The termination of reinforcing intracranial stimulation: An ecological approach

Physiology and Behavior, Vol. 7, pp. 215-220. Pergamon Press, 1971. Printed in Great Britain

The Termination of Reinforcing Intracranial Stimulation: An Ecological Approach' BERNARD

B. S C H I F F ,

BENJAMIN

RUSAK i AND

ROBERT

BLOCK

University o f Toronto, Toronto, Canada

(Received 13 N o v e m b e r 1970) SCHIFF, B. B., B. RUSAKAND R. BLOCK. The termination of reinforeing hztracranial stimulation; an ecological approach. Pr~SIOL. BEnnY. 7 (2) 215-220, 1971.---The average duration of reinforcing intracranial stimulation (ICS) accepted by rats in a shuttle box is increased when these rats are tested in the presence of other male or female rats, or in a larger testing area. Time on the nonstimulation side of the shuttle box is unaffected indicating a selective interaction between the electrical stimulus and the test environment. It is concluded that the tolerence for ICS is increased as the environment provides increased support for exploration which is being elicited by the electrical stimulus. It is proposed that the termination of ICS and the variables affecting it might be understood in terms of an adaptation which regulates behavior between field and home.

Termination of ICS

Self-stimulation

Elicited exploration

ANIMALS will behave so as to initiate and also terminate electrical stimulation through the same electrode in a number of brain sites [2, 6, 7, 9, 11, 12, 17, 18]. The positive reinforcement properties of this stimulation have been well studied [5, 9, 13]. Considerably less is known about why animals terminate this stimulation. The most widely accepted explanation has been that there is a physiological spread of current to other structures which mediate punishment [2, 11, 12]. However, a number of experiments have challenged the punishment hypothesis and shown it to be inadequate [6, 7, 17, 18]. Our understanding of reinforcing intracranial electrical stimulation (ICS) has been assisted by examining the properties of the stimulation under semi-ecological conditions [5]. It seems reasonable that such an approach might be useful in understanding why animals terminate this stimulation. There are two experiments which have demonstrated environmental influences on the regulation of duration. Mendelson [8] has shown that rats will accept longer durations of electrical stimulation when given an opportunity to perform consummatory responses which are elicited by the stimulation. Phillips et aL [10] have shown that the average duration of stimulation accepted is decreased if the animals are tested in an environment where there are spatial relations between the presence and absence of electrical stimulation, and in the presence of portable objects which the animal carries from the place of stimulation to the place where there is no stimulation. The following experiments extend these observations to other aspects of the test environment.

EXPERIMENT 1

The first experiment examined the effects of the presence of other animals on the regulation of intracranial stimulation (ICS) in a shuttle box. Two different procedures were employed and will be reported separately as Experiments I a and lb.

Experiment l a Animals. The experimental animals were 12 male hooded rats who had bipolar electrodes implanted in a variety of diencephalic structures. The animals were selected from a larger population of similarly operated rats because they reliably initiated and terminated electrical stimulation through their respective electrodes by moving back and forth in a shuttle box. All animals were housed individually in wire cages and were kept on ad lib food and water. Apparatus. The animals were tested in a grey shuttle box (24 x 8 x 12 in.) which was constructed of wood except for one long side which was made of wire mesh. The mesh screen separated the shuttle box from a grey wooden box of identical dimensions which was divided into two equal compartments along its short axis. The floor of the shuttle box rested on a pivot such that the weight of the animal moving from one side to the other tilted the floor and operated microswitches located at either end. The switches were wired so that the presence of the animal on one side of the box operated the electrical stimulator. The electrical stimulus was a continuous 60 cycle sine wave

1This research was supported by a grant from the National Research Council of Canada NRC APB 149. The present report is based on data collected for a senior honors thesis and a masters thesis done by the second and third authors respectively. sPresent Address: Department of Psychology, University of California, Berkeley, California 94720.

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delivered through a 150k ~ impedance. Current was monitored at all times. The animal was connected to the source of stimulation through a commutator so as to allow for free movement. Each crossing from the nonstimulation side of the shuttle box to the stimulation side was recorded by a digital counter. Two running time meters recorded the total amount of time spent on either side of the shuttle box. The average duration of current accepted on each crossing (ON Time) and the average time between stimulations (Reset Latency) were calculated from these data. Continuous records of the duration of each crossing were taken. This was accomplished by operating a pulse former off of the stimulation side of the shuttle box. The pulse former emitted a pulse every 0.5 sec and stepped the pen of a cumulative recorder over slowly moving paper. When the animal terminated the stimulation the pen returned to its base leaving a record of the duration that the animal had been stimulated to the nearest 0.5 sec. The Reset Latencies appeared as horizontal lines along the baseline. Operations and histology. Operations were performed under Equithesin anesthesia supplemented by ether when necessary. A single bipolar electrode was implanted intracranially in each animal, aimed at one of several hypothalamic loci which were known to be reinforcing. The wires were insulated except for the cross section where they had been cut, and the tips were separated by 0.5 ram. At the end of the experiment, the animals were anesthetized and perfused with normal saline followed by formalin solution. Frozen sections 40~t thick taken every 200~ through the electrode tract were preserved and stained with cresyl violet. Procedure. Beginning at least one week postoperatively all operated animals were allowed to explore the test apparatus 10 min a day for three successive days. Following this the current was introduced and increased by 5 ~A steps until it was clear that the animals were, or were not responding to the stimulation. Those animalswhich reliably initiated and terminated stimulation by running back and forth in the shuttle box were then tested using the current intensity that maintained that behavior. The animals were tested for 10 min a day. For 5 min the adjacent compartments were empty, and for the other 5 min a male hooded rat was placed in each of the compartments. The order of testing in the presence and absence of the stimulus animals was altered on successive days. Testing continued for an even number of days ranging from 4 to 8 days. The intensity of the stimulating current ranged from 5~A to 20~A. Results. The results are summarized in Table 1. All of the experimental animals accepted longer average durations of stimulation during each crossing (increased ON time) in the presence of stimulus animals (p < 0.02 by a Wilcoxon matched-pairs signed-ranks test). Five of these

animals showed small increases (less than 20 pet cent), ho~ever the other seven animals showed incrcases which ranged from 40 to 400 per cent (4--30 sec respectively). Two of these animals showed increased ON time only after several days of testing, and another showed large increases on the first two days which disappeared over the next four days of testing. Since the mean ON times were taken for all aJaimals on all test days, they underestimate the changes which ~crc actually observed. The average time on the nonstimulation side of the shuttle box (Reset latency) decreased slightly in the presence of the stimulus animals, however this was not statistically significant.

Experiment 1b This experiment differed from the previous one in two ways. First the comparisons were made between days rather than within days to see if the changes in the regulation of duration reflected absolute differences between the test conditions or were responses to intrasession stimulus change. The procedures in this experiment were also better for observing changes in the response to the presence of stimulus animals over successive days of testing. Second, the stimulus animals were females rather than males to test for the generality of the effect. Subjects. The animals for this experiment were eight male hooded rats. Three of these were also run in Experiment la. The other five were naive. The new animals were selected on the same basis as were those in the previous experiment with the added requirement that they had stable ON Times over many days of testing in the empty shuttle box. The surgical and histological procedures, and the apparatus were the same as in Experiment la. Procedure. All animals were tested daily for 10 rain in the empty shuttle box at a current which maintained reliable shuttling (8-20tzA). Testing continued for each animal until it had stable ON Times for at least four successive days, The major criterion for stability was that changes which were observed between days were not systematic. The animals selected on this basis generally did not fluctuate more than one second across repeated tests. Each animal was then tested for 2--4 successive days with stimulus females in the adjacent compartments. They were then retested in the empty box for several days to verify the stability of their performance. Results. The results are presented in Fig. 1. ON Times and Reset Latencies are shown for each animal on every day they were tested in the presence of stimulus females, as well as for the two days of responding in the empty box just preceding and just following these test days. ON Times in the presence of stimulus females were greater than in the empty box (p < 0.01 using a Wilcoxon matched-pairs signed-rank test). There were no significant changes in Reset Latencies or in ON Times in the empty box measured before and after presentation of the stimulus females.

TABLE 1 EFFECT OF MALE RATS PRESENT ON ICS REGULATION IN THE SHUTTLE BOX

Empty Box Mean ON Time (sec) Mean Reset Latency (sec)

Animals Present

13.6

18.3

3.5

2.8

DISCUSSION

A majority of the experimental animals accepted longer durations of brain stimulation when they were tested in the presence of other, male or female, animals. Some of these animals did not do so initially, but did after repeated testing (e.g. G9 and BA1 in Experiment lb). It is possible, then, that with more testing in the presence of stimulus animals all of the subjects would have shown increased ON Times. The changes in the regulation of duration observed in

TERMINATION OF REINFORCING ICS

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these experiments were not coincident with any other obvious changes in the animals' behavior. Typically the stimulated animals moved about the hot side of the shuttle box sniff-rag the walls and floor of the apparatus. When there were male or female rats present in the adjacent compartments, the stimulated animal did orient towards them as well as to the rest of the test environment. However, it did appear (particularly in the case of those animals who showed large increase in ON Time) that the increased tolerance for stimulation could not be accounted for only by responses directed towards the stimulus animals. Rather, the presence of other animals resulted in the animals' spending more time exploring the total test environment. On the nonstimulation side of the shuttle box the animals were relatively inactive by comparison with their behavior during stimulation. They also did not appear to respond to the presence of other animals. This is reflected in the Reset Latencies which did not change. The locomotor exploration we observed during ICS has been reported previously [3]. In another study (Schiff and Zysman; manuscript in preparation) we have demonstrated that this behavior shares several properties with other elicited behaviors such as feeding and drinking, It is possible then that the increased tolerance for brain stimulation in the presence of the stimulus animals reflects the support these stimuli provide for the elicited exploration, just as there is increased tolerance in the presence of food when the electrical stimulation elicits eating [8]. The fact that the effect is not specific to the sex of the stimulus animal, that there was not specific orientation to the stimulus animals during ICS, and that most of the experimental animals in Experiment 1b habituated to the presence of the stimulus animals all converge on such a conclusion. In the following experiment we test this further.

EXPERIMENT

2

In the previous experiment we concluded that the presence of other animals increased the animals' tolerance for ICS by providing increased support for the centrally elicited locomotor exploration. It is possible, if unlikely, that the stimulus animals had this effect by virtue of a more specific relationship to unidentified patterns of activity, such as sex or aggression, which were being facilitated by the electrical stimulus. The purpose of this experiment is to see if variation in the test environment which is unambiguously nonspecific will interact with ICS in the manner indicated. To this end we have manipulated the amount of stimulation without altering the specific stimuli in the test environment. This was accomplished by varying the testing area.

Method Animals. The animals were 12 male hooded rats. Ten of these had been run in the previous experiment, and two were naive. Maintenance, selection, histological and operative procedures were identical with those of Experiment la. Apparatus. The apparatus consisted of two unpainted wooden shuttle boxes with wire mesh floors which were raised 3 in. off the ground. One box measured 24 × 8 x 12 in. The floor of the second box was exactly twice the size. The stimulation and recording equipment were identical with that described in Experiment 1. They were operated when the experimental animal moved from one side of the box to the other across the beam of a photoelectric unit which was placed 5 in. beyond the middle of the box. The stimulation was terminated when the animal broke the beam of another photoelectric unit which was placed 5 in. on the other side

218

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of the midline. The distance between the two photoelectric cells was identical in the two boxes so that the responses required to initiate and terminate the electrical stimulus were the same. Procedure. Each animal was run daily in each of the two shuttle boxes. The two tests were each 10 min long and were separated by at least an hour. The order of testing in the two boxes was alternated on successive days. The animals were run for an even number of days ranging from 4 to 10 days.

Results The results of this experiment are summarized in Table 2. the mean O N time in the large box was greater than in the small box (p < 0.01 using a Wilcoxon Matched-pairs signedrank test). In four animals the mean increase was trivial (less than 10 per cent), however the other eight animals showed mean increases which ranged from 50 per cent (5 sec) to 350 per cent (30 sec). Two of these animals began to show increased O N times only after 6 days of testing. One showed it for the first two days and then not again for eight days. The others showed varying durations in the large box on successive test days but always longer ON times in the large box than in the small box. Since the mean ON times were calculated for all animals on all test days they underestimate the magnitude of the observed increases. These results are comparable to those of Experiment 1. Also, as in Experiment 1, the small reduction in mean Reset Latency was not statistically significant.

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TABLE 2 INTERACTIONOF SHUTTLEBOX AREA WITH ICS REGULATION

Mean ON Time

Small Box

Large Box

13.7

19.5

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5.0

(sex) Mean Reset Latency

(sex)

Figure 2 is a sample record of the individual responses for one animal tested in this experiment as well as in Experiment 1a. This record is typical of those we observed in that there was a large amount o f variability in the durations accepted on each crossing. In Experiment l b where we had selected animals because they showed stable mean ON Times across several days of testing we observed comparable intrasession variability. Histology. In all there were 19 rats used in the three experiments. Histological analysis showed that seven electrodes were in Forel's Fields HI and Hs, seven were in the median forebrain bundle, three were in the zona incerta, and there was one each in the posterior hypothalarnus and the substantia nigra. There were not apparent relationships between the loci of the stimulating electrodes and the behavior observed in any of the experiments. DISCUSSION

Enlarging the testing area resulted in increased ON Times comparable to those observed in the presence o f other animals.

The increases did not represent the extra time it might have taken the animal to traverse the greater distances of the larger shuttle box. First, the actual distance between the photoelectric cells which operated the stimulator were the same in both boxes. Second, the stimulation and nonstimulation sides of the shuttle box were enlarged equally, but the changes in time were selective to the stimulation side. Third, if both of the preceding arguments are suspect, the extra distances involved could have been easily covered in less than a second while the increases in ON Times were considerably greater than that. It is concluded, therefore, that the larger space afforded greater opportunity for the exploration which was elicited centrally, and that this resulted in the acceptance of longer durations of ICS. I t might appear peculiar in the light of this conclusion that some animals did not respond to the changes in the test environment, since all showed increases in activity while being stimulated. However, the appearance of the component responses of exploration such as sniffing and locomotion do not guarantee that the animal is interacting with its environment, i.e. exploring. Unlike feeding and drinking exploratory responses do not depend on feedback from the environment for their occurrence and one could mistake the occurrence of exploration where other consummatory activities are not subject to this confusion. In fact the observation that some animals begin to show increased O N Time only after repeated testing in the presence of the larger box or stimulus animals may be viewed as comparable to Valenstein's [14, 15] demonstration that some animals begin to eat only after repeated ICS in the presence of food. The difference being that in the case of feeding the component responses appear reeoguizable only after the animal begins to respond to the environment while in the case of exploration there are no

TERMINATION OF REINFORCING ICS

219

such obvious changes in the topography of the responses as the animals begins to actually explore. The object of this research was to examine the question of why animals terminate reinforcing brain stimulation by describing the interactions between this behavior and semiecological variation in the test environment. The existing data are that animals will accept longer durations of ICS when there is increased environmental support for exploratory (this experiment) or consummatory [8] activity elicited by the stimulating electrode. However, if there are portable objects in the field which can be removed from a place where the animals receive ICS, to a place where they do not, object carrying takes precedence over other activities and the duration of stimulation accepted is decreased [10]. These data provide further difficulty for the already challenged punishment hypothesis which proposes a physiological spread of the stimulating current to aversive mechanisms [2, 11, 12]. The selective activation of reinforcing pathways underlying species specific behaviors [5] may increase the reward-to-punishment ratio and result in increased tolerance for ICS by postponing the switching from reward to punishment. However, it is difficult to imagine a physiological system in which this could involve times as long as one minute. The insufficiency of the punishment hypothesis is made most apparent by the observation that stimulation is terminated sooner when the animals are object carrying. This is particularly striking because the behavior of the object carrying rat, as observed in our laboratories, appears to be as vigorous and motivated as that of an animal shuttling in an empty box. It is hardly likely that object carrying could result in more rapid physiological spread to an aversive system, which is what the punishment hypothesis would necessarily conclude. It should be noted, however, that there probably are instances related to the position of the stimulating electrode which are accountable for by the punishment hypothesis. Some of the existing confusion in the literature may result from the confusion of two quite different phenomena. Mendelson [8] proposed an alternative to the punishment hypothesis on the basis of his experiments. In particular he proposed that the induction of drive by the electrical stimulus becomes aversive and the animal terminates the stimulation to reduce drive. This formulation is based on the observation that when given the opportunity to perform the elicited responses the tolerance for stimulation increases. However, the results of the present experiments indicate that it is the eliciting properties rather than the drive reducing properties of the exteroceptive stimuli which increase tolerance for ICS. The expression of locomotor exploration is increased rather than made possible by our manipulations of the test environment. Similarly, Mendelson [8] showed that increasing the palatability of the food increases the tolerance for ICS in stimulus bound feeders. Furthermore, a drive reduction explanation would have difficulty with the apparent reduction in tolerance for stimulation in the object carrying rats. Following is an attempt at explanation which is inclusive of the existing data and heuristic. It rests on a description of how an animal regulates its behavior between home and field. Unfortunately, there is very little data pertaining directly to

this and so the description is largely an hypothesis based on logical considerations relating to optimizing survival. The animal must leave the home to provide for what the security of home does not. However, the field is dangerous and so the animal should be constantly motivated to return home [1, 4]. Accordingly, we would expect that the animal would enter field and flee from it repeatedly. Such behavior has been described in the laboratory rodent by Welker [19]. He found that if animals are given access to an open field from a small dark safe compartment, that they make brief and frequent forays into the field, always returning to the safe compartment. Galef (personal communication) has made similar observations in the wild rat under conditions which better approximate home and field. The duration of each visit into the field should, logically, be related to the conditions of field. Given that the adaptation which results in the animal's venturing into field is to procure the means of survival, one might expect that the duration of each visit will reflect the support the field gives for survival related activities. Thus, we might expect the animal to spend longer time in the field if it provides more support for exploratory activity and consummatory activity. However, the visit to field should be terminated by finding a portable object which could be carried home [1, 4]. It has been suggested [10] that ICS produces a central state comparable to that which differentiates home from field. This was proposed to account for the fact that the stimulation will elicit object carrying if presented under spatial conditions which are consistent with the environmental relations that elicit carrying. We suggest that this might be extended to explain why animals terminate iCS and how this behavior has been shown to interact with the test environment. This view of ICS can incorporate other demonstrated properties of the phenomenon. For example, it could account for the association of exploratory responses with all reinforcing ICS [3], the relatively high probability of eliciting object carrying or hoarding [10] and the low probability of eliciting consummatory activity such as eating and drinking with reinforcing stimulation, and the precedence which electrically elicited hoarding takes over elicited eating [10]. It could similarly be related to the relative nonspecificity and functional plasticity of brain sites associated with consummatory activity [14, 15]. This formulation could also lead to unique predictions concerning the interaction between testing conditions and ICS based on a careful analysis of variables which regulate home and field behavior in various species. Such an observation has already been made by Valenstein et al. [16] who point out that guinea pigs, which use natural burrows rather than nests, did not display object carrying behavior although they selfstimulated efficiently in a shuttle box. The correctness of the particular formulation is an empirical question. However, the usefulness of the general approach is indicated by the breadth of its application and the uniqueness of predictions it could lead to. It is an approach which is characterized by an appreciation of the ecological determinants of animal behavior, and explanation in terms of mechanisms of adaptation rather than specific theories of motivation.

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2. Bower, G. H. and N. E. Miller. Rewarding and punishing effects from stimulating the same place in the rat's brain. J. comp. physiol. Psychol. 51: 669-674, 1958.

220 3. Christopher, M. and C. H. Butter. Consummatory behaviors and locomotor exploration evoked from self-stimulation sites in rats. J. comp. physiol. Psychol. 66: 335-339, 1968. 4. Eibl-Eibesfeldt, I. The interaction of unlearned behavior patterns and learning in mammals. In: Brain Mechanisms and Learning, edited by J. F. Delafresnaye. Springfield, I11. Thomas, 196t, p. 53. 5. Glickman, S. E. and B. B. Schiff. A biological theory of reinforcement. Psychol. Rev. 74: 81-109, 1967. 6. Hodos, W. Motivational properties of long durations of rewarding brain stimulation. J. comp. physiol. Psychol. 59: 219-224, 1965. 7. Keesey, R. E. and D. B. Lindsley. Duration of stimulation and the reinforcing properties of hypothalamic stimulation. Am. Psychologist 17: 375, 1962. 8. Mendelson, J. Lateral hypothalamic stimulation: Inhibition of aversive effects by feeding, drinking and gnawing. Science 166: 1431-32, 1969. 9. Olds, J. Hypothalamic substrates of reward. Physiol. Rev. 42: 554-604, 1962. 10. Phillips, A. G., V. C. Cox, J. W. Kakolewski and E. S. Valenstein. Object carrying by rats: An approach to the behavior produced by brain stimulation. Science 166: 903-905, 1969.

SCHIFF, RUSAK AND BLOCK 11. Roberts, W. W. Both rewarding and punishing effects IYom stimulation of posterior hypothalamus of cat with same electrode at same intensity. J. comp. physiol. Psychol. 51 : ~ 7 . 1958. 12. Stein, L. An analysis of stimulus-duration preference in self-stimulation of the brain. Z comp. physiol. Psychol. 55: 405-414, 1958. 13. Trowill, J. A., J. Panksepp and R. Gandelman. An incentive model of rewarding brain stimulation. Psychol. Rev. 76: 264-281, 1969. 14. Valenstein, E. S., V. C. Cox and J. W. Kakolewski, Modification of motivated behavior elicited by electrical stimulation of the hypothalamus. Science 159: 1119-1121, 1968. 15. Valenstein, E. S., V. C. Cox and J. W. Kakolewski. The hypothalamus and motivated behavior. In: Motivation, edited by J. Tapp. New York: Academic Press, 1969, p. 242. 16. Valenstein, E. S., V. C. Cox and J. W. Kakolewski. Reexamination of the role of the hypothalamus in motivation. Psychol. Rev. 77: 16-31, 1970. 17. Valenstein, E. S. and T. Valenstein. When does reinforcing brain stimulation become punishing? Am. Psychol. 18: 436, 1963. 18. Valenstein, E. S. and T. Valenstein. Interaction of positive and negative reinforcing neural systems. Science 145: 1456, 1964. 19. Welker, W. I. "Free" versus "forced" exploration of a novel situation by rats. PsychoL Rep. 3: 95-108, 1957.