s t h e l o s s o f r e t e n t i o n . S i n c e t h e s e c o n d ECS i m p a i r s r e t e n t i o n i n a t i m e - d e p e n d e n t manner and a p p e a r s t o be i n d e p e n -dent o f d i s i n h i b i t o r y and p u n i s h i n g e f f e c t s , i t s d i s t u r b a n c e o f r e t e n -t i o n i s c o n s i s t e n t w i t h memory c o n s o l i d a t i o n t h e o r y . The f i n d i n g t h a t r e t e n t i o n i s d i s r u p t e d a t a l l by t h e second ECS s u g g e s t s t h a t c o n s o l i -d a t i o n i s n o t s t o p p e d f o l l o w i n g t h e f i r s t ECS. W i t h i n t h e c o n t e x t o f c o n s o l i d a t i o n t h e o r y , t h e p r e s e n t f i n d i n g o f an e x t e n d e d amnesia g r a d i e n t w i t h t h e two ECSs a p p e a r s e x p l a i n a b l e i n s e v e r a l r e a s o n a b l e ways. One p o s s i b i l i t y i s t h a t t h e f i r s t ECS w h i l e i t s e l f n o t c o m p l e t e l y d i s r u p t i n g c o n s o l i d a t i o n does p r o d u c e e f f e c t s w h i c h p o t e n t i a t e t h e d i s r u p t i v e n e s s o f t h e second ECS. The enhanced e f f e c t i v e n e s s o f t h e second ECS i n d i s t u r b i n g r e t e n t i o n may be due t o 24 c e r t a i n p h y s i o l o g i c a l and m e t a b o l i c changes c a u s e d by t h e f i r s t ECS w h i c h t h e n p o t e n t i a t e t h e d i s t u r b i n g e f f e c t o f t h e se c o n d ECS and a l l o w i t t o d i s r u p t more c o m p l e t e l y t h e c o n s o l i d a t i o n p r o c e s s . F o r example, b r i e f p e r i o d s o f energy r e s e r v e d e p l e t i o n i n the b r a i n have been f o u n d f o l l o w i n g a s i n g l e ECS ( K i n g , Lowry, Passonneau,and Venson, 1967; F e r r e n d e l l i and McDougal, 1971). I f t h i s m e t a b o l i c d e p l e t i o n i s p r o l o n g e d o r i n c r e a s e d by a second ECS, t h e d i s t u r b i n g e f f e c t upon c o n s o l i d a t i o n may become s u f f i c i e n t t o p r e v e n t r e t e n t i o n . I n a d d i t i o n , t h e b i o c h e m i c a l e f f e c t s p r o d u c e d by an ECS i s n o t r e s t r i c t e d t o a d i s -t u r b a n c e o f en e r g y r e s e r v e s . D i s t u r b a n c e s o f p r o t e i n s y n t h e s i s (Cotman, B a n k e r , Z o r n e t z e r , a n d McGaugh, 1 9 7 1 ) , f r e e f a t t y a c i d s p o o l ( B a z a n , 1 9 7 1 ) , s e r o t o n i n , n o r e p i n e p h r i n e and 3 , 4 - d i h y d r o x y p h e n y l e t h y -l a m i n e l e v e l s ( H i n e s l a y , N o r t o n , a n d A p r i s o n , 1968; Essman, 1970) and a c e t y l c h o l i n e a c t i v i t y ( A d a m s , • H o b l i t , a n d S u t k e r , 1969) have been f o u n d . The d i s r u p t i o n o f c o n s o l i d a t i o n by t h e ECS t r e a t m e n t s o b s e r v e d i n t he p r e s e n t e x p e r i m e n t may I n v o l v e any o r a l l o f t h e s e b i o c h e m i c a l d i s t u r b a n c e s . A l t e r n a t i v e l y , t h e r e s u l t s o f t h e p r e s e n t e x p e r i m e n t may be due t o t h e f i r s t ECS p a r t i a l l y d i s r u p t i n g and s l o w i n g c o n s o l i d a t i o n s u c h t h a t t h e o v e r a l l d u r a t i o n o f t h e c o n s o l i d a t i o n p r o c e s s i s p r o l o n g e d . T h i s p r o l o n g i n g o f t h e c o n s o l i d a t i o n p r o c e s s t h u s makes p o s s i b l e t h e d i s r u p t i v e e f f e c t o f a s e c o n d ECS even when i t i s g i v e n a t a t i m e a f t e r l e a r n i n g when by i t s e l f i t w o u l d be q u i t e i n e f f e c t i v e i n d i s -t u r b i n g r e t e n t i o n . I n an e a r l i e r e x p e r i m e n t w i t h 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 as t h e d i s t u r b i n g a g e n t , A l b e r t (1966a) has found e s s e n -t i a l l y t h e same r e s u l t s . When a b r i e f p e r i o d o f s p r e a d i n g d e p r e s s i o n , 25 w h i c h d i d n o t by i t s e l f d i s t u r b r e t e n t i o n was g i v e n s h o r t l y a f t e r t r a i n i n g , i t e n a b l e d a l a t e r p e r i o d o f s p r e a d i n g d e p r e s s i o n t o d i s r u p t r e t e n t i o n a t a t i m e when t h e second t r e a t m e n t o f s p r e a d i n g d e p r e s s i o n by i t s e l f was n o t e f f e c t i v e . A l b e r t i n t e r p r e t e d t h e s e r e s u l t s as s u g -g e s t i v e o f a s l o w i n g e f f e c t upon c o n s o l i d a t i o n i n d u c e d by t h e f i r s t t r e a t m e n t o f s p r e a d i n g d e p r e s s i o n . R e c e n t l y , C h e r k i n (1969) has s i m i l a r l y s u g g e s t e d t h a t under c e r t a i n c o n d i t i o n s an amnesic t r e a t m e n t may o n l y s l o w memory c o n s o l i d a t i o n . H i s r e s u l t s w i t h the c o n v u l s a n t f l u r o t h y l s u g g e s t t h a t a s l o w i n g e f f e c t upon c o n s o l i d a t i o n o c c u r s f o l -l o w i n g l e s s p o t e n t o r l e s s s e v e r e amnesic t r e a t m e n t s . The o c c u r r e n c e of s l o w i n g and p o t e n t i a t i o n e f f e c t s may n o t be m u t u a l l y e x c l u s i v e . The amnesia f o u n d f o l l o w i n g t h e two ECSs a t 5 m i n u t e s and 1 h o u r , f o r i n s t a n c e , c o u l d be t h e r e s u l t o f b o t h t h e s e e f f e c t s o c c u r r i n g t o g e t h e r . The e x t e n t o f t h e p r e s e n t f i n d i n g s , however, do n o t p e r m i t a d e f i n i t i v e e v a l u a t i o n o f t h i s p o s s i b i l i t y n o r f o r t h a t m a t t e r o f t h e s l o w i n g e f f e c t o r t h e p o t e n t i a t i o n e f f e c t a l o n e as t h e more l i k e l y e x p l a n a t i o n f o r the p r e s e n t f i n d i n g s . However, a l l o f t h e s e e x p l a n a t i o n s a r e c o n s i s t e n t w i t h t h e c o n c l u s i o n 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 l l o w i n g t h e - f i r s t ECS. C o n s i d e r e d o u t s i d e t h e framework o f c o n s o l i d a t i o n t h e o r y , t h e s t r o n g e s t a l t e r n a t e e x p l a n a t i o n f o r t h e p r e s e n t f i n d i n g s seems t o be t h a t s u g g e s t e d by W i e n e r ( 1 9 7 0 ) . He p r o p o s e d t h a t E C S - i n d u c e d r e t e n -t i o n d e f i c i t s a r e due t o t h e f a c t t h a t ECS a l t e r s b r a i n c h o l i n e r g i c a c t i v i t y f o l l o w i n g l e a r n i n g . There have been a number o f r e s u l t s s u g g e s t i n g t h a t changes i n b r a i n c h o l i n e r g i c a c t i v i t y i s r e f l e c t e d i n p e r f o r m a n c e v a r i a t i o n s . D e u t s c h (1971) has r e c e n t l y summarized t h i s 26 e v i d e n c e w h i c h s u g g e s t s t h a t c h o l i n e r g i c a c t i v i t y i m m e d i a t e l y a f t e r l e a r n i n g i s v e r y h i g h , b u t th e n d e c l i n e s o v e r a number o f h o u r s f o l -l o w i n g l e a r n i n g . However, t h i s d e c l i n e g r a d u a l l y d i s s i p a t e s a g a i n o v e r t i m e (up t o 14 d a y s ) . A p p a r e n t l y , i f e x p e r i m e n t a l m a n i p u l a t i o n s such as a n t i c h o l i n e s t e r a s e i n j e c t i o n ( D e u t s c h , 19 71) o r ECS (Adams e t a l . , 196S) w h i c h i n c r e a s e s a c e t y l c h o l i n e l e v e l s i n t h e b r a i n a r e g i v e n a t t i m e s when a c e t y l c h o l i n e l e v e l s a r e h i g h f o l l o w i n g l e a r n i n g , t hey can i n t e r f e r e w i t h r e t e n t i o n p e r f o r m a n c e . W i e n e r ' s r e s u l t s s u g g e s t t h a t t h i s i s t h e manner by w h i c h ECS t r e a t m e n t s i n t e r f e r e w i t h r e t e n t i o n . W i e n e r found t h a t a s e r i e s o f 5 ECSs given a t 5 m i n u t e s , 30 m i n u t e s , 7 days,and 14 days a f t e r t r a i n i n g i n t e r f e r e d w i t h r e t e s t p e r -formance b u t n o t i f t h e ECSs were g i v e n 1 d ay, 3 d a y s , 5 d a y s , o r 31 days a f t e r t r a i n i n g . T h i s p a t t e r n o f r e s u l t s i s e s s e n t i a l l y i d e n t i c a l t o t h a t f o u n d w i t h a n t i c h o l i n e s t e r a s e d r u g s ( D e u t s c h , 1971) and i t r e -i n f o r c e s t h e p o s s i b i l i t y t h a t E C S - i n d u c e d r e t e n t i o n l o s s e s a r e due t o the a l t e r a t i o n o f c h o l i n e r g i c a c t i v i t y i n t h e b r a i n . I m p l i c a t i o n s f o r Recent F i n d i n g s The c o n c l u s i o n drawn from the p r e s e n t f i n d i n g s t h a t c o n s o l i d a t i o n can c o n t i n u e f o l l o w i n g an ECS p r o v i d e s a u s e f u l and p a r s i m o n i o u s t h e o -r e t i c a l b a s i s f o r i n t e r p r e t i n g s e v e r a l r e c e n t d i s c o v e r i e s r e p o r t e d i n the c o n s o l i d a t i o n l i t e r a t u r e . The f o l l o w i n g d i s c u s s i o n s u g g e s t s how t h e e v i d e n c e p r o v i d e d by t h e p r e s e n t e x p e r i m e n t makes p o s s i b l e t h e a s s i m i l a -t i o n o f t h e s e f i n d i n g s w i t h i n c o n s o l i d a t i o n t h e o r y , a) The v a r i a t i o n i n amnesia g r a d i e n t s The p r e s e n t f i n d i n g t h a t memory c o n s o l i d a t i o n can c o n t i n u e f o l l o w i n g an ECS t r e a t m e n t s u g g e s t s one p o s s i b l e way o f r e s o l v i n g t h e e v i d e n c e on 27 the differences in amnesia gradients obtained following variations in ECS parameters (Alpern and McGaugh, 1968; Miller, 1968; Pagano et a l . , 1969; Ray and Barrett, 1969). It appears that the differences in amnesia gradients may be resolved as an effect due to the di f f e r e n t i a l effectiveness of ECS (with different parameters) in stopping consolida-tion; that i s , the greater retention usually found (in terms of shorter amnesia gradients) following weaker ECS treatments may be best explained as a result of the amount of consolidation which continues following the ECS treatment. Presumably, this post-treatment consolidation makes possible retention upon retesting. This interpretation follows from the previous discussion that the effect of an ECS may only slow or partially disturb consolidation such that the consolidation process i t s e l f is not disrupted completely. With respect to the variations in amnesia gradients found in separate experiments (i.e., short amnesia gradients: Chorover and Schiller, 1965; Ouartermain et a l . , 1965; long amnesia gradients: Kopp et a l . , 1966; McGaugh, 1966), i t seems that i f the ECS treatment used in each of these experiments are also d i f f e r e n t i a l l y effective in stopping consolidation, the amount of amnesia found following the ECS would be directly related to the amount of consolidation which takes place after the ECS treatment. The more effective an ECS is in sup-pressing consolidation, the greater is the probability of finding more severe retention interference (i.e., in finding a longer amnesia gradient). b) Recovery from retrograde amnesia Recently several experiments reported a recovery from ECS-induced 28 r e t r o g r a d e amnesia ( Z i n k i n and M i l l e r , 1967; K o h l e n b e r g and T r a b a s s o , 1 9 6 8 ) . A c c o r d i n g t o c o n s o l i d a t i o n t h e o r y , E C S - i n d u c e d r e t r o g r a d e amnesia i s t h e r e s u l t o f t h e ECS d i s r u p t i n g c o n s o l i d a t i o n b e f o r e t h e p r o c e s s e s w h i c h are i n v o l v e d i n memory s t o r a g e have been c o m p l e t e d . T h i s t y p e o f i n t e r f e r e n c e p r e s u m a b l y s h o u l d be permanent b e c a u s e i f memory s t o r a g e p r o c e s s e s were d i s r u p t e d by t h e ECS, t h e p h y s i c a l b a s i s f o r r e c a l l w o u l d n o t have been formed and no r e c o v e r y f r o m amnesia s h o u l d , t h e r e f o r e , o c c u r . The r e c e n t f i n d i n g s t h a t r e c o v e r y from ECS-i n d u c e d amnesia can o c c u r i s n o t c o n s i s t e n t w i t h t h i s f o r m u l a t i o n o f t h e c o n s o l i d a t i o n t h e o r y . The two most r e a s o n a b l e e x p l a n a t i o n s o f f e r e d f o r t h e s e f i n d i n g s on t h e r e c o v e r y from E C S - i n d u c e d r e t r o g r a d e amnesia appear t o be 1) the r e t r i e v a l i n t e r f e r e n c e h y p o t h e s i s o f U e i s k r a n t z (1966) and 2) t h e i n c o m p l e t e d i s r u p t i o n o f c o n s o l i d a t i o n h y p o t h e s i s o f K i n g and G l a s s e r ( 1 9 7 0 ) . The r e t r i e v a l i n t e r f e r e n c e h y p o t h e s i s p r o p o s e d t h a t p o s t -t r a i n i n g ECS i n t e r f e r e s w i t h r e c a l l by c r e a t i n g h i g h l e v e l s o f " n o i s e " i n t h e -memory r e t r i e v a l s y s t e m . As t h i s " n o i s e " l e v e l d e c r e a s e s o v e r t i m e , t h e i n t e r f e r e n c e w i t h r e c a l l i s r e d u c e d and r e c o v e r y f r o m amnesia o c c u r s . The se c o n d h y p o t h e s i s a t t r i b u t e s t h e r e c o v e r y f r o m amnesia t o the i n c o m p l e t e d i s r u p t i o n o f c o n s o l i d a t i o n by an ECS. I t s u g g e s t s t h a t i n c a s e s where c o n s o l i d a t i o n i s o n l y p a r t i a l l y d i s r u p t e d , r e c o v e r y o f memory may o c c u r s p o n t a n e o u s l y o r a f t e r r e p e a t e d e x p o s u r e to s t i m u l i a s s o c i a t e d w i t h t h e o r i g i n a l l e a r n i n g s i t u a t i o n . A p p a r e n t l y t h e i n c o m p l e t e d i s r u p t i o n o f c o n s o l i d a t i o n e n a b l e s t h e e s t a b l i s h m e n t o f some memory components w h i c h make p o s s i b l e the r e c o v e r y from a m n e s i a . E v i d e n c e on t h e r e l a t i o n s h i p o f the e f f e c t i v e n e s s o f ECS and t h e 29 efficacy of the recovery from amnesia (Pagano et a l . , 1969; Mi l l e r , 1968) are cited in support of this alternative explanation. The results of the present experiment are apparently more consis-tent with the second explanation for the recovery phenomenon. The find-ings of this experiment that retention was disrupted by the ECSs given at 5 minutes and 1 hour but not at 24 hours and 25 hours after training indicates that the ECS-induced amnesia i s not attributable to an inter-ference with retrieval because the ECS-treatment-retest intervals of the present experiment are the same (48 hours) following both ECS treatments so that at the time of retention testing, the level of interfering "noise" in the memory retrieval system, i f induced, would be equivalent. If the effect of the ECSs, according to Weiskrantz's formulation (1966), i s to disturb memory retrieval rather than memory consolidation, the amount of retention disturbed or not disturbed following these ECS treatments should, therefore, be the same. The nature of the present results suggests that the recovery from ECS-induced amnesia i s more lik e l y due to processes (i.e., consolidation) which occur after the ECS treatment. A component which may be formed during this post-ECS consolidation period and which may serve to mediate the recovery from amnesia i s a residual memory trace. (This concept w i l l be discussed further in the next section). Obviously, i f the formation of this residual memory trace occurs subse-quent to the ECS treatment, i t w i l l be dependent on the degree of con-solidation which can go on following the ECS. Miller (1968) and Pagano et a l . (1969) have both provided results which indicate that the rate of recovery from ECS-induced amnesia is related to the severity of the ECS stimulation. No recovery or very l i t t l e recovery may follow when a high intensity ECS is given after learning, but when a low 30 intensity ECS is administered, recovery from amnesia is quite strong. Considered with the evidence of the present experiment, i t seems possible that the greater efficacy of the recovery from amnesia following weaker ECS treatments may be directly related to the amount of post-ECS consoli-dation a c t i v i t i e s . The amount of post-treatment consolidation activity presumably is greater following a weaker ECS. This interpretation i s generally consistent with that of King and Glasser (1970) who suggested that the recovery from amnesia is due to the incomplete disruption of consolidation by the ECS treatment, c) The reminder effect The present evidence that memory consolidation can continue f o l -lowing an ECS also provides a useful theoretical basis for resolving within a consolidation framework some other recent findings which are not easily assimilated into consolidation theory. F i r s t l y , Nachman and Meinecke (1969), Pfingst and King (1969) and Kesner, McDonough,and Doty (1970) have each reported that i f animals were trained in an avoidance response with a one-trial learning paradigm and then given an ECS within seconds of this training, amnesia was observed as usual with this type of experimental procedure upon retest 24 hours later. But i f the same animals were trained again and again given an ECS immediately after the training, very l i t t l e or no amnesia was found upon a second retest. Secondly, Lewis, Misanin,and Miller (1968) and Quartermain, McEwen,and Azmitia (1970) have described conditions under which memory lost after ECS can be restored following appropriate reminders. Animals were trained in passive avoidance and amnesia was induced by post-training ECS. When the animals were then given a reminder shock (a footshock given outside 31 the t r a i n i n g a p p a r a t u s a f t e r t h e r e t e s t t r i a l ) a r e c o v e r y o f r e t e n t i o n was o b s e r v e d . I t a p p e a r s from t h e s e r e s u l t s t h a t ECS d i s r u p t i o n o f r e t e n t i o n was n o t t o t a l , and t h a t r e s i d u a l memory e x p r e s s e d t h r o u g h a r e c o v e r y o f memory f o l l o w i n g a r e m i n d e r o r f o l l o w i n g a second t r a i n i n g -ECS p a i r i n g can s u r v i v e t h e e f f e c t s o f t h e i n i t i a l ECS t r e a t m e n t . B o t h o f t h e s e groups o f f i n d i n g s a r e n o t a p p a r e n t l y c o n s i s t e n t w i t h c o n s o l i d a t i o n t h e o r y b e c a u s e a c c o r d i n g t o t h e c o n s o l i d a t i o n t h e o r y , the e f f e c t s o f t h e ECS a d m i n i s t e r e d i m m e d i a t e l y f o l l o w i n g t r a i n i n g o r i m m e d i a t e l y f o l l o w i n g a second t r a i n i n g t r i a l s h o u l d p r e v e n t r e t e n t i o n by d i s r u p t i n g c o n s o l i d a t i o n ; no r e s i d u a l memory s h o u l d be p r e s e n t once c o n s o l i d a t i o n i s d i s r u p t e d by ECS. That t h i s c o n c l u s i o n i s n o t i n v a r i a b l y t r u e i s s u g g e s t e d by th e e v i d e n c e o f t h e p r e s e n t e x p e r i m e n t . Because memory c o n s o l i d a t i o n s e e m i n g l y can c o n t i n u e f o l l o w i n g an ECS, i t f o l l o w s from t h i s t h a t a r e s i d u a l memory t r a c e m i g h t be formed as a r e s u l t o f c o n s o l i d a t i o n a c t i v i t y w h i c h o c c u r s f o l l o w i n g t h e ECS t r e a t m e n t . As d i s c u s s e d a b o v e, t h i s post-ECS c o n s o l i d a t i o n may be b e h a v i o u r a l l y e x p r e s s e d as a s p o n -taneous r e c o v e r y from a m n e s i a ; a l t e r n a t i v e l y , i t may c o n s i s t o f t h e f o r m a t i o n o f p r o c e s s e s w h i c h a r e t h e b a s i s upon w h i c h a r e m i n d e r f o o t -s h ock o r a se c o n d t r a i n i n g t r i a l ( f o l l o w e d by ECS) can b r i n g a b out r e t e n t i o n The s i g n i f i c a n c e o f a r e s i d u a l memory t r a c e i n a t t e n u a t i n g t h e e f f e c t s o f a second ECS i n d i s t u r b i n g r e t e n t i o n i s c e n t r a l t o K e s n e r e t al.'s (1970) i n t e r p r e t a t i o n o f t h e i r f i n d i n g s . They s u g g e s t : " I t . . . seems p r o b a b l e t h a t an ECS does n o t d e s t r o y i n f o r m a t i o n b u t b l o c k s f u l l development o r a l t e r s t h e a c c e s s i b i l i t y o f such i n f o r m a t i o n . S i m i l a r i n f o r m a t i o n r e c e i v e d a t a l a t e r t i n e may t h e n f u n c t i o n a l l y i n t e r a c t w i t h 32 that from the previous experience". This interpretation i s supported by their finding that when information storage was blocked more effect-ively by giving the ECS very shortly (0 to 0.5 second) after training, more training-ECS pairings can be given before significant retention of the training occurs. From one point of view, i t appears from these results that certain essential components of the memory trace are established very rapidly after acquisition. Although these components of the memory trace are not sufficient to enable the expression of memory in some situations (for example, following the f i r s t training-ECS pairing), they are nevertheless sufficiently established to attenuate greatly the effects of a second ECS as shown by the experiments of Nachman et a l . (1969), Pfingst et a l . (1969), and Kesner et a l . (1970). Previously, Albert (1966b) has provided some results which similarly suggest that some components involved in memory storage are formed rapidly after learning. Like the memory components described by Kesner et a l . (1970) which do not appear to be susceptible to ECS-induced disturbances, Albert found memory components which are immune to the disruptive effect of spreading depression or cathodal polarization since i f anodal po l a r i -zation i s applied shortly after a spreading depression or cathodal polar-ization treatment, the usually induced amnesia i s largely reversed. Presumably, the memory components not destroyed by spreading depression or by cathodal polarization are those components which enabled the at-tenuation of amnesia produced by anodal polarization. Albert (1966b) suggested that these memory components may consist of intracellular molecular changes acting as information holding mechanisms because this type of information holding mechanisms (molecular changes) seems to be 33 t h e s o r t w h i c h may be a b l e t o w i t h s t a n d t h e k i n d s o f e l e c t r i c a l d i s -t u r b a n c e s s u c h as t h o s e c r e a t e d by ECS, s p r e a d i n g d e p r e s s i o n , o r c a t h o d a l p o l a r i z a t i o n . However, t h e r e s i d u a l memory components w h i c h seem t o be r e s p o n s i b l e f o r t h e a t t e n u a t i o n o f the amnesic e f f e c t s o f a second ECS fo u n d i n t h e e x p e r i m e n t s o f K e s n e r e t a l . ( 1 9 7 0 ) , P f i n g s t e t a l . (1969), and Nachman e t a l . (1969) may n o t n e c e s s a r i l y be formed b e f o r e t h e o n s e t o f t h e ECS t r e a t m e n t as s u g g e s t e d by K e s n e r e t a l . I n v i e w o f t h e p r e s e n t e v i d e n c e t h a t c o n s o l i d a t i o n can c o n t i n u e a f t e r ECS, i t i s p o s s i b l e t h a t t h e p r o -c e s s e s w h i c h a r e i n v o l v e d i n t h e f o r m a t i o n o f a r e s i d u a l memory t r a c e may a l s o o c c u r f o l l o w i n g t h e ECS t r e a t m e n t . Of c o u r s e , i f an ECS o f a c e r t a i n p a r a m e t e r i s v e r y e f f e c t i v e i n d i s t u r b i n g c o n s o l i d a t i o n p r o c e s s e s o r i f t h e ECS i s g i v e n v e r y i m m e d i a t e l y f o l l o w i n g a c q u i s i t i o n ( i . e . , 0-0.5 se c o n d as i n K e s n e r e t al.'s e x p e r i m e n t ) , i t i s p r o b a b l e t h a t memory c o n s o l i d a t i o n can be c o m p l e t e l y d i s r u p t e d . The r e s u l t s o f K e s n e r e t a l . (1970) d e s c r i b e d above i l l u s t r a t e s t h i s p o s s i b i l i t y v e r y p r e c i s e l y . I f post-ECS memory c o n s o l i d a t i o n o c c u r s i n t h e e x p e r i m e n t a l s i t -u a t i o n s d i s c u s s e d above, t h e i d e a o f some r e s i d u a l memory h a v i n g a m a j o r f u n c t i o n i n a t t e n u a t i n g t h e e f f e c t s o f t h e s e c o n d ECS t r e a t m e n t a p p e a r s t o be more i n l i n e w i t h c o n s o l i d a t i o n t h e o r y w h i c h assumes t h a t e s t a b -l i s h i n g memory components r e q u i r e a p r o l o n g e d g e s t a t i o n p e r i o d . There i s some e v i d e n c e w h i c h s u g g e s t s t h a t t h e p r o c e s s e s w h i c h seem t o u n d e r l i e the r e c o v e r y from E C S - i n d u c e d amnesia f o l l o w i n g a r e m i n d e r f o o t s h o c k (and p o s s i b l e a l s o f o l l o w i n g a s e c o n d t r a i n i n g - E C S p a i r i n g ) may i n v o l v e c o n s o l i d a t i o n . Q u a r t e r m a i n e t a l . (1970) found t h a t t h e amnesic agent c y c l o h e x i m i d e w h i c h has been found t o d i s r u p t 34 c o n s o l i d a t i o n a f t e r t r a i n i n g (Barondes and Cohen, 1968) d i s t u r b e d i n a s i m i l a r manner when i n j e c t e d b e f o r e t h e r e m i n d e r t r i a l t h e p r o -c e s s e s w h i c h a r e e s s e n t i a l i n r e t e n t i o n r e c o v e r y f o l l o w i n g t h e r e m i n d e r s t i m u l u s . T h i s f i n d i n g s u g g e s t s t h a t t h e r e c o v e r y o f memory i n i t i a t e d by a r e m i n d e r may a l s o i n v o l v e c o n s o l i d a t i o n a c t i v i t y s i n c e i f t h i s r e -s t a r t e d r e c o v e r y p r o c e s s i s p r e c e d e d by a c y c l o h e x i m i d e i n j e c t i o n , t h e r e c o v e r y o f t h e memory i s p r e v e n t e d . Of c o u r s e , t h i s e v i d e n c e i s o n l y t e n t a t i v e , and a d d i t i o n a l e x p e r i m e n t a l v e r i f i c a t i o n i s r e q u i r e d . C o n c l u s i o n The p r e s e n t t h e s i s has c o n s i d e r e d one way o f i n t e r p r e t i n g some o f t h e d a t a on t h e d i s r u p t i o n o f r e t e n t i o n i n d u c e d by an amnesic a g e n t . A number of r e c e n t r e s u l t s i n c l u d i n g t h o s e o f t h e p r e s e n t e x p e r i m e n t s a r e c o n s i s t e n t w i t h t h e 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 may c o n -t i n u e f o l l o w i n g a s i n g l e ECS. T o g e t h e r , t h e s e r e s u l t s s u g g e s t t h a t t h e e f f e c t o f many amnesic t r e a t m e n t s may be t o d i s t u r b t h e c o n d i t i o n s f o r c o n s o l i d a t i o n r a t h e r t h a n t o d e s t r o y t h e i n f o r m a t i o n b e i n g s t o r e d . A c c o r d i n g t o t h i s p o i n t o f v i e w , i t a p p e a r s p o s s i b l e t h a t i f t h e n e c -e s s a r y c o n d i t i o n s ( w h i c h may c o n s i s t o f b i o c h e m i c a l [ B y r n e , 1970] o r b i o e l e c t r i c a l [ J o h n , 1967] changes) f o r c o n s o l i d a t i o n can be r e - e s t a -b l i s h e d f o l l o w i n g an amnesic t r e a t m e n t , t h e development o f l o n g - t e r m memory woul d be p o s s i b l e . I n t h e case o f t h e p r e s e n t e x p e r i m e n t , p r e s u m a b l y , t h e s e c o n d i t i o n s a r e n o t c o m p l e t e l y d e s t r o y e d by t h e f i r s t ECS o r a r e r e - e s t a b l i s h e d s p o n t a n e o u s l y s u c h t h a t p o s t - t r e a t m e n t c o n -s o l i d a t i o n makes p o s s i b l e t h e r e t e n t i o n found f o l l o w i n g t h e s i n g l e ECS t r e a t m e n t g i v e n a t 5 m i n u t e s a f t e r t r a i n i n g . I n s e v e r a l o t h e r r e c e n t e x p e r i m e n t s , t h e r e i s some e v i d e n c e t h a t t h e s e c o n d i t i o n s can be r e -35 established a r t i f i c i a l l y by administering various agents following an amnesic treatment. McGaugh (1968) has reported that the administration of a central nervous system stimulant, strychnine sulphate, can attenuate the amnesic effect of an ECS when given within 3 hours of the ECS treat-ment. Albert (1966b) has found that the disruptive effects of corti c a l spreading depression or of cathodal polarization are greatly reduced when anodal polarization i s applied within several hours afterward. Barondes and Cohen (1968) have found that manipulations which generate "arousal" ( i . e . , footshock, amphetamine) can re-establish long-term memory following a period of cerebral protein synthesis inhibition induced by cycloheximide. This evidence suggests that some i n i t i a l components which are involved in memory storage are not susceptible to the same disturbance as i s consolidation. It appears that these components (i . e . , infor-mation holding mechanisms) may consist of independent and distinct processes which are parts of a very complex sequence of events leading to the eventual storage of information. This general interpretation is in agreement with several more precise elaborations formulated previously ( i . e . , Albert, 1966b; John, 1967). It should also be pointed out that the supporting evidence upon which a l l the issues considered here are based, although substantial, are certainly not complete. The present interpretation acknowledges alternative explanations ( i . e . , Neilson, 1968; Pinel, 1968; Schneider and Sherman, 1968; Spevack and Suboski, 1969; Wiener, 1970) suggested for the basis of the retention deficits produced by amnesic agents. 36 References Adams, H.E., P.R. Hoblit,and P.B. 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