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Flight behaviour elicited by electrical stimulation of the hypothalamus and midbrain in rats : Escape… Clarke, Robert John 1972

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FLIGHT BEHAVIOUR ELICITED BY ELECTRICAL STIMULATION OF THE HYPOTHALAMUS AND MIDBRAIN IN RATS: ESCAPE AND AVOIDANCE PROPERTIES by ROBERT JOHN CLARKE B.Sc., U n i v e r s i t y of B r i t i s h Columbia, 1969 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the Kinsmen Laboratory of N e u r o l o g i c a l Research DEPARTMENT OF PSYCHIATRY We accept t h i s t h e s i s as conforming to the re q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA May, 1972 In presenting t h i s thesis i n p a r t i a l fulfilment of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t freely available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The University of B r i t i s h Columbia Vancouver 8 , Canada ABSTRACT Emotional, motivational, or species-specific behaviour can be el i c i t e d by intracranial e l e c t r i c a l stimulation (ICS) in unanesthe-tized and unrestrained animals with chronically implanted electrodes. The purpose of this investigation was to describe and quantify, using an escape and avoidance task, a behaviour called f l i g h t , using rats as the experimental animal. An enclosed test box was used that had a hole in one wall covered by a moveable clear plastic plate. With the interior light on and exterior lights off, the hole represented the only opening in the box. Flight was then operationally defined as plate-pushing in response to ICS (escape response). It was found that only 25% of rats which showed manifestations of f l i g h t on pre-test screening would perform the escape response. After establishing reliable escape, the rats were given the opportunity to avoid ICS, at the thres-hold voltage for escape, by responding to a signal (bell, light or click) predicting the occurrence of ICS. In over 200 t r i a l s there were at most only 107o avoidances and no tendency for faster responding. A current explanation for this, proposed by W. W. Roberts, was tested by allowing these rats to press a bar for brief ICS at the voltage used in avoidance. Only 407o of the subjects would self-stimulate. These, and other results from the literature suggest that rewarding onset of ICS, as in the Roberts hypothesis, is insufficient to explain the lack of avoidance. The electrode sites producing escape were found to be in the central gray of the midbrain, and in both the medial and lateral divisions of the middle to posterior hypothalamus near the fornix. The sites pro-ducing similar behavioural manifestations but not escape were found to be in the same regions of the hypothalamus and midbrain. i i i TABLE OF CONTENTS Page Abstract i i -Table of Contents i i i L i s t of Tables i v L i s t of Figures » v Acknowledgement v i Introduction D e f i n i t i o n of theories 1 (a) Emotion 1 (b) Motivation 5 Research leading to the present i n v e s t i g a t i o n 9 (a) Description: e f f e c t s and l o c a t i o n 9 (b) Q u a n t i f i c a t i o n of ICS behaviour 14 (c) Conditioning 17 (d) Summary 21 Methods Subjects o 22 Surgery .' 22 Apparatus 23 Procedure 28 (a) Screening ; 28 (b) Escape t r a i n i n g 28 (c) Avoidance t r a i n i n g 29 (d) S e l f - s t i m u l a t i o n 30 (e) Histology 30 Results Stimulation e f f e c t s 32 Escape 35 Avoidance 40 Se l f - s t i m u l a t i o n 44 Histology 44 Discussion 49 References 59 i v LIST OF TABLES Table Page I Type and frequency of stimulation e f f e c t s i n hypothalamus and midbrain 34 II Behaviour, l o c a t i o n , threshold and number of t r i a l s for escape subjects 36 III Mean response time per session (+ standard deviation) for each subject and WS modality 42 IV Average bar pressing rate with and without ICS at the voltage indicated 45 LIST OF FIGURES Figure Page 1 Side view of one wall of the plate box 25 2 Semischematic diagram of the escape training apparatus 26 3 Semischematic diagram of the avoidance training apparatus 27 4 Mean escape time versus stimulating voltage for subjects 43, 48, 50 and 56 38 5 Escape latency as a function of time for subjects 48 and 56 39 6 Mean latency (+ standard deviation) per session for a l l subjects as a function of the number of training sessions 41 7 Location of electrodes producing escape by plate-pushing 46 8 Location of electrodes f a i l i n g to produce • escape by plate-pushing 47 ACKNOWLEDGEMENT I would like to thank Dr. Juhn A. Wada for his advice and encouragement in a l l aspects of the research and preparation of this thesis. Greatly appreciated was the technical assistance of Ed Jung Anne Hamm and Marina Koskinen. Thanks also go to the faculty, staff and students of the Kinsmen Laboratory of Neurological Research for many favours, great and small, throughout my association with them. The financial support of the Department of Psychiatry, and the Medical Research Council of Canada through a grant to Dr. J. A. Wada is gratefully acknowledged. 1 INTRODUCTION A new understanding of the n e u r a l mechanisms of emotional and motivated behaviour has been brought about through the use of e l e c t r o d e s c h r o n i c a l l y implanted i n the b r a i n s of unanesthetized and u n r e s t r a i n e d animals. I t was found that e l e c t r i c a l s t i m u l a t i o n of d i s c r e t e b r a i n areas ( i n t r a c r a n i a l s t i m u l a t i o n , ICS) could induce complex behaviours resembling those seen during normal emotional and m o t i v a t i o n a l s t a t e s . This lead to the development of a method to q u a n t i f y t h i s behaviour and to determine i t s p r o p e r t i e s w i t h respect to n a t u r a l l y e l i c i t e d s t a t e s . D e f i n i t i o n s and t h e o r i e s . The concepts of emotion and m o t i v a t i o n are complex and the d i f f i -c u l t y of p r o v i d i n g an adequate d e f i n i t i o n has been q u i t e apparent i n recent reviews (Brady, 1960; Grossman, 1967; G o l d s t e i n , 1968). Of p a r t i c u l a r i n t e r e s t here i s a concept that i s r e l e v a n t to how an o r -ganism s u r v i v e s i n i t s environment. Most t h e o r e t i c a l explanations have three components: i n i t i a t i n g s t i m u l i , c e n t r a l s t a t e , response. For each theory, the d e f i n i t i o n f o l l o w s from the emphasis placed on one or more components. (a) Emotion. There have been d e f i n i t i o n s of emotion i n ages past. Bindra (1970) i n a h i s t o r i c a l review of emotion, and Masserman (1941) i n h i s i n t r o d u c t i o n have i n d i c a t e d that s i n c e the Greek p h i l o s o p h e r s , man has been aware of h i s "passions" and has attempted to l o c a l i z e them - 2 -to such regions as the heart, the pineal body or the ventricles. The modern story of emotions is considered by most people to begin with the ideas of William James which were published in his "Principles of Psychology" in 1890. He recognized that emotion had two aspects: the experiential and the expressive; the former being the subjective feelings, the latter the.autonomic and somatic changes. The third component of the theory was the "exciting fact". According to James the order of events was: exciting fact, expression, experience. Such a counterintuitive approach ensured that the theory would be remembered for years to come. A similar peripheral theory of emotion was pro-posed by Carl Lange at the same time. These theories are known collec-tively as the James-Lange theory and the implications of i t are s t i l l a matter of controversy (Fehr and Stern, 1970; Valins, 1970). Although James1 original formulation was in introspective ter-minology and thus untestable, considerable research involving peri-pheral manifestations of emotion was stimulated. This research neces-sa r i l y involves human subjects because a verbal report as to how the subject "feels" is needed. Yet due to possible confusion between the concepts of experience and expression, or a disregard for the difference, many experimenters have inferred the presence of affect in animal sub-jects (Goldstein, 1968). It is clear then that animals should not be used as subjects in experiments testing the theory that emotional ex-perience is due to the feedback of peripheral behavioural information. The central mechanisms of emotional experience and expression, have been accented in several theories. Cannon (1927, 1931) brought - 3 -out a thalamic theory as an a l t e r n a t i v e to that of James-Lange. Cannon recognized that experience and expression were separate, a t t r i b u t i n g these to a c t i v i t y i n the thalamus. He postulated the thalamus as a "center" of emotion which added an "emotional quale" to the incoming sensory s t i m u l i on their way to the cortex. Dis-i n h i b i t i o n of the thalamus by the cortex caused the expression to occur through autonomic and somatic pathways near the hypothalamus. One of the main points of Cannon's theory i s the c o r t i c a l i n -h i b i t i o n of the thalamus. Arnold (1950, 1960) i n her theory, saw t h i s as being an e x c i t a t o r y connection. This theory was considerably more complex than Cannon's since i t attempted to r e c o n c i l e not only c e n t r a l and peripheral theories ( i . e . James-Lange) but a l l the experi-mental evidence, of which there was a considerable amount at that time. Furthermore, she attempts to a t t r i b u t e various emotional reactions to s p e c i f i c parts of the brain. Hebb's theory i s even more speculative and hypothetical than Arnold's, and Lindsley's accounts better the experimental findings (Goldstein, 1968). Hebb formulated a theory about hypothetical neural mechanisms which when disrupted produced emotion. Lindsley's a c t i v a t i o n theory summarizes the r e l a t i o n s h i p between the e l e c t r i c a l a c t i v i t y of the brain and emotional arousal. Besides Cannon's theory, the most i n f l u e n t i a l theory of emotion has been that of James Papez (1937). Papez was an anatomist and while looking for a r e l a t i o n s h i p among the structures in the medial wall of the hemispheres formulated a r e l a t i o n s h i p between these structures - 4 -and the a v a i l a b l e evidence on emotion. He considered the cortex of the cingulate gyrus as the place mediating emotional experience. The impulses reached the cingulate gyrus by way of the hypothalamus and went out again the same way. The r o l e of the hypothalamus i n the ex-pression of emotion was emphasized i n a d d i t i o n to i t s many r e c i p r o c a l connections to structures involved i n emotional experience. MacLean (1949) enlarged the anatomical bounds of Papez's concept and agreed that the hypothalamus was an e s s e n t i a l part of the e f f e c t o r mechanism of emotion. In ad d i t i o n to the structures commonly regarded as part of the limbic system or " v i s c e r a l b r a i n " as he c a l l e d i t , MacLean (1955) suggested that the c e n t r a l gray of the brainstem was "interdependent" on the limbic system with regard to emotional processes. The evidence for a l l these c e n t r a l theories was derived at f i r s t from a b l a t i o n studies on animals and c l i n i c a l observations on man. The f i r s t experiments were transections of the brainstem at various l e v e l s done by Goltz, Woodworth and Sherrington, Dusser de Barenne and Cannon (Brady, 1960). These transections produced rage responses which were better integrated with the diencephalon i n t a c t than with only the mid-brain i n t a c t . I t seemed that as one progressed r o s t r a l l y i n the b r a i n -stem, the autonomic components, at l e a s t , of the rage response became more complete. Bard (1928) determined that the structure e s s e n t i a l for well coordinated and d i r e c t e d rage behaviour was the hypothalamus. Other emotional behaviours as the r e s u l t of a b l a t i o n were reported by Kluver and Bucy (1939) for temporal lobe lesions i n monkeys. There were many - 5 -other examples of both limbic and c o r t i c a l structures which when removed or damaged produced changes i n behaviour and emotionality (Grossman, 1967). Further evidence for the r o l e of brain structures i n emotion was derived from studies i n which d i s c r e t e areas of the b r a i n were stimulated e l e c t r i c a l l y . This technique which has done so much to provide information on the brain was popularized by the Nobel Prize winner W. R. Hess (1954). By l o c a l i z i n g the electrode t i p , he and his coworkers were able to map most of the brain with respect to the stimulating e f f e c t s . The hypothalamus and v i c i n i t y were found to pro-duce, on stimulation, responses such as fear and anger. This and sub-sequent studies found that stimulation of the hypothalamus produced not only emotional responses such as rage and fear but also motiva-t i o n a l behaviour such as feeding, drinking and copulating (Grossman, 1967; Thompson, 1967). (b) Motivation. In the past emotional states such as anger, f e a r , joy, depression, have been considered conceptually apart from motivational states such as hunger, t h i r s t , sexual desire and maternal care (Bindra, 1969). Emotions tend to be unorganized, involve high l e v e l s of arousal and occur i r r e g u l a r l y due to chance external f a c t o r s . Bindra has shown that there are more s i m i l a r i t i e s than di f f e r e n c e s between the two con-cepts and has proposed a theory to explain them on the basis of a common construct c a l l e d " c e n t r a l motive s t a t e " . - 6 -The current view is to consider emotion as a special class of motivated behaviour (Milner, 1970). Milner defines motivation as "certain hypothetical states of the nervous system that determine what actions the organism w i l l perform at any moment" (p. 297). The example given is of a dog which eats because i t is hungry. Hunger, the central state, is a form of motivation in this case. Another example is a dog which runs because i t is afraid. Fear i s the central state and is a form of motivation. This central state can be operationally defined by quantifying the actions of the animal when i t obtains food or runs to a safe place. As with emotion, there is a tendency to imply a central subjective state in addition to any behavioural meaning. Milner suggests that the term emotion should be reserved for the introspected central states with the hope that the dif -ference between subjective state and overt behaviour would be made clear by the terminology. Stellar's (1960) view of motivation is in terms of drive, goal-directed activity and satiation. Satiety is the reduction of motivated behaviour following the achievement of a goal. Drive is the intensity of motivated behaviour. The other term is self-explanatory. The experi-mental measure of these involves consummatory behaviour under various conditions. This terminology has been developed because the typical examples of consummatory behaviour have been eating and drinking. The concept has been extended to include also such behaviour as the avoidance of noxious stimulation. - 7 -Stellar has suggested a neural mechanism for motivated behaviour. His earlier theory (1954) stresses heavily the role of the hypothalamus. This is due to the strong evidence for a lateral excitatory and medial inhibitory hypothalamic system in the regulation of food intake. Stellar, using this model, generalized i t to include other motivated behaviour and added enough factors to make i t work and account for available evidence. His more recent paper (1960) reiterates the role of the hypothalamus and acknowledges even more factors which act on the system. One of these factors is learning, and how previously neutral stimuli can become asso-ciated with the arousal of motivation. The role of stimuli in motivation has yet to be considered. In addition to behaviour, which can be measured, and the hypothetical cen-t r a l state defined as motivation by this measurement there is a stimulus (or stimuli) which initiates them. Some theories explain emotion and motivation on the basis of the stimuli which e l i c i t them. Hammond (1970) specified these stimuli as either rewards or punishments or the absence of them. They can also be stimuli which can predict the occurrence of reward or punishment. This is accomplished by learning. The responses produced by such stimuli are classified as either approach or withdrawal. The neural basis of such a theory has been well investigated since the discovery (Olds and Milner, 1954; Olds, 1962) of areas of the brain where ICS is rewarding or punishing. Another view of emotion and motivation has been proposed by etholo-gists and some investigators of the neural aspects of behaviour. Their - .8 -basic ideas are the same but the terminology is different. Brown (1969) questions the usefulness of the term "emotion" to describe behaviour in animals such as j e l l y f i s h , insects'or frogs (for example) even though such behaviour may be functionally equivalent to a human's. A l l animals have some mechanisms which enable them to survive in their environment. The simplest mechanism is a reflex. It i s an important determinant of behaviour in animals with primitive nervous systems. In animals higher in the phylogenetic scale, with better developed nervous systems, complex adaptive behaviours occur in addition to simple reflexes. Within a given species these behaviour patterns are consistent and the name species-typical behaviour has been applied to them. The study of behaviour in a wide range of species has helped the understanding of the neural organization of such behaviour. Just as the nervous system gets more complex as you go up the phylogenetic scale, so i t does when you go from lower to higher levels in a given species (Brown, 1969). The example cited by Brown is the stimulation of a motor neuron in the Octopus, giving an arm movement. Stimulation at progressively higher levels gives movement of a l l arms, placing arms in attention position, and f i n a l l y the attention position including other parts of the body. Another example is the previously mentioned studies on brain transected animals which indicated progressively greater organization of behaviour from the spinal cord up to the forebrain. The best examples, however, have come from the behaviours produced by the e l e c t r i c a l s t i -mulation of localized areas of the brain in animals from bullfrogs to - 9 -man (Doty, 1969). Here complex behaviours produced by ICS have included eating, drinking, gnawing, hoarding, attack, sexual behaviour, object c a r r y i n g and maternal behaviour (Valenstein, Cox and Kakolewski, 1969, 1970). Research leading to the present i n v e s t i g a t i o n . E a r l y attempts at o u t l i n i n g the neural mechanisms of behaviour involved stimulation of the brain with observation of the e f f e c t s . By i d e n t i f y i n g the stimulation sites, maps were made and structures i d e n t i -f i e d with p a r t i c u l a r e f f e c t s . Concern over whether c e r t a i n e f f e c t s resembled natural behaviour or not lead to f i r s t the q u a n t i f i c a t i o n of ICS induced behaviour and then to the a p p l i c a t i o n of learning p r i n c i p l e s . (a) D e s c r i p t i o n : e f f e c t s and l o c a t i o n . In 1927, W. R. Hess reported h i s discovery of c e n t r a l l y induced emotional behaviour to the German P h y s i o l o g i c a l Society (Akert, 1961). I t was cl e a r then that e l e c t r i c a l stimulation of a d i s c r e t e area of the brain could i n i t i a t e the neural a c t i v i t y involved i n the coordination of complex motor behaviour. Hess c a l l e d i t a f f e c t i v e defense and was able to c o r r e l a t e i t with b r a i n s t r u c t u r e s . In the region of the p e r i -f o r n i c a l nucleus i n cats near the descending column of the f o r n i x i n the hypothalamus, he obtained a defense re a c t i o n which resembled the behaviour of a normal cat confronted by a dog. I t included assumption of a defense p o s i t i o n , angry v o c a l i z a t i o n s , r e t r a c t i o n of the ears, d i l a t a t i o n of p u p i l s , h i s s i n g , s p i t t i n g and a we l l d i r e c t e d attack. - 10 -Other components are lashing t a i l , unsheathing claws, defecation, urination, salivation, piloerection, sweating of the footpads, res-piratory activation and retraction of the nictitating membrane (Akert, 1961). Not obvious in the unanesthetized, behaving animal are muscle dilatation, increased blood pressure and vasoconstriction of blood vessels in skin and intestines (Abrahams, Hilton and Zbrozyna, 1960). Hunsperger (1956) using Hess' method investigated more f u l l y these affective reactions, extending the anatomical boundaries and discriminating more details of the behaviour. He distinguished bet-ween affective defense, as described above, and f l i g h t , which has many of the same components but leads to running instead of attack. Affective defence was obtained from two central zones: the periforni-cal region of the rostral hypothalamus as described above, and the middle portion of the midbrain central gray. These two zones are embedded in an unbroken f i e l d extending from the gray matter of the preoptic area back to central gray of the midbrain. From this peri-pheral zone the f l i g h t reaction is obtained. This simple correlation of stimulation locus with stimulation effect i s complicated by the strength of stimulation variable. There are mixed effects at the borders of these zones, of course, but an increase of voltage w i l l tend to reverse the threshold behaviour. Strong stimulation of the central zones may cause the cat to suddenly jump off the table, and strong stimulation of the peripheral zone can evoke an affective defence reaction. - 11 -Subsequent papers by Hunsperger (Fernandez de Molina and Hunsperger, 1959, 1962; Hunsperger, 1963) have reiterated his view of the organization of affective reactions and have extended the system into the amygdala. He has also attempted to resolve the mixed effects into their components by using threshold stimulation and a very small stimulation electrode (Brown, Hunsperger and Rosvold, 1969a,b). Using this method, a growling reaction, a hissing reaction and two types of fl i g h t were produced. His f l i g h t type "a" is characterized by the cat looking about "as i f in search of an exit" and then jumping from the table. Flight type "b" consists of exploration and sniffing of the surroundings followed by jumping off the table. Flight types "a" and "b" were obtained from the intermediate zone and caudo-lateral hypo-thalamus respectively. Suprathreshold stimulation s t i l l gave mixed effects but they conclude that the predominant characteristic of the response depends on the stimulation locus. Yasukochi (1960) obtained a type "a" fl i g h t response from the anterior hypothalamus which he labelled as fear or anxiety. A f l i g h t type "b" response was obtained from the posterior hypothalamus. This behaviour is suff i c i e n t l y vague that several words could describe i t . Yasukochi uses "yearning" or "curiosity". He notes that some cats when stimulated in a "fear" region would attempt to escape through any small hole in their cage. Glusman and Roizin (1960) also describe f l i g h t responses which include carefully organized attempts to escape - 12 -from an enclosure i f an opening was provided. Some animals also searched and explored the cage before escaping. At higher current intensities an aggressive response was changed to "violent panicky f l i g h t " , a result similar to Hunsperger's. Also in agreement with him were the histological localization of the stimulating electrodes. Romaniuk (1963, 1965, 1967) disagreed with the above formulation in two respects. He did not obtain f l i g h t from high intensity stimu-lation of a rage point. Only the latency and intensity of the response were changed and not the nature of the response. He also did not ob-tain the same localization within the hypothalamus. He found a dorsal-ventral division between f l i g h t and rage. This was especially prominent in the medial hypothalamus where the typical rage response is obtained from the ventromedial nucleus. Both the hypothalamus and midbrain were investigated by.Skultety (1963), in an attempt to replicate Hunsperger's 1956 results. Flight is defined as "agitated scurrying about the box" and attempts to get out of the box. These effects were obtained from the hypothalamus but not from the rostral midbrain, below the superior colliculus. Flight was obtained, however, from the central gray in the caudal midbrain. It was characterized only by attempts by the cat to escape from the apparatus. There were no searching movements. In the experiments reported so far, the experimental animal has been the cat. Although patterns of aggressive-defensive behaviour can - 13 -be obtained by e l e c t r i c a l s t i m u l a t i o n of the b r a i n s of f r o g s , a l l i g a -t o r s and w i l d ducks (Doty, 1969) the. d i s c u s s i o n w i l l be r e s t r i c t e d to mammals. An e x p l o r a t o r y e s c a p e - l i k e locomotion w i t h elements of a „ search f o r an escape route was obtained i n the opossum by Roberts, Steinberg and Means (1967). Traczyk ( c i t e d i n B a l i n s k a , Romaniuk and Wyrwicka, 1964) obtained a f l i g h t r e a c t i o n by s t i m u l a t i n g the hypo-thalamus of r a b b i t s . Rabbits have a l s o been used i n the study of drugs on ICS induced a g g r e s s i v e - d e f e n s i v e r e a c t i o n s (Val'dman and Kozlovskaya, 1970; S i l v e s t r i n i , 1958). Fear, defense and rage have been obtained i n dogs by Fonberg (1967). I n the monkey, Delgado, Rosvold and Looney (1956) des c r i b e d a fear response. One of t h e i r e l e c t r o d e s was near the c e n t r a l gray of the midbrain. In man there have been many r e p o r t s of s u b j e c t i v e emotional experiences from s t i m u l a t i o n of many areas of the b r a i n . For example, Sano et a l (1970) have report e d f e e l i n g s of intense horror on s t i m u l a t i n g the p o s t e r i o r hypothalamus. S p i e g e l , K l e t z k i n and Szekely (1954) and Nashold, Wilson and Slaughter (1969) summarize r e p o r t s of pa i n on s t i m u l a t i o n of the midbrain tectum and c e n t r a l gray. Heath and M i c k l e (1960) r e p o r t a n x i e t y and discomfort from the r o s t r a l hypothalamus and t e n s i o n and rage from the caudal diencephalon and mesencephalic teg-mentum. In r a t s rage type responses have been de s c r i b e d to a great ex-tent ( f o r example, Panksepp and T r o w i l l , 1969; Panksepp, 1971) but e x p l i c i t d e s c r i p t i o n s of a f l i g h t response are d i f f i c u l t to f i n d . The f l i g h t response, i n the form described i n cats does appear i n experiments where the hypothalamus of the r a t i s s t i m u l a t e d f o r some other purpose. - 14 -In that case f l i g h t is labelled under the general heading of "other effects" (Woodworth, 1971; Vergnes and K a r l i , 1970). (b) Quantification of ICS behaviour. The terminology used has varied from author to author. Such terms as alarm reaction, rage, aggressive-defensive reactions, affec-tive defense, attack, threat, f l i g h t , fear, escape, agonistic behaviour, emotional reactions, species specific defence reaction and stimulus-bound behaviour have a l l been used to describe the results of stimu-lating the hypothalamus, mesencephalon and other parts of the brain. Some responses are so general that there are a host of words to describe i t . This is true for the sniffing, exploration, curiosity, general ac-t i v i t y and general locomotion obtained at most points in the hypothala-mus. There is obviously a need to evaluate and quantify these behaviours systematically. This is done by providing suitable environmental objects on which the animal can act. A simple example is eating produced by the a v a i l a b i l i t y of food coupled with hypothalamic stimulation (Margules and Olds, 1962). A similar example has already been provided with respect to affec-tive behaviour. It is noted in most papers that the cat, besides looking ferocious, w i l l also attack the experimenter or a stuffed model cat (Brown et a l , 1969a,b). Similarly with f l i g h t , part of the definition is that the animal w i l l attempt to escape from wherever i t is by whatever means available. This can be observed in almost any test situation but i t is s t i l l a crude method of evaluating behaviour. - 15 -It is usually sufficient to characterize the effects of ICS by providing an environmental object on which the animal can act. The strength of response can be measured and is usually the time required for a particular response. Wasman and Flynn (1962) for example provided their cats with a rat to attack. The latency to i n i t i a l movement and attack latency were recorded. In addition, the attack behaviour was rated by the experimenter and an independent observer, a technique used by Roberts (1958 a) to separate his cats into alarm and f l i g h t groups. Renfrew (1969) provided his monkeys with a rubber hose to attack and the number of bites made was auto-matically recorded. The measure of f l i g h t has been done similarly. The animal is provided with a means of escape and the latency to do so is recorded. In the same manner as for attack, the latency to i n i t i a l movement may be recorded (Siegel and Skog, 1970) or the time required to perform a certain response may be recorded. There have been three basic res-ponses used: shuttle-box running, maze running, and plate-pushing. Coupled with these, many studies have also determined the threshold current necessary to produce a response or have studied the effect of stimulus parameters (Renfrew, 1969; Bower, 1959). The most common method of measuring f l i g h t i s the use of a two compartment box or shuttle-box. Flight is then defined as the crossing of the barrier between the two compartments. A system of photo-cells - 16 -can then detect the crossing and with a clock in the c i r c u i t , can measure escape latency and terminate ICS (Stokman and Glusman, 1968). This method has been used with cats by Stokman and Glusman (1969, 1970), Roberts (1958a,b), Cohen, Brown and Brown (1957), and Brown and Cohen (1959); and with rats by Stein (1965), Mogenson (1962), Cox (1967), and Wolfle et a l (1971). Another method is to provide a runway or maze through which the cat (Roberts, 1958a,b) or rat (Bower and Miller, 1958) can escape. Again, appropriate use of photo-cells allows the measurement of running time and also terminates ICS. Delgado, Roberts and Miller (1954) trained their cats to escape from foot shock by rotating a paddle wheel and then substituted ICS for foot shock. Nakao (1958) used this method but instead of the wheel used a paddle covering a hole in the testing chamber. He noticed that cats which had not been pretrained with foot shock would press the paddle to terminate ICS only i f they showed manifestations of f l i g h t . They learned to push the paddle after accidentally pushing i t in attemp-ting to escape from the box. Nakao obtained paddle-pushing from s t i -mulation of f l i g h t areas in the hypothalamus and in the midbrain (Nakao, Yoshida and Sasaki, 1968). Using the same plate-pushing technique, also in cats, Wada and Matsuda (1970) and Wada et a l (1970) found that not a l l points that produced f l i g h t or escape behaviour would, on testing in the plate box, lead to plate-pushing. Therefore a definition of fli g h t based on the plate-pushing task is more exclusive since i t e l i -minates responses such as general locomotion which would not be excluded - 17 -in a shuttlebox or runway task. It has not yet been determined in the rat how many points giving similar behaviour are capable of pro-ducing a plate-pushing response. (c) Conditioning. Most investigators have implied, on the basis of their obser-vations and/or measurements of ICS induced behaviours, that they are not merely stereotyped motor acts but are the outcome of a central motivational state. One of the properties of motivated behaviour i s that i t can be influenced by learning. This enables an animal, for example, to avoid a situation that has been previously associated with some danger (Milner, 1970). To further characterize the pro-perties of ICS induced behaviours there have been numerous attempts to condition them to neutral stimuli, and to compare the results of ICS with "natural" motivational stimuli such as footshock. The o r i -ginal purpose in doing so was to determine whether or not ICS produced an emotional experience in addition to emotional behaviour (Masserman, 1941). Masserman (1941, 1943) reasoned that i f ICS of the hypothalamus was accompanied by a meaningful subjective experience then the animal could learn to respond to a signal which predicted the occurrence of ICS. After numerous pairings of various stimuli with hypothalamic ICS he succeeded in conditioning only some autonomic effects in some cats even though ICS was producing rage responses. Using footshock instead of ICS he did obtain a conditioned response. Since Masserman's work - 18 -there have been several studies which have and have not obtained conditioning of ICS induced behaviour. In contrast to Masserman's findings, pairing of ICS with neutral stimuli has produced a conditioned response to the stimuli alone (Nakao, 1958). It has also been noticed that dogs showed conditioned responses to the apparatus after receiving hypothalamic stimulation i n i t (Fonberg, 1967). Cats have shown active avoidance of a distinctive compartment where they received ICS and have shown passive avoidance of a food tray (Nakao, 1958; Delgado et a l , 1954). Ross et a l (1965) on pairing mid-brain ICS in cats with a tone or clicks obtained f i r s t an attentional and then an emotional conditioned response which resembled f l i g h t ob-tained from the hypothalamus. In a l l of these situations, the animal has no control over the occurrence of ICS. The more typical experimental situation, as discussed above, is to have some action of the animal terminate (escape from) ICS. The animal can then be provided with a warning stimulus (bell, light, etc.) to see i f i t can avoid ICS by responding to the warning stimulus. Fonberg (1967) found that dogs would avoid ICS producing "fear-flight" but not rage by performing a leg flexion during the warning stimulus. Romaniuk (1964) stimulating f l i g h t points in cats obtained the condi-tioned avoidance response of raising on their hind legs. Ross et a l (1965) in addition to the unavoidable ICS situation discussed previously, allowed their cats to avoid ICS by producing an "emotional conditioned response" to a warning signal. - 19 -Using a shuttle-box response (Cohen et a l , 1957; Brown and Cohen, 1959) or paddle-wheel turning (Delgado et a l , 1954), avoid-ance to ICS was obtained. Roberts (1958a) using both a shuttle-box and T-maze obtained avoidance from "alarm" points but not from f l i g h t points. Stokman and Glusman (1970) also failed to obtain avoidance from f l i g h t points in the hypothalamus. Wada and Matsuda (1970) failed to obtain avoidance from hypothalamic ICS in a plate-pushing situation whereas Nakao (1958) did obtain i t . Wada et a l (1970) noted a difference between hypothalamic and midbrain ICS in i t s a b i l i t y to produce avoidance. In rats, only Mogenson (1962) was able to obtain two-way active avoidance. Even then only two of his three animals would do i t . Wolfle et a l (1971) obtained some one-way avoidance but not two-way. Stein (1965), Cox (1967) and Johnson and Levy (1969) also failed to obtain two-way shuttle-box avoidance with either hypothalamic or mid-brain ICS. In a T-maze situation Bower and Miller (1958) found that rats remained in the start box u n t i l the onset of hypothalamic ICS. Since rats have not been trained to date on a plate-pushing task i t is not known whether this measure of " f l i g h t " would produce avoidance i f a warning stimulus was provided. A current explanation for failure of an animal to avoid a s t i -mulus that i t w i l l terminate has been proposed by Roberts (1958a). He proposed that the onset of ICS was rewarding and that i t s continu-ation became aversive. Therefore the animal would be rewarded for - 20 -waiting for ICS onset and then would rapidly turn i t off to avoid punishment. Roberts tested this hypothesis (1958b) and provided some support for his view. Bower and Miller (1958) pretested their rats with several measures of rewarding ICS effects and found on subsequent avoidance training a failure to avoid. Brown and Cohen (1959) however, obtained both approach and avoidance at the same hypothalamic site, a result contrary to that predicted by Roberts' hypothesis. Their ICS effects were similar to that which Roberts describes as "alarm" and which he found produced avoidance and showed l i t t l e reward effects. Roberts admits (1958b) that there is considerable overlap in reward areas and f l i g h t areas. Nevertheless, i t seems that f l i g h t areas tend also to be rewarding. That this is an oversimplification i s shown not only by experi-ments where approach could not be obtained from points that did not produce avoidance (Wada and Matsuda, 1970) but also from the results • of stimulating the midbrain. Although there are some reports of reward areas in the midbrain (Cooper and Taylor, 1967; Mayer et a l , 1971), the area in and around the central gray is considered to be involved with pain and aversion (Olds and Olds, 1963; Routtenberg, 1970; Spiegel et a l , 1954). If Roberts' hypothesis were true, and i f midbrain stimulation is aversive, then there would be more reports of avoidance of midbrain ICS. - 21 -(d) Summary. A variety of behaviours described as emotional or motivational have been produced by ICS presumably by direct activation of neurons involved in the postulated central state which governs natural be-haviour. One such behaviour has been described as f l i g h t . It can be e l i c i t e d from areas of the hypothalamus (HYP) and midbrain (MB) of cats. In addition to some autonomic effects, the main characteris-tic of this behaviour is the search for an exit from an enclosure. This part of the behaviour pattern has been used to measure ICS induced f l i g h t by means of an enclosure with a small hole. When the cat tries to get out the ICS is terminated (escape). When a warning signal (WS) is provided the cat may or may not terminate the WS (avoidance). Since there is some controversy in the literature over the properties of HYP and MB ICS that produce f l i g h t and since the plate-pushing method has not been applied in species other than the cat, the present study was undertaken to determine the following: 1. Description of f l i g h t in rats produced by HYP and MB ICS. 2. Quantification of the f l i g h t response using a plate-pushing task. 3. Determine i f the rat w i l l avoid HYP and/or MB ICS. 4. Test the Roberts hypothesis using a self-stimulation task. 5. Anatomical organization of f l i g h t behaviour as defined above. - 22 -METHOD Subjects. The subjects (S) were 30 male and female hooded rats obtained from Blue Spruce Farms (New York). They were housed individually in an airconditioned (25°C) room with a 12-12 light-dark cycle. Food (Purina Rat Chow) and water were available ad libitum. At the time of surgery their weight was 250-400 grams. Surgery. The electrodes were stainless steel wires (0.19 millimeters diameter) insulated with glass capillary tubing after the method of Nakao (1958). Overall diameter of the insulated electrode was approxi-mately 0.30 mm. Only the cross section of the tip was exposed. A l l electrodes were checked for integrity prior to implantation. The rats were anesthetized with Nembutal (60 mg/kg) and placed in a Kopf stereotaxic instrument. After exposing the calvarium, four stainless steel machine screws were installed as anchors for the dental cement. One to four electrodes were then implanted at various HYP and MB sites chosen from the atlas of Konig and Klippel (1963). A wire attached to one of the anchoring screws was the indifferent electrode. The electrode wires were then joined to amphenol male pins (220-P02) embedded in an amphenol connector strip (221-1260). The entire assembly was molded into the completed plug through the use of dental acrylic cement. Aseptic technique was used throughout; post-operative recovery was uneventful and no infection was noticed. At least one week was allowed before testing. - 23 -Apparatus. Monopolar stimulation was provided by a Grass S 4 stimulator set to deliver monophasic square wave pulses, 1 msec in duration, at a rate of 100 pulses per second. Voltages ranged from 0.5 to 3 volts (V) with most values f a l l i n g between 0.8 and 1.5V. The depth electrode was negative. Stimulation was conducted to the animal by means of 5 light-weight flexible wires ending in an amphenol connector strip (221-1160) with amphenol female pins (220-S02). There were basically 3 pieces of apparatus: an observation chamber, a plate-box for escape and avoidance and a self-stimulation box. For observation of ICS induced behaviour a large box (61 x 61 x 71 cm) was used i n i t i a l l y , followed by a smaller box (30 x 30 x 60 cm). The small box was enclosed on a l l sides and top with brown fibre-board except for a hinged Plexiglas front through which the S entered and l e f t . Electrode wires entered through a hole in the roof of the box. For these obser-vations the S was connected directly to the stimulator. The plate-box had the same composition and interior dimensions as the small observation box with the following modifications. The Plexi-glas door was replaced by a one-way viewing mirror that was fixed as part of the wall. The top of the box was then the only access into and out of the box. The top was tight f i t t i n g and was equipped with a 60 watt light bulb enclosed externally such that a l l the light was directed into the box through a piece of translucent paper. High on - 24 -the w a l l opposite the mirror was a 4 i n c h speaker. The bottom of the box was a g r i d of 1/8 i n c h brass rods spaced 5/8 i n c h (1.58 cm) center to center and r a i s e d about 2 cm above the f l o o r . The main f e a t u r e of the box was a 4 x 4 cm window covered by a P l e x i g l a s p l a t e (Figure 1) lo c a t e d on the w a l l adjacent to the m i r r o r . The p l a t e was f l u s h w i t h the i n s i d e w a l l and a movement of the p l a t e outward of about 0.6 cm closed a microswitch. When the S was i n the box the room l i g h t s were out and the box l i g h t was on, ena b l i n g the experimenter to observe S without S being able to see out. When S was being tested f o r p l a t e - p u s h i n g , S was connected to the s t i m u l a t o r v i a a s w i t c h i n g u n i t (Figure 2) which s t a r t e d both the ICS and a c l o c k ( I n d u s t r i a l Timer Corporation) which measured l a t e n c y f o r p l a t e - p u s h i n g to the nearest 0.01 second. ICS could be stopped e i t h e r by S p r e s s i n g the p l a t e or by the experimenter. For the avoidance t r a i n i n g another s w i t c h i n g u n i t was used (Figure 3). I t allowed a 5 sec.(^Wj) f o l l o w e d by a 0.5 sec. pause, f o l l o w e d by ICS f o r up to approximately 10 sec. The c l o c k measured from WS onset. The^WSy'were b e l l s , l i g h t s and c l i c k s . The l i g h t was a 60 watt desk lamp that was placed j u s t under the top of the box. The b e l l was an e l e c t r i c (6v) d o o r b e l l producing 100 d e c i b e l s . I t was placed on a s h e l f 1 meter away from the box. The c l i c k s were generated by a Grass S4 s t i m u l a t o r a t a r a t e of 5 / s e c , a m p l i f i e d and fed to the speaker i n the box. In a l l cases the i n t e n s i t y was s u f f i c i e n t to produce an i n i t i a l s t a r t l e response i n a l l S. . 25 Figure 1 Side view of one wall of the plate box. Shown in the clear plastic plate which when moved 0.6 cm to the right closes the switch. Scale: f u l l size. Wall 4 cm 7 cm Grid floor o o o o Plastic plate to counter • 26 Figure 2 Semischematic diagram of the escape training apparatus. The clock and ICS are started by the experimenter and terminated by S. The number of ICS presentations is automatically counted. from plate } Counter Stop Start to subject Switch Unit A Stimulator Clock 27 Figure 3 Seraischematic diagram of the avoidance training apparatus. The sequence 5 sec. WS, 0.5 sec. delay, ICS is init i a t e d by start and is terminated by a plate-push by S. Timing is from WS onset and a l l plate-pushes are recorded. Start Stop Switch Unit B Counter 2. WS timer . 5 sec delay Stimula tor ICS timer light b e l l click from plate to subject - 28 -The self-stimulation test again used the 30 x 30 x 60 cm fibre-board box with a Plexiglas door and the addition of a bar 2 x 10 cm located 12 cm above the floor in the wall adjacent to the door. Dep-ression of the bar by 0.4 cm closed a switch which initiated a 0.25 sec. train of pulses from the stimulator. Switching and timing was done by a Neuropsych Corporation unit. Number of bar presses was recorded on a d i g i t a l counter. Procedure. (a) Screening. After recovery from surgery S were brought to the testing area on one or two occasions to familiarize them with the procedure of con-necting to the stimulator. This f a c i l i t a t e d subsequent handling. On being placed in the observation box a few minutes was allowed for ex-ploration, then ICS was administered starting with 0.5V and increasing in 0.1V increments u n t i l the stimulation effect was characterized. Stimulation never exceeded 4V. If there were more than one electrode per animal then the most anterior ones were tested f i r s t . The stimu-lation effect and the voltage producing i t were recorded. It was noted that a l l of the effects obtained in the large observation box could be seen in the small box. Consequently, most screening was done there. Some of the later S's were screened directly in the plate-box. (b) Escape training. After screening, S were tested in the plate-box to see i f they would escape from (i.e. terminate) ICS by pushing the plate. The - 29 -g r o u p t e s t e d h e r e was s m a l l e r t h a n the o r i g i n a l group due t o the ex-c l u s i o n o f S w h i c h showed no e f f e c t or o n l y s t e r e o t y p e d motor move-ments s u c h as head t u r n i n g , eye b l i n k i n g , c i r c l i n g movements o r i s o -l a t e d l i m b movements. V a r i o u s c u r r e n t i n t e n s i t i e s were used and i f a r e s p o n s e was made, the time was r e c o r d e d . S t i m u l a t i o n r a r e l y ex-ceeded 30 s e c . d u r a t i o n . I f some r e s p o n s e s were made, t h a t p o i n t was t e s t e d on the f o l l o w i n g days t o see i f i t became an e s t a b l i s h e d r e s -ponse. U s u a l l y , however, i t became a p p a r e n t i n t h e f i r s t few t r i a l s w hether or n o t a S w o u l d push t h e p l a t e . F o l l o w i n g the s e l e c t i o n o f S and e l e c t r o d e s i t e s t h a t p r o d u c e d p l a t e - p u s h i n g , f u r t h e r t r a i n i n g was u n d e r t a k e n i n d a i l y s e s s i o n s i n o r d e r t o e s t a b l i s h a s t a b l e r e s -ponse and t o d e t e r m i n e t h e t h r e s h o l d f o r the r e s p o n s e . ICS was g i v e n e v e r y 60 s e c . ( c ) A v o i d a n c e t r a i n i n g . Once th e e s c a p e r e s p o n s e was b e i n g p r o d u c e d r e l i a b l y , S was g i v e n an o p p o r t u n i t y t o a v o i d ICS. The 5 s e c . WS was a b e l l , l i g h t or 5/sec c l i c k w h i c h was p r e s e n t e d a l o n e a t f i r s t t o i n s u r e t h a t t h e y caused no p l a t e - p u s h i n g . The WS was t h e n p a i r e d w i t h HYP o r MB I C S . There was a 0.5 s e c . d e l a y between o f f s e t o f WS and o n s e t o f ICS. Each p r e s e n -t a t i o n o f WS and ICS c o n s t i t u t e d a t r i a l . T r i a l s were g i v e n e v e r y 60 s e c . F o r each WS m o d a l i t y 200 t r i a l s were g i v e n o v e r 8 t o 10 d a i l y s e s s i o n s . There was u s u a l l y a t l e a s t one week between m o d a l i t i e s . The o r d e r of WS m o d a l i t i e s v a r i e d f r o m one S to a n o t h e r . The time f r o m WS o n s e t to the p l a t e - p u s h i n g r e s p o n s e was r e c o r d e d . The maximum time - 30 -was 16 sec. at which time the ICS was automatically terminated. The current used was normally just above the threshold for the escape res-ponse. A score of 16 for a t r i a l resulted in the voltage being raised by O.lV to insure that S would make a response within 16 sec. (d) Self-stimulation. After completion of the avoidance training S were placed in the self-stimulation apparatus for 30 minutes each day for several days. The number of bar presses for each 15 minute period were recorded. On some days S received no stimulation and on the remaining days re-ceived stimulation at the setting used in avoidance training. Stimu-lation and non-stimulation days were presented in random order. There were at least 3 days of stimulation. Some of the earlier S were trained for self-stimulation before screening. This consisted of daily.half-hour sessions in the box with current available at various levels. Those S not pressing the bar were given "free" ICS in an effort to induce responding. (e) Histology. At the completion of a l l testing S were anesthetized with Nembutal and after clamping the abdominal aorta and cutting the vena cava, physio-logical saline followed by 10% formalin was perfused through the heart. After soaking in formalin overnight the brain was removed after d r i l l i n g the dental cement away from the anchoring screws and removing the elec-trodes. The electrodes were checked again for integrity. The brains - 31 -were blocked in paraffin and cut in 10 u sections for staining with Luxol Fast Blue and Cresyl Violet (Klliver and Barrera, 1953). The stimulation sites were taken to be the area immediately under the point of deepest penetration of the electrode. The structure at this point was determined by comparison with the atlas of Konig and Klippel (1963) and where possible, by comparison with the nuclear structures given in the atlas of Christ (1969). - 32 -RESULTS Stimulation effects. The 30 S were implanted with a total of 81 electrodes (50 HYP, 31 MB). Five S were eliminated from the study at the beginning due to dislodging of the electrodes or breaking of the pin connectors. Throughout the study the number of S was reduced for these reasons. There were also some deaths due to respiratory infection and one un-explained death. Stimulation effects were obtained from 25 S having a total of 67 electrode sites (42 HYP, 25 MB). Of these 67 sites tested for stimulation effect 22 (33%) pro-duced forced motor movements or had high thresholds. The effects i n -cluded head turning, body twisting, eye blinking, isolated limb move-ment and turning in ci r c l e s . Head movements were the most frequent effect. The remaining 45 points were considered as giving positive results. In order to f a c i l i t a t e description these positive effects were a r b i t r a r i l y divided into 3 classes; activity, locomotion and running. The f i r s t class could be described as general ac t i v i t y increases, exploration, curiosity and sniffing. This frequently resembled the ex-ploratory activity on i n i t i a l placement in the apparatus. This activity was restricted to one area at a time. After exploration of that area, the next one was looked at so that eventually the entire apparatus was explored. The second pattern of behaviour, locomotion, was similar with the exception that S explored or searched the apparatus quickly by either - 33 -walking or running from one point to the other. In the large test chamber S moved along the walls i n a predominant clockwise or counter-clockwise d i r e c t i o n , u s u a l l y pausing at the corners to look around or s n i f f . Other S just walked or ran i n a general c i r c u l a r pattern. There was some jumping, us u a l l y at the corners of the box. The t h i r d class of behaviour was c a l l e d episodic running be-haviour (ERB). I t was very s i m i l a r to the w i l d , f r a n t i c running and jumping seen during an audiogenic seizure, hence the designation ERB. T y p i c a l l y t h i s was an all-or-none phenomenon i n that the S either sat motionless or burst into f r a n t i c running when a c e r t a i n current thres-hold was passed. In some S t h i s threshold, e l e c t r i c a l l y or behaviour-a l l y , was not as sharp. At current l e v e l s below the ERB threshold S would run i n t e r m i t t e n t l y or dart r a p i d l y from one point to another. Even though these motor e f f e c t s were quite spectacular, the current producing them was not d i f f e r e n t from that producing other behaviours. Table I shows the number of electrode s i t e s producing these three classes of behaviour. I t also c l a s s i f i e s the response according to the stim u l a t i o n s i t e . In s p i t e of the a r b i t r a r y nature of the c l a s s i f i c a -t i o n i t i s clear that ERB was obtained mostly from the MB while the other behaviours were obtained from the HYP. The ERB obtained from the HYP resembled f a s t running and jumping more than i t resembled the explosive running obtained from the MB. Hypothalamic ERB also did not have such a sharp threshold. Some S i n the locomotion category, p a r t i -- 34 -Table I Type and frequency of stimulation effects in hypothalamus and midbrain. Effect HYP MB Activity 13 1 Locomotion 10 2 ERB 4 15 - 35 -c u l a r l y those showing walking or running, would at higher c u r r e n t l e v e l s produce ERB. S i m i l a r l y increased s t i m u l a t i o n of an " a c t i v i t y " s i t e could produce "locomotion". In a l l three c a t e g o r i e s some S showed be-haviour i n d i c a t i v e of an attempt to get out of the apparatus. This i n -cluded jumping towards the open top of the box or pushing on a corner of the p l a s t i c door (the corner opposite the h i n g e s ) . Escape. From the group of 45 p o s i t i v e s i t e s as determined above, 31 were teste d i n the plate-box to see i f ICS would produce p l a t e - p u s h i n g . Where negative and p o s i t i v e s i t e s occurred i n the same animal, both were t e s t e d . S u c c e s s f u l plate-pushing was obtained from 7 (23%) of the p o s i t i v e s i t e s . This represents 10% of the s i t e s or 257„ of the animals that were screened. Each S v a r i e d i n the number of ICS p r e s e n t a t i o n s r e q u i r e d to e s t a b l i s h p l a t e - p u s h i n g . Subjects w i t h MB e l e c t r o d e s pushed i t on the f i r s t t r i a l w h i l e those w i t h HYP e l e c t r o d e s took up to 5 t r i a l s . I n a l l cases the area of the p l a t e was the center of a t t e n t i o n f o r those S that l a t e r pushed i t . Subjects a l s o v a r i e d i n the t o t a l number of t r i a l s g i ven. Table I I summarizes the behaviour of the plate-pushers (as c l a s s i f i e d above), the e l e c t r o d e s i t e , the t h r e s h o l d f o r p l a t e -pushing and the number of escape t r i a l s . Escape l a t e n c i e s were at f i r s t q u i t e v a r i a b l e and remained that way u n t i l an optimum voltage was determined. Too low a voltage would not produce plate-pushing and too high a vo l t a g e d i s r u p t e d performance - 36 -Table I I Behaviour, location, threshold and number of t r i a l s for escape subjects. Effect Rat Location of Threshold Number of number electrode (volts) escape t r i a l s Activity 47 HYP 0.6 235 48 HYP 0.6 20 43 HYP 0.8 325 Locomotion 50 HYP 0.9 145 61 HYP 1.0 30 48 MB 1.0 300 ERB 56 MB 1.10 55 - 37 -usually by producing gnawing or wild running. Figure 4 shows the relationship of voltage to latency for 4 sites. In general, increased voltage produced faster responding. For S # 43 the disrupting effect of higher voltage is clearly seen. For # 56 the best response was pro-duced by 1.10V. The 1 sec. latency is maximum that S is physically capable of performing. The method used by each subject in plate-pushing also contributed to variation in latencies. On some t r i a l s S would ci r c l e the box before pressing (# 43, 61, 47), jump in two corners before pressing (# 47), gnaw (# 43, 61), or perform a stereotyped head and neck movement ( 48 HYP ) . Extensive training was given to S 43 and 47 to reduce these behaviours. Circling before pressing persisted but at reduced frequency. The response from the MB rats was quite charac-t e r i s t i c . At below threshold levels they sat quietly and at above threshold levels responded (sometimes after a short latent period) with a direct and lightning fast movement. Hypothalamic responses were slower and more deliberate. Another source of variation was changing thresholds. A within session change was most conspicuous in the case of the MB electrodes in S 48 and 56. Subject # 48 would not respond to less than 1.40V at the beginning of a session but by the end, would respond to 1.0V . This is also shown by the decreased latency over t r i a l s at a given vol-tage as shown in Figure 5. This pattern persisted throughout 300 escape t r i a l s . Subject # 56 behaved in an opposite manner; latency 38 Figure 4 Mean escape time versus stimulating voltage for subjects 43, 48, 50 and 56. The means are based on 5 to 10 consecutive one minute t r i a l s . Ordinate: mean escape time ( s e c ) ; Abscissa: voltage. MEAN ESCAPE TIME (SEC) ro OJ -j* oi o ^ CM k^. cn 01 - J oo l 1 1 1 r 1 I 1 1 1 1 1 : ' Figure 5 Escape latency as a function of time for subjects 48 and 56. The presentation of voltages is in the order l i s t e d . LATENCY ( S E C ) L A T E N C Y ( S E C ) - 40 -increased within a session. It was necessary to increase voltage during a session or, for a given voltage, latencies progressively increased (Figure 5). This was more obvious in blocks of 10 or 20 t r i a l s . For both S however there was a current level which produced reliable performance. Avoidance. Five of the 7 escape points were used in avoidance training. Subjects 47 and 48 (HYP) were excluded because of rapidly deteriorating performance and motor side effects respectively. In spite of adequate responding to ICS and 200 to 600 pairings with various warning stimuli, a l l S failed to avoid ICS. One S (# 43) made 12 avoidances in 200 t r i a l s , two made 3 (# 50, 61) and two made no avoidance responses (# 48, 56). When the total number of avoidance t r i a l s is considered the maxi-mum avoidance rate was 3%. In considering individual sessions of 20 t r i a l s , the maximum avoidance rate was 207» and this occurred only once. There was no tendency for S as a group to improve over sessions (Figure 6). The order of WS modalities presented to each S and the average res-ponse time for each session (with i t s standard deviation) are presented in Table III. To be noted is the variation within a session and variation among sessions. Among sessions there is no tendency to respond faster for any site or modality with the possible exception of 56L. When res-ponding was the fastest and with the least v a r i a b i l i t y (48C) the escape latency was never faster than the 1 sec. maximum that this S would per-41 Figure 6 Mean latency (+ standard deviation) per session for a l l subjects as a function of the number of training sessions. The dotted line represents the response time required for i t to be considered an avoidance. Table III Mean response time per session (+ standard deviation) for each subject and WS modality. S No. WS D A Y S 1 2 3 4 5 6 7 8 9 10 43 (HYP) L 13.18+3.02 12.00+2.88 8.29+1.16 9.94+3.33 10.49+3.03 9.66+3.54 8.73+2.54 8.98+3.43 9.78+2.46 9.55+2.44 B 9.42+3.99 10.56+3.60 9.08+3.45 9.99+3.78 9.50+5.15 9.69+4.23 10.10+2.48 8.51+1.09 10.00+3.06 -C 7.72+1.44 9.08+2.15 7.88+1.80 10.38+2.49 7.67+1.36 8.29+1.85 7.56+1.34 8.62+1.77 7.60+1.33 8.08+1.58 48 (MB) L 6.66+0.20 8.18+0.67 10.84+1.73 11.06+3.27 9.48+2.60 9.00+1.22 9.60+1.13 7.46+0.63 10.27+2.69 -B 8.50+1.06 6.91+0.58 7.88+1.04 10.31+1.50 8.74+2.25 7.90+0.83 8.39+0.91 10.17+1.11 9.02+1.02 -C 6.70+0.11 6.53+0.25 6.60+0.16 6.51+0.11 6.55+0.17 6.54+0.11 6.53+0.15 6.52+0.12 6.52+0.16 6.56+0.13 50 (HYP) B 11.62+1.19 10.51+1.90 9.79+1.55 10.59+1.08 10.85+2.33 9.80+4.23 11.06+1.27 10.31+0.91 10.41+1.11 -L 7.77+0.74 7.64+0.63 7.67+0.66 8.61+0.65 8.72+0.72 8.28+0.75 7.81+0.45 7.75+0.54 7.52+0.62 7.95+0.81 56 (MB) B 7.00+0.81 6.81+0.38 8.44+2.40 8.09+2.50 8.44+2.44 9.71+3.60 8.13+2.51 7.05+0.42 - -L 9.47+2.11 9.33+3.77 9.06+3.20 6.79+0.39 6.62+0.15 8.29+1.69 6.78+0.37 7.68+0.89 7.57+1.25 8.04+1.05 61 (HYP) L 9.89+4.48 11.09+2.73 10.27+2.89 10.82+3.11 12.46+2.37 11.60+3.75 12.52+3.12 9.82+3.75 11.87+3.60 -4> - 43 -form without a WS. Subjects with longer and more variable latencies continued to perform in this way with a slight decrement over sessions in some cases. Over sessions and modalities there was a general ten-dency for the required voltage to increase. Within session v a r i a b i l i t y was generally larger for long latencies (43L) and smaller for short latency responses (48C).. This in turn was related to the voltage and the threshold changes mentioned previously for escape. In contrast to most of the escape sessions, an effort was made to maintain a steady voltage. Progressive increases in latency within a session up to the maximum allowed necessitated the raising of the voltage to maintain a response thus producing a higher mean and standard deviation. Two S showed faster responses within a session (43,48). Other inconsisten-cies in response which also occurred for escape contributed to variation here also. One such variation mentioned previously was the stereotyped res-ponse such as c i r c l i n g before responding. This also occurred here but i t was noted that on some t r i a l s a preparatory response was made. This was obvious in the case of the S that circled. They would come to the plate in preparation for ICS at which time they responded without c i r c l i n g . Such preparatory responses were occurring at a maximum of 50% of the time but usually less. The behaviour of the MB subjects was interesting in that # 56 always stayed near the plate and # 48 always faced the wall opposite the plate. Both responded quickly and directly but produced variable latencies at times due to a strong effect of a small change of voltage on the response time near the threshold. - 44 -Self-stimulation. Table IV summarizes the results,for the 5 S used in the avoidance training. Most bar-presses occurred within 5 min. of being placed in the box. After S had explored the box they remained inactive through-out most of the remaining time. This behaviour was generally the same when ICS was available. For S 43 and 50 the rate with stimulation was significantly above the non-stimulation rate as determined by a Mann-Whitney U-test (Sokal and Rohlf, 1969).. That the apparatus was capable of generating high bar-press rates for ICS is shown by the rates of up to 2800/30 min. obtained from another electrode site in # 50. Similar high rates were obtained from other S which were tested before the plate-pushing test. Histology. The stimulation sites for S which were tested for plate-pushing were plotted on diagrams of coronal sections from the atlas of Kbnig and Klippel (1963). Figure 7 shows the location of electrodes which produced plate-pushing. Figure 8a and 8b shows the HYP and MB sites respectively which did not. Successful escape was produced by elec-trodes in the MB central gray (483, 563) and in the HYP near the fornix. One site was medial to the fornix in the dorsomedial nucleus (505) and the rest were located lateral to the fornix in the region of the medial forebrain bundle (MFB) in the lateral hypothalamus (475, 614) and border-ing on the fields of Forel and zona incerta (435, 485). Figure 8 shows - 45 -T a b l e IV Average bar pressing rate with and without ICS at the voltage indicated. Rat no. Electrode site Average rate/30 min No stimulation Average rate/30 min Stimulation Voltage * 43 HYP 5 38 1.20 48 MB 8 12 1.40 * 50 HYP 24 54 1.0 56 MB 14 19 1.50 61 HYP 16 15 1.20 Significantly above no stimulation rate ( p^O.OS, 1-tailed Mann-Whitney U-test ). 46 Figure 7 Location of electrodes producing escape by pl a t e -pushing. Sites are i d e n t i f i e d by the subject number and the pin number of the electrode. S o l i d c i r c l e s s i g n i f y a locomotion stimulation e f f e c t and s o l i d squares represent an ERB e f f e c t . The antero-posterior coordinate from these sections from the a t l a s of Konig and K l i p p e l (1963) are given i n the upper l e f t of each s e c t i o n . 47 Figure 8 Location of electrodes f a i l i n g to produce escape by plate-pushing: (a) Hypothalamus (b) Midbrain Same designation as for Figure 7 with the addition of an open c i r c l e to represent forced motor movements. Sites 472 and 452 are open circles located in the cerebral aqueduct. 595 465 455 - 48 -that some of the electrodes having extrapyramidal or no effect were located outside the brain, in the cerebral aqueduct or in subthalamic structures. However, many of the sites producing locomotion or ERB were located in structures apparently identical to those producing similar effects and escape as shown in Figure 7. - 49 -DISCUSSION The main stimulation effect obtained from the HYP and MB could be called simply motor act i v i t y . More specifically, three classes of be-haviour were distinguished: forced motor movements, locomotion, and wild-running. Forced motor movements are of interest mainly to those studying the central control of motor systems (Koella, 1969) but they occur frequently as an additional behaviour or a "side-effect" of s t i -mulation. Most studies report these effects as such. It has been noted that these effects can interfere with the performance being evaluated (Mogenson, 1962). It was observed here both the motor effects which did not e l i c i t subsequent plate-pushing and those which were superimposed on a plate-pushing behaviour. Wild running, frequently obtained from the MB was labelled episodic running behaviour (ERB) due to i t s resemblance to part of an audiogenic seizure (Wada and Ikeda, 1966). It has also been called rapid intermittent locomotion (Woodworth, 1971). It is usually d i f f i c u l t to control and so is included with the motor effects as a reason for screening the S from an experiment (Cox, 1967). There are cases, par-ticularly in the HYP where a reduced current produces less than wild running. Such S are l i k e l y to succeed in a shuttle-box or runway task. The third class of behaviour identified in this study was locomotion which varied from slow walking to less than frantic running. The speed at which this is done is proportional to the current intensity. Such be-haviour i s ideally suited for shuttlebox and runway tasks since the for-ward locomotion would eventually get the animal to the "off" side. In - 50 -i t s less intense form i t resembles exploratory activity. In line with the ethological approach to behaviour i t can be noted that the explora-tory activity seen here and elsewhere (Roberts, 1969; Valenstein et a l , 1970) is a species-specific behaviour in the rat and that the running along the wall of the test box seen here resembles the species-specific thigmotaxic response (Bafnett, 1963). Roberts (1969, 1970) and Valenstein et a l (1970) note that exploratory locomotion is seen in the absence of environmental stimuli with which S can interact or when a goal directed consummatory response (such as eating, drinking or gnawing) has not yet been established. It seems then, that ICS induced exploration is a be-haviour waiting to happen, given appropriate environmental circumstances. In the screening procedure used here such conditions were avail-able to a certain extent. Some S behaved as i f they were trying to get out of the box either by jumping in the corners or trying to widen the crack in the door. The frantic searching, darting, running movements of some S could also be interpreted as f l i g h t , perhaps more appropriately than the other since this is the kind of behaviour that would benefit the animal in a real life-threatening situation. The plate-box provides a more appropriate environment for the S to display f l i g h t behaviour and i t was found that some rats would push the plate to terminate ICS. The rat's behaviour i s , therefore, similar to that described as f l i g h t in cats (Roberts, 1958a; Skultety, 1963) and produces plate-pushing as in cats (Nakao, 1958; Wada and Matsuda, 1970; Wada et a l , 1970). Qualita-tively the two classes of f l i g h t distinguished, locomotion and ERB, are comparable with Yasukochi's "fear" and "yearning" and Brown et a l (1969a) - 51 -type "b" and type "a" f l i g h t responses respectively. The description of Brown et a l in cats corresponds quite closely with the behaviour observed here; i.e. quiet, deliberate f l i g h t and rapid, agitated, aroused f l i g h t . Analogous with f l i g h t Flynn et al (1970) found a "quiet biting attack" and "affective attack" in cats. Even though these behaviours are qualitatively different, their outcome in terms of either f l i g h t or attack is the same. Once again i t must be stressed that appropriate environmental objects must be present for these be-haviours to be shown. A further observation, made in cats by Wada and Matsuda (1970), Wada et a l (1970) and in rats in the present study, was that not a l l points showing manifestations of searching or f l i g h t would produce escape in the plate-box. Only 50% of the cats and 25% of the rats would escape. This is not unreasonable in view of the fact that most of the rats' behavi-our is subject to large amounts of interpretation and that the exploratory behaviour commonly seen can be prerequisite to any number of responses i f a goal object i s present (Valenstein et a l , 1970). The plate-box s i t u -ation can presumably select only those behaviours related to f l i g h t as defined by attempts of the S to remove themselves from the apparatus. The alternative, which might be called non-specific selection of a plate-pushing response, is unlikely in view of the i n a b i l i t y of the escape res-ponse even after extensive training to transfer to another electrode in the same animal; and the observation that only one of a pair of closely spaced electrodes produced escape in spite of the otherwise identical stimulation effects for both. In this latter situation i t is particularly - 52 -obvious that the plate-pushing t e s t i s more d i s c r i m i n a t i v e than a s h u t t l e - b o x t e s t s i n c e both behaviours (forward locomotion) would give good performance i n the s h u t t l e - b o x or i n a runway. Even though r a t s would escape from HYP and MB ICS by p l a t e -pushing, none of these same r a t s would avoid i t by responding during a s i g n a l which p r e d i c t e d the occurrence of ICS. Except f o r the r e -port by Mogenson (1962), these r e s u l t s are i n agreement w i t h other attempts to produce avoidance of ICS i n the r a t ( S t e i n , 1965; Cox, 1967; Bower and M i l l e r , 1958; Johnson and Levy, 1969; W o l f l e et a l , 1971). They are a l s o i n agreement w i t h Roberts' (1958a) and Wada and Matsuda's (1970) r e s u l t s w i t h HYP ICS i n c a t s . In g e n e r a l , the r e s u l t of no avoidance i s found w i t h a l l types of apparatus. F a i l u r e to produce avoidance of ICS i s not a general property of a l l s i t e s i n the b r a i n . Avoidance has been obtained by Nakao (1958), Cohen et a l (1957), Brown and Cohen (1959), Romaniuk (1964) and Roberts (1958a) i n a number of s i t u a t i o n s and u s i n g s t i m u l a t i o n of areas s i m i l a r to those f a i l i n g to produce avoidance. More i n t e r e s t i n g are the cases where avoidance has been obtained from the MB but not the HYP (Wada et a l , 1970) or where avoidance occurs i n some animals and not others i n the same experiment (Stokman and Glusman, 1970; W o l f l e et a l , 1971; Roberts, 1958a; Fonberg, 1967). In some cases t h i s can be a t t r i b u t e d to d i f f e r e n c e s i n s t i m u l a t i o n e f f e c t or e l e c t r o d e s i t e . W o l f l e et a l (1971) found d i f -ferences i n avoidance between s i t e s i n c e n t r a l gray and s i t e s i n adjacent tegmentum. Wada et a l (1970), however, w i t h a l l e l e c t r o d e s i n c e n t r a l - 53 -gray found that four out of six cats avoided WS, and Stokman and Glusman (1970) with a l l electrodes in HYP found that one of their four cats would avoid. Current intensity would seem to be a factor but most studies used threshold levels. In a l l these studies and the one reported here there is no apparent factor which might account for the differences observed. Even though there was no tendency toward avoidance in this ex-periment there was an increase in preparatory responses. This has been noted in other studies as well. That the S can form an associ-ation between ICS and neutral stimuli is shown in studies where suc-cessful passive avoidance (Cox, 1967) and conditioned suppression (Wolfle et a l , 1971) have been obtained. Wolfle et a l also used a one-way active avoidance task and found a greater incidence of avoid-ance than in the two-way situation. These techniques have been used extensively to study the motivational properties of footshock. In several studies ICS has been compared with footshock. Avoidance of footshock has been used as a control in some studies to insure that S are capable of responding. Nakao (1958) pretrained his cats with footshock and subsequently obtained avoidance of ICS. Cox (1967) comparing the two in rats found l i t t l e transfer of training to the ICS task. Romaniuk (1964) found that the course of acquisition of an avoidance response was the same for footshock as i t was for ICS. A comparison of footshock with ICS under contingent and non-contingent associations with the WS showed that the properties of ICS were quite different from footshock (Stokman and Glusman, 1970). - 54 -Just as the natural model for ICS induced eating is the eating done by a food deprived animal so the model for ICS induced f l i g h t is the behaviour induced by peripheral e l e c t r i c a l shock. By observing that S do not avoid flight-producing ICS but do avoid footshock one might conclude that ICS does not induce a central state comparable with that produced by footshock. This conclusion should not be made without taking into consideration the fundamental differences between the two. For example, footshock can disrupt performance by e l i c i t i n g competing responses such as freezing. Here pain is involved as well as any central state of fear. The animal may freeze or may run to a safe place i f an opportunity is provided (Bolles, 1970). With ICS pain may or may not be involved. Delgado et a l (1954, 1956) obtained avoidance from structures involved in the transmission of pain. How-ever, ICS in the HYP is known to produce strongly rewarding effects (Olds, 1962) and a hypothesis put forward by Roberts (1958a,b) seemed to account for failure to avoid on the basis of rewarding onset of ICS. In the present experiment self-stimulation rates were low for a l l S. Rates without ICS are comparable to Olds and Olds (1963) rates, but the rates with ICS are not even as high as Routtenberg's (1970) or Stein's (1965) rates for non-reward. The criterion of self-stimulation given by each author appears to be quite arbitrary. Since prior stimulation ex-perience might have produced a lower rate in the present experiment the criterion of s t a t i s t i c a l significance was used. By this method self-stimulation was obtained from two out of three animals with HYP electrodes or two out of five total electrodes. Although bar-press rate is limited - 55 -as an indicator of reward effect (Valenstein, 1964) i t has been used in a number of studies which tend to support Roberts' hypothesis. The Bower and Miller study (1958) in rats used sites known to produce self-stimulation. In a l l experiments using the HYP i t is not unreasonable to expect electrodes to give rewarding effects. More surprising are the reports of self-stimulation from the MB (Crow, 1972; Mayer et a l , 1971; Cooper and Taylor, 1967) and in particular from the central gray where shuttle-box escape was obtained in the same rat (Wolfle et a l , 1971). Signs of pain and fear often accompany the effect and i t takes a longer period of time for i t to develop. Sometimes i t does not develop at a l l and sometimes this i s in an animal that w i l l not avoid. There are also some S which w i l l both avoid and self-stimulate. A l l of Brown and Cohen's (1959) cats made approach and avoidance responses at the same si t e . The majority of f l i g h t points overlap with reward points but there are enough non-overlapping points in the literature and particu-la r l y in the present experiment to suggest that the Roberts hypothesis is insufficient to explain a l l the data. That f l i g h t and reward points have separate mechanisms but overlapping structures is suggested by recent demonstrations of differing thresholds for reward and motivational behaviours (Olds, Allan and Briese, 1971; Ba l l , 1970; Huston, 1971). The HYP and MB are functionally equivalent with regard to escape and avoidance behaviour although a higher proportion of ERB was obtained from MB. Hunsperger (1956) considered the zone giving affective reactions to be continuous from the hypothalamus to the midbrain. He also considers - 56 -the HYP and MB areas as independent sources of behaviour since the stimulation effects of a MB site are not affected by lesions rostral to i t . The wide distribution of sites e l i c i t i n g escape in the present study would support the concept of an extensive system governing this type of behaviour. Sites yielding escape were found in both the lateral and medial divisions of the middle to posterior area of the HYP. There were no electrodes in the anterior HYP or in the posterior nucleus. These are the areas that have been used in cats by Nakao (1958) and Roberts (1958a) respectively. The posterior nucleus of the HYP is par-ticularly interesting since i t gradually merges with the central gray area of the MB. In spite of claims of homogeneity of neural systems, there have been very few electrodes placed in this transition zone. The lateral and dorsal boundaries of the HYP are not distinct anatomi-cally and the lateral hypothalamic area merges with the zona incerta and fields of Forel (Nauta and Haymaker, 1969), where extrapyramidal motor effects are obtained. The main fiber system through the HYP is the medial forebrain bundle which has been associated with reward (Valenstein, 1966) while the corresponding system in the central gray area is the dorsal longitudinal fasciculus which has been associated with punishment (Olds and Olds, 1963). The MB area is also associated with the termination of pain pathways from the spinal cord (Mehler, 1966). This along with reports of pain from MB stimulation in man (Nashold et a l , 1969) and pain and fear-like activity in animals make self-stimulation an unlikely combination with these in the MB yet the bar-press rates by rats indicate that they are indeed combined. - 57 -The involvement of pain in the MB but not the HYP seems to be a funda-mental difference between the two areas but the method of bar-pressing for ICS cannot distinguish between the two. Nevertheless, the fact that S w i l l terminate (and quickly) both HYP and MB ICS in this experiment and in others suggests that the fundamental nature of ICS is aversive. An alternative explanation is that ICS is not aversive (except at higher intensities) and is only an e l i c i t e d motor behaviour which requires that the act be performed in order to be rewarding (Roberts, 1970). In line with this i s the speculation that plate-pushing be considered as a type of stimulus bound consummatory behaviour in the same way that feeding behaviour has been considered (Valenstein et a l , 1970; Valenstein, 1969). Valenstein's group has presented evidence showing important differences between natural and stimulus bound behaviours. One observation is that apart from any reward value of ICS, the performance of the e l i c i t e d act is rewarding. This, and some additional work (Valenstein, 1971) which showed that the response induced by ICS is resistant to change after being established, could explain the failure of S to avoid in this ex-periment. Under the condition of the present experiment, escape respon-ding would be maintained by the rewarding consequence of performing the plate-pushing response in the presence of ICS. Implied is that the association of the WS with the response would be less rewarding. Escape responding would also be maintained due to the fact that the response has been well established by pretraining. Even though an association may have been formed between WS and ICS, the S has been trained to respond in a fixed pattern using the cue properties (Mogenson and Morrison, 1962) of ICS. - 58 -Although Valenstein's group has accumulated evidence incom-patible with the view that ICS e l i c i t s a central motivational state identical with that produced by natural stimuli, i t is possible to gain access to the neural substrate underlying several species-typical behaviours. That they can be produced and directed towards appropriate goals on an interactive basis with the environment, should be enough of a similarity, given suitable means of quantification, to further our understanding of behaviour. - 59 -REFERENCES Abrahams, V. C , S. M. H i l t o n and A. Zbrozyna. 1960. 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