Hippocampal RSA (theta), apnea, bradycardia and effects of atropine during underwater swimming in the rat

Electroencephalography and Clinical Neurophysiology, 1977, 4 2 : 3 8 9 - - 3 9 6

389

© E l s e v i e r / N o r t h - H o l l a n d Scientific Publishers Ltd.

HIPPOCAMPAL RSA (THETA), APNEA, B R A D Y C A R D I A AND EFFECTS OF ATROPINE U N D E R W A T E R SWIMMING IN THE R A T *

DURING

IAN Q. WHISHAW ** a n d T I M O T H Y S C H A L L E R T

Department of Psychology, University of Lethbridge, Lethbridge, Alberta (Canada) ( A c c e p t e d for p u b l i c a t i o n : J u n e 17, 1 9 7 6 )

Many electroenceph alographic (EEG) studies have shown that the rhythmical slow activity (RSA or theta rhythm) which can be recorded from the hippocampus proper and dentate gyrus in the rat (Winson 1974; Bland and Whishaw 1976) is closely related to concurrent voluntary or Type I m o t o r activity (Vanderwolf 1969, 1975; Whishaw and Vanderwolf 1973). Amplitude and frequency may also be related to the details of movement; amplitude increases as the size of movement increases, while frequency increases with the force or vigor with which a movement is initiated (Whishaw and Vanderwolf 1973). However, during continuous l o c o m o t o r activity such as walking, trotting, or swimming, RSA frequency remains constant (Bland and Vanderwolf 1972; Whishaw and Vanderwolf 1973). The significance of the RSA relation to m o v e m e n t is n o t known b u t these studies have suggested that RSA may be a sign that the hippocampus is involved in some way with the organization and execution of movement. The attention of researchers has been drawn to the possibility that RSA may be related to other rhythmical physiological or behavioral activity such as respiration (or sniffing), heart rate, and vibrissae movements (Komisaruk 1970; Kurtz and Adler 1973; Macrides 1975). Theoretically, RSA could be an artifact, a physiological sign, or, as sug* This research was s u p p o r t e d by the N a t i o n a l Research C o u n c i l of Canada, G r a n t No. A 8 2 7 3 . ** T o w h o m r e p r i n t s s h o u l d be addressed.

gested ~by Komisaruk (1970), a direct pacemaker of such rhythmical peripheral events. Finally, RSA could have a modulatory action such as has been suggested for sniffing (Macrides 1975). The purpose of the present experiment was to vary respiration, heart rate, and vibrissae movement and observe concomitant change in hippocampal RSA. A naturally occurring behavior was chosen for observation since physiological manipulations, such as brain stimulation which has been used to dissociate heart rate and RSA (Whishaw et al. 1972), may not accurately reflect normal relations. One way to arrest respiration, sniffing, and vibrissae movement is to have a rat swim underwater. If these events are related to RSA it would be expected that RSA might change or be absent during the apnea (respiratory arrest) of underwater swimming. If, on the other hand, RSA is related solely to movement it would be expected that RSA could remain relatively unchanged. It was expected that heart rate might change in frequency since all diving vertebrates examined show slowing of the heart (bradycardia) during underwater swimming (Andersen 1966). Electrocardiograph (EKG) records have not been taken in the rat during diving. Therefore, we recorded EKG activity and related it to RSA during underwater and surface swimming. In addition to describing physiological changes this paper describes simple techniques for obtaining EEG and EKG during surface and underwater swimming.

390 Methods

A nim a ls Twelve adult ( 4 0 0 - - 5 0 0 g) male S p r a g u e - D a w l e y rats were used in the e x p e r i m e n t s . Surgical procedure Animals were a n e s t h e t i z e d w i t h s o d i u m p e n t o b a r b i t a l (50 m g / k g , i n t r a p e r i t o n e a l ) and E E G and E K G e l e c t r o d e s i m p l a n t e d . Bipolar r e c o r d i n g e l e c t r o d e s were i m p l a n t e d in each dorsal h i p p o c a m p u s and s e n s o r i - m o t o r c o r t e x . Coordinates for hippocampal placements were: 4.0 m m p o s t e r i o r and 2.5 m m lateral to b r e g m a , and 3.5 m m ventral f r o m the skull surface. C o o r d i n a t e s f o r n e o c o r t i c a l elect r o d e s were: 1.0 m m anterior, 1.0 m m lateral and 1.5 m m ventral. T h e skull was aligned with b r e g m a and l a m b d a on the h o r i z o n t a l plane. E l e c t r o d e s consisted o f t w o 250 p N i c h r o m e wires insulated to t h e cross-section o f the tips. T h e tips were staggered 0 . 5 - 1.0 m m . Male c o n n e c t o r s w e r e soldered to the wires a n d the assemblies w e r e fixed in place with d e n t a l c e m e n t a n c h o r e d t o j e w e l e r ' s screws inserted in the skull. A m a l e c o n n e c t o r soldered to a j e w e l e r ' s screw in the f r o n t a l b o n e served as a g r o u n d c o n n e c t i o n during recording. E l e c t r o d e s for E K G r e c o r d i n g w e r e 1 cm d i a m e t e r gold plated discs sewed into cutane o u s m a x i m u s muscles over the ventral segm e n t of the 6 t h rib. (A n u m b e r of E K G rec o r d i n g e l e c t r o d e s were tested b u t only the discs w e r e f o u n d to p r o d u c e artifact-free r e c o r d i n g during v i g o r o u s m o v e m e n t . ) T h e wires f r o m the discs w e r e d r a w n up u n d e r the skin and soldered to m a l e c o n n e c t o r s which were fixed to the skull w i t h dental c e m e n t . Recording and data analysis T h e rats were c o n n e c t e d to a p o l y g r a p h w i t h shielded p h o n o - a r m cable. C o n n e c t i o n s on the head a s s e m b l y were w a t e r - p r o o f e d b y c o a t i n g t h e m with m e l t e d p a r a f f i n w a x (congealing p o i n t 49°C). When t h e w a x h a r d e n e d the c o n n e c t i o n s w e r e shielded f r o m w a t e r and f i r m l y s u p p o r t e d so t h a t m o v e m e n t

I.Q. WIfISI-tAW, T. SCttALLERT a r t i f a c t was eliminated. EEG activity was r e c o r d e d with h a l f - a m p l i t u d e filters set at 1 and 75 c/see; E K G with filters at 10 and 75 c/see. A m a n u a l l y activated m a r k e r was used to indicate b e h a v i o r on the chart. R e c o r d s were a n a l y z e d by m e a s u r i n g f r e q u e n c y and a m p l i t u d e of individual waves with a clear plastic ruler (ram scale) as p r e v i o u s l y described (Whishaw and V a n d e r w o l f 1973).

Drugs A t r o p i n e sulfate (50 m g / k g ) was dissolved in a physiological saline vehicle and given via the i n t r a p e r i t o n e a l route. Procedure R e c o r d i n g s were m a d e w h e n the rats were s w i m m i n g on the surface or u n d e r w a t e r in a 108 × 108 c m t a n k filled to a d e p t h o f 30 cm with 38°C water. Animals were forced to swim u n d e r w a t e r b y placing t h e m at the b o t t o m of t h e tank. T h e y s w a m spont a n e o u s l y to the surface or, if light pressure was app]ied to their backs, t h e y s w a m across t h e t a n k and t h e n s w a m to t h e surface. Each rat was required to swim across the t a n k b o t h on the surface and u n d e r w a t e r 6 t i m e s with surface and u n d e r w a t e r trials given in r a n d o m order. Core t e m p e r a t u r e was m o n i t o r e d before and a f t e r the s w i m m i n g tests with a rectal p r o b e inserted 6.5 cm. E E G activity was r e c o r d e d f r o m 7 rats d u r i n g u n d e r w a t e r and surface s w i m m i n g . E E G and E K G were r e c o r d e d f r o m 5 additional animals b e f o r e and a f t e r 50 m g / k g a t r o p i n e sulfate.

Results The p a t t e r n o f s w i m m i n g in t h e r a t has been previously described (Whishaw and Vanderwolf 1971). Usually the animals p a d d l e d using their hind legs with the f r o n t p a w s t u c k e d u p u n d e r their chins. T h e f r o n t paws o c c a s i o n a l l y were used f o r s w i m m i n g , p a r t i c u l a r l y w h e n the animals were turning. Vibrissae m o v e m e n t s did n o t occur. T h e

HIPPOCAMPAL RSA AND UNDERWATER SWIMMING

pattern of swimming underwater appeared identical to that displayed during surface swimming except that respiration was arrested and the nostrils were closed. The EEG recordings showed that hippocampal RSA and neocortical desynchronization occurred during both surface and underwater swimming. An example of hippocampal and neocortical EEG during surface and underwater swimming is shown in Fig. 1. Measures of RSA frequency during surface swimming showed that the mean frequency and standard errors were 8.3 + 0.11 c/sec (range, 7.7--9.0 c/sec; measure based on 10 sec samples/condition/rat). RSA frequency during underwater swimming was reduced in every animal resulting in an overall mean of 7.7 +- 0.10 c/sec (range, 6.6--8.8 c/sec). This difference was significant; t (6) = 5.5, P

391

< 0.01. The distribution of RSA frequency based on measures of individual waves is shown in Fig. 2. It can be seen in Fig. 2 that the entire frequency spectrum was slower during underwater as compared to surface swimming.

Effects of atropine Hippocampal RSA and neocortical desynchronization were recorded during surface and underwater swimming after rats were given atropine sulfate (50 mg/kg). Mean RSA frequency during surface swimming was 8.4 +0.7 c/sec (range, 7.3--8.6 c/sec). During underwater swimming, RSA frequency was reduced in every animal and the overall mean reduction {0.60 c/sec) was significant; t (4) = 4.4, P < 0.05. Thus, the mean RSA frequency during the

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392

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Heart rate Fig. 3 shows the d r a m a t i c b r a d y c a r d i a r e c o r d e d during u n d e r w a t e r swimming. H e a r t rate was slowed significantly f r o m a m e a n of 8.1 + 0.12 c/see (range, 7.2--8.9 c/see) during surface swimming to a mean of 2.7 + 0.3 c/see (range, 1.2--3.1 c/see) during u n d e r w a t e r swimming. Also, during u n d e r w a t e r swimming h e a r t rate was irregular with some 1 sec e p o c h s c o n t a i n i n g n o h e a r t beats, others c o n t a i n i n g 1--3 beats. B r a d y c a r d i a o c c u r r e d with s p o n t a n e o u s diving as well as with f o r c e d submersion. It has been suggested t h a t b r a d y c a r d i a is i n d u c e d as a reflex response to w a t e r pressure a r o u n d the nasal cavity (Andersen 1963). We investigated this by holding the nose of a rat closed for 1--2 sec. When respiration was arrested by nose holding b r a d y c a r d i a similar to t h a t r e c o r d e d during u n d e r w a t e r swimming occurred. Diving b r a d y c a r d i a was b l o c k e d by injection of a t r o p i n e sulfate (50 mg/kg) as shown in Fig. 3. Mean h e a r t rate for a t r o p i n i z e d rats was 7.8 :t 0.10 c/sec (range, 7.3--8.5 c/see) during u n d e r w a t e r swimming and 8.0 ÷ 0.4 c/see (range, 7.4--8.6 c/sec) during surface swimming. This d i f f e r e n c e was n o t significant. Moreover, the mean h e a r t rate for atropinized rats during surface and u n d e r w a t e r swimming was n o t significantly d i f f e r e n t f r o m nona t r o p i n i z e d rats during surface swimming.

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HIPPOCAMPAL RSA AND UNDERWATER SWIMMING

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Discussion Despite the presence o f apnea, marked bradycardia, and vibrissae arrest, hippocampal RSA always accompanied the m o v e m e n t associated with u n d e r w a t e r swimming in the rat. These results do n o t s u p p o r t the suggestion t h a t there is a causal relation between these peripheral r h y t h m i c a l activities and RSA (Komisaruk 1970; Kurtz and Adler 1973). Specifically, RSA could n o t be an artifact or a central sign of respiratory, heart, or vibrissae activity. It also is improbable t h a t RSA is a direct m o t o r pacemaker for such activity as suggested by Komisaruk (1970). Although the f r e q u e n c y of swimming-induced RSA is reduced underwater, the small magnitude of the change c o m p a r e d to the marked respiratory and cardiac effects

suggests that RSA probably does n o t directly control these processes. Other studies also have shown that RSA and peripheral rhythmical events are n o t necessarily associated and have f o u n d that the frequency and phase o f RSA and these events o f t e n differ (Whishaw and Vanderwolf 1971; Whishaw 1972; Whishaw et al. 1972; Vanderwolf et al. 1975). However, the observation that RSA and respiration can be entrained (Macrides 1975} should be considered imp o r t a n t since it may suggest that under some circumstances RSA may m o d u l a t e sniffing. Considering all of this evidence it would appear t h a t hippocampal RSA recorded during voluntary m o v e m e n t is related specifically to the neural control of that m o v e m e n t as suggested previously (Vanderwolf 1969). Perhaps the frequencies of events such as re-

394 spiration and heart beat sometimes vary with the frequency of RSA because they also can vary with movement changes (Vanderwolf and Vanderwart 1970; Smith 1973) and/or because the neurons at many different locations have similar characteristics. Recent studies (Kramis et al. 1975; Vanderwolf 1975; Whishaw 1976; Whishaw et al. 1976) have reported that there are two types of RSA. One type of RSA is atropine sensitive, has a slightly slower frequency than the other, and is not related to overt movement. In this study we considered the possibility that the slower RSA recorded during underwater, as compared to surface, swimming might be the atropine sensitive type. However, after rats were given atropine in sufficient dose to abolish atropine sensitive RSA, RSA was still present with unchanged amplitude and frequency during underwater swimming. We concluded, therefore, that the RSA recorded during surface and underwater swimming was the same type despite the difference in frequency. The slowing of RSA frequency observed during underwater swimming should be considered a significant finding. It would be the first report of an immediate change in brain electrical activity with underwater swimming, although Elsner et al. (1970) found that the EEG of seals slowed significantly after prolonged oxygen deprivation. It seems unlikely that the RSA frequency reduction was due to hypoxia (Sainio 1972) since frequency returned to normal as soon as the animals surfaced and studies have shown that the brain receives an adequate oxygen supply during brief dives (Johansen 1964; Kerem and Elsner 1973). We considered the possibility that the reduced frequency of RSA was due to a change in motor pattern or vigor of movement. However, visual observation suggested that there was no difference between underwater and surface swimming. It is thus possible that like bradycardia, the rapid reduction in RSA frequency is related to the oxygen conservation process which occurs in diving animals.

I.Q. WHISHAW,T. SCHALLERT Andersen (1966) reported that bradycardia occurs during underwater swimming in all diving vertebrates which have been studied. Although diving bradycardia, as such, had not been reported in the laboratory rat prior to the present study, Richter (1957) had reported bradycardia as part of the sudden death response to water immersion stress in the wild rat. In view of the present findings, it seems possible that the bradycardia was due to the apnea and not necessarily the stress associated with water immersion. The present results also support the suggestion that bradycardia is related to vagal activity since it was abolished by atropine as reported first by Richet 11894) in his studies with ducks. In the rat, as in the duck (Andersen 1963) or seal (Dykes 1974), bradycardia was activated as a reflex response to head immersion. Pressure on the nostrils which precluded respiration also produced bradycardia suggesting that receptors around the snout may mediate the reflex through their trigeminal projection. Finally, the onset of bradycardia with immersion was immediate, as demonstrated in natural divers (Andersen

1966). Summary Hippocampal RSA (theta), neocortical EEG, and heart rate were recorded during surface and underwater swimming in the rat. RSA was present with slightly reduced frequency during the apnea, bradycardia, and vibrissae arrest associated with underwater swimming. Atropine sulfate (50 mg/kg) blocked bradycardia but did n o t affect RSA. Contrary to previous suggestions, no causal relation was found between RSA and respiration, heart rate, or vibrissae movement. The study supports the view that RSA is related to the neural control of voluntary movement. It is suggested that the slight reduction in RSA frequency during underwater swimming may be part of an oxygen conservation process.

HIPPOCAMPAL RSA AND UNDERWATER SWIMMING R~sum~

L'activit~ lente r yt hm i que de l'hippocampe (thSta), l'apn~e et la bradycardie, et les effets de l'atropine observes au cours de la nage sous l'eau du rat On a enregistr~ l'activit~ lente rythmique d e l ' h i p p o c a m p e ( t h & a ) , le E E G n ~ o c o r t i c a l , e t le r y t h m e c a r d i a q u e d u r a t p e n d a n t q u ' i l nageait ~ la surface et sous l'eau. Pendant l ' a p n ~ e , la b r a d y c a r d i e , e t l ' a r r & d e la v i b r i s s e a s s o c i ~ s ~ la n a g e s o u s l ' e a u , o n a c o n s t a t ~ la p r & e n c e d e l ' a c t i v i t ~ l e n t e v y t h m i q u e a v e c une fr~quence l~g~rement diminu~e. Le sulfate d ' a t r o p i n e ( 5 0 m g / k g ) a a r r & ~ la b r a d y c a r d i e mais n'a pas influenc~ l'activit~ lente rythmique. A l'encontre des suggestions ant~rieures, o n n ' a c o n s t a t ~ a u c u n r a p p o r t d e c a u s e ~ eff e t e n t r e l ' a c t i v i t ~ l e n t e r y t h m i q u e e t le r y t h m e respiratoire, nile r y t h m e c a r d i a q u e , ni le mouvement de la vibrisse. Cette &ude soutient l'hypoth&e que l'activit~ lente rythmique existe en correlation a v e c le mouvement volontaire. On sugg~re que la l~g~re d i m i n u t i o n d e l a f r ~ q u e n c e d e l ' a c t i v i t ~ lente rythmique au cours de la nage sous l ' e a u p e u t f a i r e p a r t i e d ' u n e o p e r a t i o n d e la conservation d'oxyg~ne.

References Andersen, H.T. The reflex nature of the physiological adjustments to diving, their afferent pathway. Acta physiol, scand., 1963, 58: 263--273. Andersen, H.T. Physiological adaptions in diving vertebrates. Physiol. Rev., 1966, 46: 212--243. Bland, B.H. and Vanderwolf, C.H. Diencephalic and hippoeampal mechanisms of motor activity in the rat: Effects of posterior hypothalamic stimulation on behavior and hippocampal slow activity. Brain Res., 1972, 43: 67--88. Bland, B.H. and Whishaw, I.Q. Generators and topography of hippocampal theta (RSA) in the acute and freely moving rat. Brain Res., 1976, in press. Dykes, R.W. Factors related to the dive reflex in harbor seals: Respiration, immersion bradycardia, and lability of the heart rate. Canad. J. Physiol. Pharmacol., 1974, 52: 248--258. Elsner, R., Shurley, J.T., Hammons, D.D. and Brooks,

395 R.E. Cerebral tolerance to hypoxemia in asphyxiated Weddell seals. Respir. Physiol., 1970, 9: 287--297. Johansen, K. Regional distribution of circulating blood during submersion asphyxia in the duck. Acta physiol, scand., 1964, 62: 1--9. Kerem, D. and Eisner, R. Cerebral tolerance to asphyxial hypoxia in the harbor seal. Respir. Physiol., 1973, 19: 188--200. Komisaruk, B. Synchrony between limbie system theta activity and rhythmical behavior in rats. J. comp. physiol. Psychol., 1970, 70: 482--492. Kramis, R., Vanderwolf, C.H. and Bland, B.H. Two types of hippocampal rhythmical slow activity in both the rabbit and the rat: Relations to behavior and effects of atropine, dietbyl ether, urethane, and pentobarbital. Exp. Neurol., 1975, 49: 58-85. Kurtz, R.G. and Adler, N.T. Electrophysiological correlates of copulatory behavior in the male rat: Evidence for a sexual inhibitory process. J. comp. physiol. Psychol., 1973, 84: 225--239. Macrides, F. Temporal relationships between hippocampal slow waves and exploratory sniffing in hamsters. Behav. Biol., 1975, 14: 295--308. Richet, C. Influence de l'atropine sur la dur~e de l'asphyxie chez canard. C.R. Soc. Biol. (Paris), 1894, 1: 789--790. Richter, C.P. On the phenomenon of sudden death in animals and man. Psychosom. Med., 1957, 3: 192--198. Sainio, K. Computer analysis of rabbit EEG after cerebral ischemia. Electroenceph. clin. Neurophysiol., 1974, 36: 471--479. Smith, K.U. Physiological and sensory feedback of the motor system: Neural metabolic integration for energy regulation in behavior. In J.D. Maser (Ed.), Efferent organization and integration of behavior. Academic Press, New York, 1973: 19--66. Vanderwolf, C.H. Hippocampal electrical activity and voluntary movement in the rat. Electroenceph. clin. Neurophysiol., 1969, 26: 407--418. Vanderwolf, C.H. Neocortical and hippocampal activation in relation to behavior: Effects of atropine, eserine, phenothiazines and amphetamine. J. comp. physiol. Psychol., 1975, 88: 300--323. Vanderwolf, C.H. and Vanderwart, M.L. Relations of heart rate to motor activity and arousal in the rat. Canad. J. Psychol., 1970, 24: 434--441. Vanderwolf, C.H., Kramis, R., Gillepsie, L.A. and Bland, B.H. Hippocampal rythmical slow activity and neocortical low-voltage fast activity: Relations to behavior. In: R.L. Isaacson and K.H. Pribram (Eds.), The Hippocampus; Vol. 2, Neurophysiology and Behavior, Plenum, New York, 1975, pp. 101-128. Whishaw, I.Q. Hippocampal eleetroencephalographic activity in the mongolian gerbil during natural he-

396 haviours and wheel running and in the rat during wheel running and conditioned immobility. Canad. J. Psychol., 1972, 26: 219--239. Whishaw, I.Q. The effects of alcohol and atropine on EEG and behavior in the rabbit. Psychopharmacologia (Berl.), 1976, 48: 83--90. Whishaw, I.Q. and Vanderwolf, C.H. Hippocampal EEG and behavior: Effects of variation in body temperature and relation of EEG to vibrissae movement, swimming and shivering. Physiol. Behav., 1971, 6: 391--397. Whishaw, I.Q. and Vanderwolf, C.H. Hippocampal EEG and behavior: Changes in amplitude and frequency of RSA (theta rhythm) associated with spontaneous and learned movement patterns in

I.Q. WHISHAW, T. SCHALLERT J~ats and cats. Behav. Biol., 1973, 8: 461--484. Whishaw, I.Q., Bland, B.H. and Vanderwolf, C.H. Hippocampal activity, behavior, self-stimulation, and heart rate during electrical stimulation of the lateral hypothalamus, d. comp. physiol. Psyehol., 1972, 79: 115--127. Whishaw, I.Q., Rohinson, T.E. and Schallert, T_ lntraventricular anti-cholinergics do not block choLinergic hippocampal RSA or neocortical desynchronization in the rabbit or rat. Pharmacol. Bio chem. Behav., J976, in press. Winson, J. Patterns of hippocampal theta rhythm in freely moving ral. Electroenceph. clin. Neurophysiol., 1974, 3 6 : 2 9 l - - 3 0 1