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Lesions of the caudate nucleus selectively impair “reference memory” acquisition in the radial maze
BEHAVIORAL AND NEURAL BIOLOGY 53, 39--50 (1990)
Lesions of the Caudate Nucleus Selectively Impair "Reference Memory" Acquisition in the Radial Maze MARK G.
PACKARD AND NORMAN
M.
WHITE 1
Department of Psychology, McGill University Groups of L o n g - E v a n s rats with bilateral lesions of the caudate nucleus, sham lesions, or no lesions were given one trial per day in an eight-arm radial maze. The same four maze arms were baited on each trial. The remaining four arms never contained food. Optimal performance required animals to enter each of the baited arms only once on each trial and to avoid entering the arms in the unbaited set. Rats with caudate lesions learned to enter each of the baited arms only once on each trial. H o w e v e r , these rats were severely impaired in learning to avoid entering the arms in the unbaited set. Implications for dual-memory theories are discussed. © 1990Academic Press, Inc.
One theoretical model of multiple memory systems proposes a distinction between working memory and reference memory (Honig, 1978; Olton, Becker, & Handelmann, 1979). Working memory procedures require memory for trial-discrete information, such as previously visited maze arms in a radial maze task (Olton & Samuelson, 1976). In contrast, reference memory procedures involve information pertinent to every trial of a given learning task, such as memory for the positive discriminative cue in a simultaneous discrimination task (Silveira & Kimble, 1968). The working/reference memory distinction was tested in a 17-arm radial maze task developed by Olton and Papas (1979). In this task, the same set of 8 maze arms was baited once on each trial, while the remaining arms were always unbaited. The working memory component of the task required rats to visit each of the baited arms once within a trial. The reference memory component of the task required animals to learn to avoid entering the arms in the unbaited set, which remained constant across trials. Several investigators have reported that preoperatively trained rats with lesions of the fimbria-fornix are impaired in This research was supported by grants from F O N D S F C A R province of Quebec and from the Medical R e s e a r c h Council of C a n a d a to N o r m a n White. W e thank Dr. Matthew Shapiro for helpful c o m m e n t s on an earlier version of the manuscript. Address corres p o n d e n c e and reprint requests to Mark G. Packard, D e p a r t m e n t of Psychology, McGill University, 1205 Dr. Penfield A v e . , Montreal, P. Q. Quebec, Canada H3A 1B1. 39 0163-1047/90 $3.00 Copyright © 1990by AcademicPress, Inc. All rights of reproduction in any form reserved.
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the working memory component o f this task (Davis, Taras, Pulsinelli, & Volpe, 1986; Jarrard, 1983; Nadel & McDonald, 1980; Olton & Papas, 1979). In contrast, it has been reported that hippocampal system damage has no effect on retention of the reference memory component of the task (Davis, Baranowski, Pulsinelli, & Volpe, 1987; Olton & Papas, 1979); others, however, have reported a deficit in retention of this component (Jarrard, 1983; Nadel & McDonald,~. 1980). The reported preservation of reference memory in this task after fornix/hippocampal lesions is only one among several instances of learning that survives damage to the hippocampal system (for reviews see Hirsh, 1974; O'Keefe & Nadel, 1978). Recent work from our laboratory has demonstrated that the caudate nucleus mediates some of the learning that is spared following hippocampal system damage (Packard, Hirsh, & White, 1989). The mnemonic functions of the hippocampus and caudate nucleus were doubly dissociated using two versions of the radial maze task. In the standard radial maze task (Olton & Samuelson, 1976) fimbriafornix lesions impaired choice accuracy, while lesions of the caudate nucleus had no effect. In a novel radial maze task, a sensory cue (light) signaled four randomly selected reinforced maze arms, and animals were required to revisit previously reinforced arms within a trial. Lesions of the caudate nucleus impaired acquisition of this task, while fornix lesions facilitated acquisition. These findings suggest that the caudate nucleus may mediate some of the learning abilities which survive hippocampal damage. The present experiment was designed to extend these findings by testing whether the caudate nucleus is required for acquiring of the reference memory component of the four-arms-baited, four-arms-unbaited radial maze task. METHODS
Subjects The subjects were 21 male Long-Evans rats (275-325 g). Rats were individually housed in a temperature controlled environment with the lights on from 7 AM to 7 PM. All animals were given ad libitum access to water. After arrival in the laboratory, each rat was handled individually for 5 min on each of 4 days prior to surgery.
Apparatus The apparatus was a wooden eight-arm radial maze painted flat gray and elevated 60 cm above the floor. Each arm measured 60 × 9 cm, and the center platform was 40 cm in diameter. Food cups were drilled into the floor near the end of each arm. The maze room included several extramaze cues.
CAUDATE NUCLEUS LESIONS AND MEMORY
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Surgery Rats w e r e assigned to one of three groups; caudate lesion (N = 7), s h a m - o p e r a t e d ( N = 7), or u n o p e r a t e d control (N = 7). Each rat was anesthetized with 60 m g / k g sodium pentobarbital. Lesions were m a d e using standard stereotaxic techniques. Bilateral electrolytic lesions of the caudate nucleus were m a d e at anterior and posterior sites. F o r the anterior caudate lesions, stereotaxic coordinates were AP = + 1.5 m m f r o m bregma, M L = + 2 . 8 m m , DV = - 6 . 2 m m (Paxinos & Watson, 1982). At the anterior site, 4 m A of direct current was passed for 15 s through an electrode insulated except for 0.8 m m at the tip. F o r the posterior caudate lesions, stereotaxic coordinates were AP = + 0.2 m m from bregma, M L = + 4 . 3 ram, D V = - 6 . 7 ram. At the posterior site, 5mA was p a s s e d for 20 s. The caudate lesions were made in two stages. Anterior and posterior lesions were m a d e unilaterally, and the two lesions on the other side w e r e m a d e 2 w e e k s later. Behavioral testing began 2 weeks after the second pair of lesions was made. During r e c o v e r y periods, animals were fed a daily supplement of rat c h o w mash. N o n e of the caudate animals was aphagic or adipsic at the time of testing, and their gross m o t o r m o v e m e n t s a p p e a r e d normal. S h a m - o p e r a t e d animals underwent operating procedures identical to those p e r f o r m e d on caudate rats, except that no current was passed through the electrodes.
Procedure Preliminary training consisted of a 2-day habituation period, during which the animals were individually placed on the maze for 5 min and allowed to explore with no food available a n y w h e r e on the maze. Food trials began on D a y 3. F o r each animal, a different set of four m a z e arms was used for the baited set, and this set remained constant on all trials. On each daily trial, the animals were individually placed on the m a z e and allowed to c h o o s e freely a m o n g the eight arms until the four food pellets had been obtained. Records were kept of the arms entered and the order of entry, as well as the time required to complete the trial. Visits to a r m s in which a food pellet had already been obtained were scored as working m e m o r y errors. Visits to arms which n e v e r contained food w e r e scored as reference m e m o r y errors. Trials were run once a day for 25 days.
Histology After the completion of behavioral testing, the animals with lesions were anesthetized with a 1-cc injection of 30% chloral hydrate and perfused with a 10% formal-saline solution. Their brains were r e m o v e d and fixed in a 10% formal-saline solution. F r o z e n sections were cut at 20 txm
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PACKARD AND WHITE
and every fifth section was mounted and stained using the KleuverBerea method (Salthouse, 1964).
RESULTS
Histology Reconstructions of the lesions are illustrated in Fig. 1. Anterior caudate lesions produced damage that ranged from AP 1.6 to 0.1 mm from bregma (Paxinos & Watson, 1982). Posterior caudate lesions damaged the ventral-lateral caudate from AP 0.1 to - 1.2 mm from bregma. In all animals, bilateral caudate damage was extensive. The lesions did not damage the septal nuclei, nucleus accumbens, or the anterior commissure; however, occasional partial damage to golbus pallidus and cortex overlying the caudate was observed. Extracaudate damage did not correlate with the behavioral results.
Behavior Acquisition of the working memory component of the task is illustrated in Fig. 2. The caudate lesions had no effect on the animal's ability to
~_0.8 FI6. 1. Illustration of the minimum (hatched) and maximum (dark + hatched) extent of caudate lesions. Bilateral caudate damage was extensive in all rats. Taken from Paxinos and Watson (1982) atlas.
43
C A U D A T E N U C L E U S LESIONS AND MEMORY
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learn to enter each of the arms only once on each trial. A two-way onerepeated-measures A N O V A computed on the data in Fig. 2 revealed no significant Group differences IF(2, 18) = 0.412]. A significant effect of Trials revealed that working m e m o r y performance for all groups improved over trials [F(24, 18) = 6.99, p < .01]. Acquisition of the reference m e m o r y component is illustrated in Fig. 3. In contrast to the finding for working memory, caudate lesions impaired the animal's ability to discriminate between the baited and unbaited sets of arms. A two-way one-repeated-measures A N O V A computed on the data in Fig. 3 revealed a significant effect of Groups [F(2, 18) -- 63.8, p < .01]. N e w m a n - K e u l s post hoc tests showed that the caudate group ~,
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PACKARD AND WHITE
was significantly impaired on this behavior relative to unoperated controls (Q = 3.84). In addition, the ANOVA revealed a significant main effect of Trial [F(24, 18) = 4.72, p < .01], indicating that all groups improved over the 25 trials. Thus, there is evidence of improvement in the ability to discriminate between the sets of baited and unbaited maze arms by the caudate animals. However, it should be noted that the level of discrimination achieved by the caudate animals after 25 trials is about the same as that achieved by control and sham animals within the first 5 trials (Fig. 3). Therefore, it is apparent that caudate rats suffer a severe impairment in the acquisition of the reference memory component of this task. Because the same four arms were baited on every trial, animals may have solved both the reference and working memory components of the task by using a repeated, egocentric response pattern. The repeated use of an egocentric response pattern within the set of baited arms would not have required animals to remember which arms had been visited within a trial, or which arms were in the unbaited set. The degree to which animals used such a strategy was determined by examining their tendency to use consistent patterns of right, left, or a combination of fight and left turns when visiting the baited maze arms. For each animal, the total number of times that a particular pattern was used was computed. An animal was defined as an egocentric responder if the frequency of one particular pattern was greater than the sum of the frequencies of all alternative patterns. The egocentric response analyses were computed on trials 10-25, because unoperated control and sham animals had acquired both the reference and working memory components by the 10th trial, and caudate rats had acquired the working memory component. The egocentric analyses showed that two of seven unoperated control rats consistently displayed a RRR pattern in selecting the baited arms on trials 10-25. One of seven sham-operated rats consistently displayed a L L L pattern in selecting the baited arms. None of the caudate animals displayed egocentric responding. A X2 test revealed that significantly fewer animals than would be expected by chance used egocentric responding [X2 = 5.97, p < .05]. Therefore, it is likely that unoperated control, sham, and caudate rats used mnemonic, rather than egocentric, responding to solve the task. Finally, examination of the number of arms chosen per minute on trials 10-25 revealed no reliable differences among control (2.42), sham-operated (2.23), and caudate (2.61) rats, suggesting the absence of any significant motor impairment in the rats with caudate lesions. DISCUSSION The results show that lesions of the caudate nucleus impair acquisition of the reference memory component of the four-arms-baited, four-arms-
CAUDATE NUCLEUS LESIONS AND MEMORY
45
unbaited radial maze task, which required animals to discriminate between the sets of baited and unbaited maze arms. In contrast, the working memory component of the task, which required animals to avoid revisiting previously baited arms within a trial, was unaffected by caudate lesions. The inability of caudate lesions to impair working memory in the four-arms-baited, four-arms-unbaited task is consistent with previous reports that caudate lesions do not impair working memory in the standard eight-arm radial maze task (Becker, Walker, & Olton, 1980; Cook & Kesner, 1984; Packard et al., 1989; Volpe, Johnson, Ellenberger, & Davis, 1986). Previous studies have suggested that egocentric responding represents one form of S - R learning mediated by the caudate nucleus (Abraham, Potegal, & Miller, 1983; Cook & Kesner, 1988; Potegal, 1969). Therefore, the inability of caudate animals to use an egocentric response pattern could account for their impairment on the reference memory component of the present task. However, response pattern analyses carried out on the present data indicated that control and sham-operated rats did not, in general, use egocentric response patterning in acquiring this task. Therefore, it is unlikely that an impairment in this function was responsible for the behavioral deficit observed. Furthermore, the ability of caudate rats to perform the working memory component of the task was not dependent on egocentric responding. In previous work we have also observed that, in general, normal and caudate animals do not use egocentric responding when performing accurately in the standard eight-arm radial maze task (Packard et al., 1989). The impairment in the acquisition of reference memory observed in the present study following lesions of the caudate nucleus may be considered the opposite of what has been reported following hippocampal system damage. Previous studies have found that hippocampal damage produces a transient deficit in acquiring the reference memory component of the radial maze task (Davis et al., 1987; Olton, 1983; Volpe, Pulsinelli, Tribuna, & Davis, 1984). However, the deficit reported in previous studies is not nearly as severe as that observed following caudate nucleus lesions in the present study. The working memory/reference memory distinction proposed by Olton and Papas (1979) was based both on the nature of the learning which was impaired, and on the nature of the learning which was spared following hippocampal system damage (several other dual-memory theories have also been proposed on the basis of this comparison: (Hirsh, 1974; Mishkin & Petri, 1984; O'Keefe & Nadel, 1978). Because the dual-memory distinction proposed by Olton and Papas was operationally defined in the four-arms-baited, four-arms-unbaited radial maze task, the present results are consistent with the working/reference memory theory and
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PACKARD AND WHITE
suggest that the caudate nucleus may mediate at least some aspects of reference memory. However, several studies have shown the working/reference memory distinction to be incomplete (Eichenbaum, Fagan, Matthews, & Cohen, 1988; Nadel & McDonald, 1980). For example, the Morris water maze task is a reference memory task, because the location of the hidden platform is constant across trials. The working/reference memory theory predicts that performance on this task should be spared following hippocampal damage; however, lesions of the hippocampal system impair the acquisition of this task (Morris, Garrud, Rawlins, & O'Keefe, 1982; Sutherland, Kolb, & Whishaw, 1982). The impairment in Morris water maze acquisition following hippocampal damage has been interpreted as support for the spatial mapping hypothesis of hippocampal function (O'Keefe & Nadel, 1978). However, hippocampal lesions also impair nonspatial memory performance (Olton & Feustle, 1981; Walker & Olton, 1984). Furthermore, the results of the present study, in which caudate nucleus lesions impaired acquisition of the reference memory component, are inconsistent with the spatial mapping hypothesis. Acquisition of the reference memory component seems ideally suited for a spatial mapping strategy. A spatial map of the maze and environment should contain the locations of each of the four arms in the baited and unbaited sets. However, animals with caudate lesions and an intact hippocampus (and according to cognitive map theory an intact spatial mapping system) were impaired on spatial reference memory performance. An analysis of the pesent data, taken together with the results of our previous findings concerning the effects of caudate and fimbria-fornix lesions on radial maze behavior, may provide some insight into the nature of the mnemonic functions that are debilitated by hippocampal and caudate lesions. In the present experiment, normal animals tested daily on the four-arms-baited, four-arms-unbaited task stopped entering the arms that never contained food. The specific deficit exhibited by the animals with caudate lesions was a failure to stop entering these arms. At the same time, after a few trials in the maze, the caudate animals learned to visit each of the arms in the set that contained food only once within a trial. Thus, a paradox is presented by the behavior of these animals: they can learn to respond to the presence or absence of reinforcers (food) within a trial, but not from trial to trial. Because the caudate rats do not reenter baited arms, the behavioral deficit cannot be based on spatial discrimination or response inhibition. Furthermore, it is unlikely that caudate rats suffer a general impairment in long-term memory, since they are able to acquire the "win-shift" rule necessary for accurate working memory performance. A possible resolution of the paradox invokes two different connotations
CAUDATE NUCLEUS LESIONS AND MEMORY
47
of the term "reinforcement." Reinforcers have stimulus properties, and an animal can learn about the relations among these and other stimuli in its environment. For the working memory procedure in the radial maze, animals may learn about the presence or absence of reinforcers in different spatial locations. A different property of reinforcers is their tendency to strengthen stimulus-response (S-R) associations without actually being part of the information that is represented and remembered (Huston, Mondadori, & Waser, 1974; Messier & White, 1984; Thorndike, 1933). This process may be relevant for understanding deficits observed in reference memory in the radial maze. In the four-arms-baited, four-arms-unbaited task, each of the arms in the maze is " m a r k e d " by a unique set of cues, both within the maze and in the surrounding environment. Each time a rat approaches an arm the association between that arm's unique set of cue(s) and the approach response will be either strengthened by reinforcement if food is consumed, or weakened by nonreinforcement if no food is present. Over trials, a rat's responses to the cues marking the various arms will be differentially reinforced: the rat will acquire strong approach tendencies to the set of arms that always contain food and will stop approaching the arms that never contain food. This description of reference memory is consistent with the original definition, in which such procedures are based on " . . . fixed S-R a s s o c i a t i o n s . . . " which remain stable from trial to trial (Olton & Papas, 1979, p. 669). The present description adds to the original formulation the strengthening effect of reinforcers on S-R associations. The hypothesis that caudate lesions impair the ability of animals to learn tasks that can be acquired through the strengthening of S-R associations by reinforcement can explain why the animals in the present experiment were unable to learn which arms always contained food. At the same time, because these animals retained a normal hippocampal system their ability to learn about the relationships among stimuli, including the stimulus properties of reinforcers, was left intact. Hence, they were able to remember the presence or absence of reinforcement within trials. This distinction between the functions of the hippocampal and caudate memory systems is the same as the one made on the basis of our previous experiments (Packard et al., 1989) using the two radial maze tasks described in the introduction. In the standard win-shift task, all arms contained food and an animal learned to visit each arm only once on the basis of a stimulus property of the reinforcers: their presence or absence. Performance on this task was impaired by fimbria-fornix lesions but not by caudate lesions similar to those in the present experiment. In the novel task, four randomly selected arms were lit and only those arms contained food; an animal was required to enter each of these arms twice
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PACKARD AND WHITE
within a trial. An animal required only an approach response to light strengthened by reinforcement to perform this task; no knowledge of stimuli and their relations was required. Performance on this task was impaired by caudate lesions and facilitated by fimbria-fornix lesions. Several other learning tasks for which caudate lesions impair acquisition can also be understood within an S-R framework, including avoidance paradigms (Allen & Davison, 1973; Kirkby & Polgar, 1974; Mitcham & Thomas, 1972; Winocur, 1974), left/right maze discrimination (Cook & Kesner, 1988), and cued Morris water maze performance (Whishaw & Kolb, 1985; Whishaw, Mittleman, Bunch, & Dunnett, 1987). In the cued Morris water maze task, for example, the location of the escape platform is marked by a visual cue. Acquisition of the task requires only an approach response to the cued platform. Attaining the reinforcer (reaching the platform) may simply strengthen the tendency of the visual cue to elicit an approach response. It is noteworthy that acquisition of cued Morris water maze performance is spared by hippocampal system damage (Morris et al., 1982; Sutherland et al., 1982). Several lines of research have attributed a "sensori-motor" integration function to the caudate nucleus (e.g., Evenden & Robbins, 1984; Whishaw, O'Conner, & Dunnett, 1986). The present suggestion, that the caudate nucleus mediates stimulus-response memory, is consistent with this notion; adding the idea that the relatively permanent facilitation of specific sensori-motor relationships by reinforcement may form the basis of S-R memory. Additional research will be required to further the hypothesis that the role of reinforcers is one of the critical differences in the operating principles of the hippocampal and caudate memory systems. REFERENCES Abraham, L., Potegal, M., & Miller, S. (1983). Evidence for caudate nucleus involvement in an egocentric spatial task: Return from passive transport. Physiological Psychology, 11, 11-17. Allen, J. D., & Davison, C. S. (1973). Effects of caudate lesions on signaled and nonsignaled Sidman avoidance in the rat. Behavioral Biology, 8, 239-250. Becker, J. T., Walker, J. A., & Olton, D. S. (1980). Neuroanatomical basis of spatial memory. Brain Research, 200, 307-320. Cook, D., & Kesner, R. P. (1988). Caudate nucleus and memory for egocentric localization. Behavioral and Neural Biology, 49, 332-343. Davis, H. P., Baranowski, J. R., Pulsinelli, W. A., & Volpe, B. T. (1987). Retention of reference memory following ischemic hippocampal damage. Physiology and Behavior, 39, 783-786. Davis, H. P., Taras, M., Pulsinelli, W. A., & Volpe, B. T. (1986). Reference and working memory of rats following ischemic induced hippocampal damage. Physiology and Behavior, 37, 387-392. Eichenbaum, H., Fagan, A., Matthews, P., & Cohen, N. J. (1988). Hippocampal system dysfunction and odor discrimination learning in rats: Impairment or facilitation depending on representational demands. Behavioral Neuroscience, 102, 331-339.
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Evenden, J. L., & Robbins, T. W. (1984). Effects of unilateral 6-hydroxydopamine lesions of the caudate-putamen on skilled forepaw use in the rat. Behavioral Brain Research, 14, 61-68. Hirsh, R. (1974). The hippocampus and contextual retrieval of information from memory: A theory. Behavioral Biology, 12, 421-442. Honig, W. K. (1978). Studies of working memory in the pigeon. In S. H. Hulse, W. K. Honig, & H. Fowler (Eds.), Cognitive aspects of animal behavior (pp. 211-248). Hillsdale, NJ: Erlbaum. Huston, J. P., Mondadori, C., & Waser, P. G. (1974). Facilitation of learning by reward of post-trial memory processes. Experientia, 30, 1038-1040. Jarrard, L. E. (1983). Selective hippocampal lesions and behavior: Effects of kainic acid lesions on performance of place and cue tasks. Behavioral Neuroscience, 97, 873889. Kirkby, R. J., & Polgar, S. (1974). Active avoidance in the laboratory rat following lesions of the dorsal or ventral caudate nucleus. Physiological Psychology, 2, 301-306. Messier, C., & White, N. M. (1984). Contingent and non-contingent actions of sucrose and saccharin reinforcers: Effects on taste preferences and memory. Physiology and Behavior, 32, 195-203. Mishkin, M., & Petri, H. L. (1984). Memories and habits: Some implications for the analysis of learning and retention. In N. Butters & L. R. Squire (Eds.), Neuropsychology of memory (pp. 287-296). New York: Guilford. Mitcham, J. C., & Thomas, R. K. (1972). Effects of substantia nigra and caudate nucleus lesions on avoidance learning in rats. Journal of Comparative ~and Physiological Psychology, 81, 101-107. Morris, R. G. M., Garrud, P., Rawlins, J. N. P., & O'Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature (London), 297, 681-683. Nadel, L., & McDonald, L. (1980). Hippocampus: Cognitive map or working memory? Behavioral and Neural Biology, 29, 405-409. O'Keefe, J., & Nadel, L. (1978). The hippocampus as a cognitive map. New York: Oxford Univ. Press. Olton, D. S. (1983). Memory functions and the hippocampus. In W. Seifert (Ed.), Neurobiology of the hippocampus. New York: Academic Press. Olton, D. S., Becker, J. T., & Handelmann, G. E. (1979). Hippocampus, space, and memory. Behavioral Brain Sciences, 2, 313-365. Olton, D. S., & Feustle, W. A. (1981). Hippocampal function required for nonspatial working memory. Experimental Brain Research, 41, 380-389. Olton, D. S., & Papas, B. C. (1979). Spatial memory and hippocampal function. Neuropsychologia, 17, 669-682. Olton, D. S., & Sameulson, R. J. (1976). Remembrance of places passed: Spatial memory in rats. Journal of Experimental Psychology: Animal Behavior Processes, 2, 97-115. Packard, M. G., Hirsh, R., & White, N. M. (1989). Differential effects of fornix and caudate nucleus lesions on two radial maze tasks: Evidence for multiple memory systems. Journal of Neuroscience, 9, 1465-1472. Paxinos, G., & Watson, C. (1982). The rat brain in stereotaxic coordinates. New York: Academic Press. Potegal, M. (1969). The caudate nucleus egocentric localization system. Acta Neurobiologica Experimentalis, 32, 479-494. Salthouse, T. N. (1964). Luxol fast blue " G " as a myelin stain. Stain Technology, 39, 123-128. Silveira, J. M., & Kimble, D. P. (1968). Brightness discrimination and reversal in hippocampally-lesioned rats. Physiology and Behavior, 3, 625-630. Sutherland, R. J., Kolb, B., & Whishaw, 1. Q. (1982). Spatial mapping: Definitive disruption
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by hippocampal or medial frontal cortex damage in the rat. Neuroscience Letters, 31, 271-276. Thorndike, E. I. (1933). A proof of the law of effect. Science, 17, 173-175. Volpe, B. T., Johnson, R., Ellenberger, J., & Davis, H. P. (1986). Performance of rats with either ischemic hippocampal injury, or bilateral radiofrequency lesions of the hippocampus or caudate on a 12 arm radial maze. Society for Neuroscience Abstracts, 12, 745. Volpe, B. T., Pulsinelli, W. A., Tribuna, J., & Davis, H. P. (1984). Behavioral performance of rats following transient forebrain ischemia. Stroke, 15, 558-562. Walker, J. A., & Olton, D. S. (1984). Fimbria-fornix lesions impair spatial working memory but not cognitive mapping. Behavioral Neuroscience, 98, 226-242. Whishaw, I. Q., & Kolb, B. (1984). Decortication abolishes place but not cue learning in rats. Behavioral Brain Research, 11, 123-134. Whishaw, I. Q., Mittlemann, G., Bunch, S. T., & Dunnett, S. B. (1987). Impairments in the acquisition, retention, and selection of spatial navigation strategies after medial caudate-putamen lesions in rats. Behavioral Brain Research, 24, 125-138. Whishaw, I, Q., O'Conner, W. T., & Dunnett, S. B. The contributions of motor cortex, nigrostriatal dopamine and caudate-putanTen to skilled forelimb use in the rat. Brain, 109, 805-843. Winocur, G. (1974). Functional dissociation within the caudate nucleus of rats. Journal of Comparative and Physiological Psychology, 86, 432-439.
Lesions of the Caudate Nucleus Selectively Impair "Reference Memory" Acquisition in the Radial Maze MARK G.
PACKARD AND NORMAN
M.
WHITE 1
Department of Psychology, McGill University Groups of L o n g - E v a n s rats with bilateral lesions of the caudate nucleus, sham lesions, or no lesions were given one trial per day in an eight-arm radial maze. The same four maze arms were baited on each trial. The remaining four arms never contained food. Optimal performance required animals to enter each of the baited arms only once on each trial and to avoid entering the arms in the unbaited set. Rats with caudate lesions learned to enter each of the baited arms only once on each trial. H o w e v e r , these rats were severely impaired in learning to avoid entering the arms in the unbaited set. Implications for dual-memory theories are discussed. © 1990Academic Press, Inc.
One theoretical model of multiple memory systems proposes a distinction between working memory and reference memory (Honig, 1978; Olton, Becker, & Handelmann, 1979). Working memory procedures require memory for trial-discrete information, such as previously visited maze arms in a radial maze task (Olton & Samuelson, 1976). In contrast, reference memory procedures involve information pertinent to every trial of a given learning task, such as memory for the positive discriminative cue in a simultaneous discrimination task (Silveira & Kimble, 1968). The working/reference memory distinction was tested in a 17-arm radial maze task developed by Olton and Papas (1979). In this task, the same set of 8 maze arms was baited once on each trial, while the remaining arms were always unbaited. The working memory component of the task required rats to visit each of the baited arms once within a trial. The reference memory component of the task required animals to learn to avoid entering the arms in the unbaited set, which remained constant across trials. Several investigators have reported that preoperatively trained rats with lesions of the fimbria-fornix are impaired in This research was supported by grants from F O N D S F C A R province of Quebec and from the Medical R e s e a r c h Council of C a n a d a to N o r m a n White. W e thank Dr. Matthew Shapiro for helpful c o m m e n t s on an earlier version of the manuscript. Address corres p o n d e n c e and reprint requests to Mark G. Packard, D e p a r t m e n t of Psychology, McGill University, 1205 Dr. Penfield A v e . , Montreal, P. Q. Quebec, Canada H3A 1B1. 39 0163-1047/90 $3.00 Copyright © 1990by AcademicPress, Inc. All rights of reproduction in any form reserved.
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the working memory component o f this task (Davis, Taras, Pulsinelli, & Volpe, 1986; Jarrard, 1983; Nadel & McDonald, 1980; Olton & Papas, 1979). In contrast, it has been reported that hippocampal system damage has no effect on retention of the reference memory component of the task (Davis, Baranowski, Pulsinelli, & Volpe, 1987; Olton & Papas, 1979); others, however, have reported a deficit in retention of this component (Jarrard, 1983; Nadel & McDonald,~. 1980). The reported preservation of reference memory in this task after fornix/hippocampal lesions is only one among several instances of learning that survives damage to the hippocampal system (for reviews see Hirsh, 1974; O'Keefe & Nadel, 1978). Recent work from our laboratory has demonstrated that the caudate nucleus mediates some of the learning that is spared following hippocampal system damage (Packard, Hirsh, & White, 1989). The mnemonic functions of the hippocampus and caudate nucleus were doubly dissociated using two versions of the radial maze task. In the standard radial maze task (Olton & Samuelson, 1976) fimbriafornix lesions impaired choice accuracy, while lesions of the caudate nucleus had no effect. In a novel radial maze task, a sensory cue (light) signaled four randomly selected reinforced maze arms, and animals were required to revisit previously reinforced arms within a trial. Lesions of the caudate nucleus impaired acquisition of this task, while fornix lesions facilitated acquisition. These findings suggest that the caudate nucleus may mediate some of the learning abilities which survive hippocampal damage. The present experiment was designed to extend these findings by testing whether the caudate nucleus is required for acquiring of the reference memory component of the four-arms-baited, four-arms-unbaited radial maze task. METHODS
Subjects The subjects were 21 male Long-Evans rats (275-325 g). Rats were individually housed in a temperature controlled environment with the lights on from 7 AM to 7 PM. All animals were given ad libitum access to water. After arrival in the laboratory, each rat was handled individually for 5 min on each of 4 days prior to surgery.
Apparatus The apparatus was a wooden eight-arm radial maze painted flat gray and elevated 60 cm above the floor. Each arm measured 60 × 9 cm, and the center platform was 40 cm in diameter. Food cups were drilled into the floor near the end of each arm. The maze room included several extramaze cues.
CAUDATE NUCLEUS LESIONS AND MEMORY
41
Surgery Rats w e r e assigned to one of three groups; caudate lesion (N = 7), s h a m - o p e r a t e d ( N = 7), or u n o p e r a t e d control (N = 7). Each rat was anesthetized with 60 m g / k g sodium pentobarbital. Lesions were m a d e using standard stereotaxic techniques. Bilateral electrolytic lesions of the caudate nucleus were m a d e at anterior and posterior sites. F o r the anterior caudate lesions, stereotaxic coordinates were AP = + 1.5 m m f r o m bregma, M L = + 2 . 8 m m , DV = - 6 . 2 m m (Paxinos & Watson, 1982). At the anterior site, 4 m A of direct current was passed for 15 s through an electrode insulated except for 0.8 m m at the tip. F o r the posterior caudate lesions, stereotaxic coordinates were AP = + 0.2 m m from bregma, M L = + 4 . 3 ram, D V = - 6 . 7 ram. At the posterior site, 5mA was p a s s e d for 20 s. The caudate lesions were made in two stages. Anterior and posterior lesions were m a d e unilaterally, and the two lesions on the other side w e r e m a d e 2 w e e k s later. Behavioral testing began 2 weeks after the second pair of lesions was made. During r e c o v e r y periods, animals were fed a daily supplement of rat c h o w mash. N o n e of the caudate animals was aphagic or adipsic at the time of testing, and their gross m o t o r m o v e m e n t s a p p e a r e d normal. S h a m - o p e r a t e d animals underwent operating procedures identical to those p e r f o r m e d on caudate rats, except that no current was passed through the electrodes.
Procedure Preliminary training consisted of a 2-day habituation period, during which the animals were individually placed on the maze for 5 min and allowed to explore with no food available a n y w h e r e on the maze. Food trials began on D a y 3. F o r each animal, a different set of four m a z e arms was used for the baited set, and this set remained constant on all trials. On each daily trial, the animals were individually placed on the m a z e and allowed to c h o o s e freely a m o n g the eight arms until the four food pellets had been obtained. Records were kept of the arms entered and the order of entry, as well as the time required to complete the trial. Visits to a r m s in which a food pellet had already been obtained were scored as working m e m o r y errors. Visits to arms which n e v e r contained food w e r e scored as reference m e m o r y errors. Trials were run once a day for 25 days.
Histology After the completion of behavioral testing, the animals with lesions were anesthetized with a 1-cc injection of 30% chloral hydrate and perfused with a 10% formal-saline solution. Their brains were r e m o v e d and fixed in a 10% formal-saline solution. F r o z e n sections were cut at 20 txm
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and every fifth section was mounted and stained using the KleuverBerea method (Salthouse, 1964).
RESULTS
Histology Reconstructions of the lesions are illustrated in Fig. 1. Anterior caudate lesions produced damage that ranged from AP 1.6 to 0.1 mm from bregma (Paxinos & Watson, 1982). Posterior caudate lesions damaged the ventral-lateral caudate from AP 0.1 to - 1.2 mm from bregma. In all animals, bilateral caudate damage was extensive. The lesions did not damage the septal nuclei, nucleus accumbens, or the anterior commissure; however, occasional partial damage to golbus pallidus and cortex overlying the caudate was observed. Extracaudate damage did not correlate with the behavioral results.
Behavior Acquisition of the working memory component of the task is illustrated in Fig. 2. The caudate lesions had no effect on the animal's ability to
~_0.8 FI6. 1. Illustration of the minimum (hatched) and maximum (dark + hatched) extent of caudate lesions. Bilateral caudate damage was extensive in all rats. Taken from Paxinos and Watson (1982) atlas.
43
C A U D A T E N U C L E U S LESIONS AND MEMORY
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learn to enter each of the arms only once on each trial. A two-way onerepeated-measures A N O V A computed on the data in Fig. 2 revealed no significant Group differences IF(2, 18) = 0.412]. A significant effect of Trials revealed that working m e m o r y performance for all groups improved over trials [F(24, 18) = 6.99, p < .01]. Acquisition of the reference m e m o r y component is illustrated in Fig. 3. In contrast to the finding for working memory, caudate lesions impaired the animal's ability to discriminate between the baited and unbaited sets of arms. A two-way one-repeated-measures A N O V A computed on the data in Fig. 3 revealed a significant effect of Groups [F(2, 18) -- 63.8, p < .01]. N e w m a n - K e u l s post hoc tests showed that the caudate group ~,
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Trial (Day) FIG. 3. Mean number of visits to arms in the unbaited set made by caudate, shamoperated, and unoperated control rats over 25 trials. Data shown in blocks of 5 trials.
44
PACKARD AND WHITE
was significantly impaired on this behavior relative to unoperated controls (Q = 3.84). In addition, the ANOVA revealed a significant main effect of Trial [F(24, 18) = 4.72, p < .01], indicating that all groups improved over the 25 trials. Thus, there is evidence of improvement in the ability to discriminate between the sets of baited and unbaited maze arms by the caudate animals. However, it should be noted that the level of discrimination achieved by the caudate animals after 25 trials is about the same as that achieved by control and sham animals within the first 5 trials (Fig. 3). Therefore, it is apparent that caudate rats suffer a severe impairment in the acquisition of the reference memory component of this task. Because the same four arms were baited on every trial, animals may have solved both the reference and working memory components of the task by using a repeated, egocentric response pattern. The repeated use of an egocentric response pattern within the set of baited arms would not have required animals to remember which arms had been visited within a trial, or which arms were in the unbaited set. The degree to which animals used such a strategy was determined by examining their tendency to use consistent patterns of right, left, or a combination of fight and left turns when visiting the baited maze arms. For each animal, the total number of times that a particular pattern was used was computed. An animal was defined as an egocentric responder if the frequency of one particular pattern was greater than the sum of the frequencies of all alternative patterns. The egocentric response analyses were computed on trials 10-25, because unoperated control and sham animals had acquired both the reference and working memory components by the 10th trial, and caudate rats had acquired the working memory component. The egocentric analyses showed that two of seven unoperated control rats consistently displayed a RRR pattern in selecting the baited arms on trials 10-25. One of seven sham-operated rats consistently displayed a L L L pattern in selecting the baited arms. None of the caudate animals displayed egocentric responding. A X2 test revealed that significantly fewer animals than would be expected by chance used egocentric responding [X2 = 5.97, p < .05]. Therefore, it is likely that unoperated control, sham, and caudate rats used mnemonic, rather than egocentric, responding to solve the task. Finally, examination of the number of arms chosen per minute on trials 10-25 revealed no reliable differences among control (2.42), sham-operated (2.23), and caudate (2.61) rats, suggesting the absence of any significant motor impairment in the rats with caudate lesions. DISCUSSION The results show that lesions of the caudate nucleus impair acquisition of the reference memory component of the four-arms-baited, four-arms-
CAUDATE NUCLEUS LESIONS AND MEMORY
45
unbaited radial maze task, which required animals to discriminate between the sets of baited and unbaited maze arms. In contrast, the working memory component of the task, which required animals to avoid revisiting previously baited arms within a trial, was unaffected by caudate lesions. The inability of caudate lesions to impair working memory in the four-arms-baited, four-arms-unbaited task is consistent with previous reports that caudate lesions do not impair working memory in the standard eight-arm radial maze task (Becker, Walker, & Olton, 1980; Cook & Kesner, 1984; Packard et al., 1989; Volpe, Johnson, Ellenberger, & Davis, 1986). Previous studies have suggested that egocentric responding represents one form of S - R learning mediated by the caudate nucleus (Abraham, Potegal, & Miller, 1983; Cook & Kesner, 1988; Potegal, 1969). Therefore, the inability of caudate animals to use an egocentric response pattern could account for their impairment on the reference memory component of the present task. However, response pattern analyses carried out on the present data indicated that control and sham-operated rats did not, in general, use egocentric response patterning in acquiring this task. Therefore, it is unlikely that an impairment in this function was responsible for the behavioral deficit observed. Furthermore, the ability of caudate rats to perform the working memory component of the task was not dependent on egocentric responding. In previous work we have also observed that, in general, normal and caudate animals do not use egocentric responding when performing accurately in the standard eight-arm radial maze task (Packard et al., 1989). The impairment in the acquisition of reference memory observed in the present study following lesions of the caudate nucleus may be considered the opposite of what has been reported following hippocampal system damage. Previous studies have found that hippocampal damage produces a transient deficit in acquiring the reference memory component of the radial maze task (Davis et al., 1987; Olton, 1983; Volpe, Pulsinelli, Tribuna, & Davis, 1984). However, the deficit reported in previous studies is not nearly as severe as that observed following caudate nucleus lesions in the present study. The working memory/reference memory distinction proposed by Olton and Papas (1979) was based both on the nature of the learning which was impaired, and on the nature of the learning which was spared following hippocampal system damage (several other dual-memory theories have also been proposed on the basis of this comparison: (Hirsh, 1974; Mishkin & Petri, 1984; O'Keefe & Nadel, 1978). Because the dual-memory distinction proposed by Olton and Papas was operationally defined in the four-arms-baited, four-arms-unbaited radial maze task, the present results are consistent with the working/reference memory theory and
46
PACKARD AND WHITE
suggest that the caudate nucleus may mediate at least some aspects of reference memory. However, several studies have shown the working/reference memory distinction to be incomplete (Eichenbaum, Fagan, Matthews, & Cohen, 1988; Nadel & McDonald, 1980). For example, the Morris water maze task is a reference memory task, because the location of the hidden platform is constant across trials. The working/reference memory theory predicts that performance on this task should be spared following hippocampal damage; however, lesions of the hippocampal system impair the acquisition of this task (Morris, Garrud, Rawlins, & O'Keefe, 1982; Sutherland, Kolb, & Whishaw, 1982). The impairment in Morris water maze acquisition following hippocampal damage has been interpreted as support for the spatial mapping hypothesis of hippocampal function (O'Keefe & Nadel, 1978). However, hippocampal lesions also impair nonspatial memory performance (Olton & Feustle, 1981; Walker & Olton, 1984). Furthermore, the results of the present study, in which caudate nucleus lesions impaired acquisition of the reference memory component, are inconsistent with the spatial mapping hypothesis. Acquisition of the reference memory component seems ideally suited for a spatial mapping strategy. A spatial map of the maze and environment should contain the locations of each of the four arms in the baited and unbaited sets. However, animals with caudate lesions and an intact hippocampus (and according to cognitive map theory an intact spatial mapping system) were impaired on spatial reference memory performance. An analysis of the pesent data, taken together with the results of our previous findings concerning the effects of caudate and fimbria-fornix lesions on radial maze behavior, may provide some insight into the nature of the mnemonic functions that are debilitated by hippocampal and caudate lesions. In the present experiment, normal animals tested daily on the four-arms-baited, four-arms-unbaited task stopped entering the arms that never contained food. The specific deficit exhibited by the animals with caudate lesions was a failure to stop entering these arms. At the same time, after a few trials in the maze, the caudate animals learned to visit each of the arms in the set that contained food only once within a trial. Thus, a paradox is presented by the behavior of these animals: they can learn to respond to the presence or absence of reinforcers (food) within a trial, but not from trial to trial. Because the caudate rats do not reenter baited arms, the behavioral deficit cannot be based on spatial discrimination or response inhibition. Furthermore, it is unlikely that caudate rats suffer a general impairment in long-term memory, since they are able to acquire the "win-shift" rule necessary for accurate working memory performance. A possible resolution of the paradox invokes two different connotations
CAUDATE NUCLEUS LESIONS AND MEMORY
47
of the term "reinforcement." Reinforcers have stimulus properties, and an animal can learn about the relations among these and other stimuli in its environment. For the working memory procedure in the radial maze, animals may learn about the presence or absence of reinforcers in different spatial locations. A different property of reinforcers is their tendency to strengthen stimulus-response (S-R) associations without actually being part of the information that is represented and remembered (Huston, Mondadori, & Waser, 1974; Messier & White, 1984; Thorndike, 1933). This process may be relevant for understanding deficits observed in reference memory in the radial maze. In the four-arms-baited, four-arms-unbaited task, each of the arms in the maze is " m a r k e d " by a unique set of cues, both within the maze and in the surrounding environment. Each time a rat approaches an arm the association between that arm's unique set of cue(s) and the approach response will be either strengthened by reinforcement if food is consumed, or weakened by nonreinforcement if no food is present. Over trials, a rat's responses to the cues marking the various arms will be differentially reinforced: the rat will acquire strong approach tendencies to the set of arms that always contain food and will stop approaching the arms that never contain food. This description of reference memory is consistent with the original definition, in which such procedures are based on " . . . fixed S-R a s s o c i a t i o n s . . . " which remain stable from trial to trial (Olton & Papas, 1979, p. 669). The present description adds to the original formulation the strengthening effect of reinforcers on S-R associations. The hypothesis that caudate lesions impair the ability of animals to learn tasks that can be acquired through the strengthening of S-R associations by reinforcement can explain why the animals in the present experiment were unable to learn which arms always contained food. At the same time, because these animals retained a normal hippocampal system their ability to learn about the relationships among stimuli, including the stimulus properties of reinforcers, was left intact. Hence, they were able to remember the presence or absence of reinforcement within trials. This distinction between the functions of the hippocampal and caudate memory systems is the same as the one made on the basis of our previous experiments (Packard et al., 1989) using the two radial maze tasks described in the introduction. In the standard win-shift task, all arms contained food and an animal learned to visit each arm only once on the basis of a stimulus property of the reinforcers: their presence or absence. Performance on this task was impaired by fimbria-fornix lesions but not by caudate lesions similar to those in the present experiment. In the novel task, four randomly selected arms were lit and only those arms contained food; an animal was required to enter each of these arms twice
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PACKARD AND WHITE
within a trial. An animal required only an approach response to light strengthened by reinforcement to perform this task; no knowledge of stimuli and their relations was required. Performance on this task was impaired by caudate lesions and facilitated by fimbria-fornix lesions. Several other learning tasks for which caudate lesions impair acquisition can also be understood within an S-R framework, including avoidance paradigms (Allen & Davison, 1973; Kirkby & Polgar, 1974; Mitcham & Thomas, 1972; Winocur, 1974), left/right maze discrimination (Cook & Kesner, 1988), and cued Morris water maze performance (Whishaw & Kolb, 1985; Whishaw, Mittleman, Bunch, & Dunnett, 1987). In the cued Morris water maze task, for example, the location of the escape platform is marked by a visual cue. Acquisition of the task requires only an approach response to the cued platform. Attaining the reinforcer (reaching the platform) may simply strengthen the tendency of the visual cue to elicit an approach response. It is noteworthy that acquisition of cued Morris water maze performance is spared by hippocampal system damage (Morris et al., 1982; Sutherland et al., 1982). Several lines of research have attributed a "sensori-motor" integration function to the caudate nucleus (e.g., Evenden & Robbins, 1984; Whishaw, O'Conner, & Dunnett, 1986). The present suggestion, that the caudate nucleus mediates stimulus-response memory, is consistent with this notion; adding the idea that the relatively permanent facilitation of specific sensori-motor relationships by reinforcement may form the basis of S-R memory. Additional research will be required to further the hypothesis that the role of reinforcers is one of the critical differences in the operating principles of the hippocampal and caudate memory systems. REFERENCES Abraham, L., Potegal, M., & Miller, S. (1983). Evidence for caudate nucleus involvement in an egocentric spatial task: Return from passive transport. Physiological Psychology, 11, 11-17. Allen, J. D., & Davison, C. S. (1973). Effects of caudate lesions on signaled and nonsignaled Sidman avoidance in the rat. Behavioral Biology, 8, 239-250. Becker, J. T., Walker, J. A., & Olton, D. S. (1980). Neuroanatomical basis of spatial memory. Brain Research, 200, 307-320. Cook, D., & Kesner, R. P. (1988). Caudate nucleus and memory for egocentric localization. Behavioral and Neural Biology, 49, 332-343. Davis, H. P., Baranowski, J. R., Pulsinelli, W. A., & Volpe, B. T. (1987). Retention of reference memory following ischemic hippocampal damage. Physiology and Behavior, 39, 783-786. Davis, H. P., Taras, M., Pulsinelli, W. A., & Volpe, B. T. (1986). Reference and working memory of rats following ischemic induced hippocampal damage. Physiology and Behavior, 37, 387-392. Eichenbaum, H., Fagan, A., Matthews, P., & Cohen, N. J. (1988). Hippocampal system dysfunction and odor discrimination learning in rats: Impairment or facilitation depending on representational demands. Behavioral Neuroscience, 102, 331-339.
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Evenden, J. L., & Robbins, T. W. (1984). Effects of unilateral 6-hydroxydopamine lesions of the caudate-putamen on skilled forepaw use in the rat. Behavioral Brain Research, 14, 61-68. Hirsh, R. (1974). The hippocampus and contextual retrieval of information from memory: A theory. Behavioral Biology, 12, 421-442. Honig, W. K. (1978). Studies of working memory in the pigeon. In S. H. Hulse, W. K. Honig, & H. Fowler (Eds.), Cognitive aspects of animal behavior (pp. 211-248). Hillsdale, NJ: Erlbaum. Huston, J. P., Mondadori, C., & Waser, P. G. (1974). Facilitation of learning by reward of post-trial memory processes. Experientia, 30, 1038-1040. Jarrard, L. E. (1983). Selective hippocampal lesions and behavior: Effects of kainic acid lesions on performance of place and cue tasks. Behavioral Neuroscience, 97, 873889. Kirkby, R. J., & Polgar, S. (1974). Active avoidance in the laboratory rat following lesions of the dorsal or ventral caudate nucleus. Physiological Psychology, 2, 301-306. Messier, C., & White, N. M. (1984). Contingent and non-contingent actions of sucrose and saccharin reinforcers: Effects on taste preferences and memory. Physiology and Behavior, 32, 195-203. Mishkin, M., & Petri, H. L. (1984). Memories and habits: Some implications for the analysis of learning and retention. In N. Butters & L. R. Squire (Eds.), Neuropsychology of memory (pp. 287-296). New York: Guilford. Mitcham, J. C., & Thomas, R. K. (1972). Effects of substantia nigra and caudate nucleus lesions on avoidance learning in rats. Journal of Comparative ~and Physiological Psychology, 81, 101-107. Morris, R. G. M., Garrud, P., Rawlins, J. N. P., & O'Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature (London), 297, 681-683. Nadel, L., & McDonald, L. (1980). Hippocampus: Cognitive map or working memory? Behavioral and Neural Biology, 29, 405-409. O'Keefe, J., & Nadel, L. (1978). The hippocampus as a cognitive map. New York: Oxford Univ. Press. Olton, D. S. (1983). Memory functions and the hippocampus. In W. Seifert (Ed.), Neurobiology of the hippocampus. New York: Academic Press. Olton, D. S., Becker, J. T., & Handelmann, G. E. (1979). Hippocampus, space, and memory. Behavioral Brain Sciences, 2, 313-365. Olton, D. S., & Feustle, W. A. (1981). Hippocampal function required for nonspatial working memory. Experimental Brain Research, 41, 380-389. Olton, D. S., & Papas, B. C. (1979). Spatial memory and hippocampal function. Neuropsychologia, 17, 669-682. Olton, D. S., & Sameulson, R. J. (1976). Remembrance of places passed: Spatial memory in rats. Journal of Experimental Psychology: Animal Behavior Processes, 2, 97-115. Packard, M. G., Hirsh, R., & White, N. M. (1989). Differential effects of fornix and caudate nucleus lesions on two radial maze tasks: Evidence for multiple memory systems. Journal of Neuroscience, 9, 1465-1472. Paxinos, G., & Watson, C. (1982). The rat brain in stereotaxic coordinates. New York: Academic Press. Potegal, M. (1969). The caudate nucleus egocentric localization system. Acta Neurobiologica Experimentalis, 32, 479-494. Salthouse, T. N. (1964). Luxol fast blue " G " as a myelin stain. Stain Technology, 39, 123-128. Silveira, J. M., & Kimble, D. P. (1968). Brightness discrimination and reversal in hippocampally-lesioned rats. Physiology and Behavior, 3, 625-630. Sutherland, R. J., Kolb, B., & Whishaw, 1. Q. (1982). Spatial mapping: Definitive disruption
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by hippocampal or medial frontal cortex damage in the rat. Neuroscience Letters, 31, 271-276. Thorndike, E. I. (1933). A proof of the law of effect. Science, 17, 173-175. Volpe, B. T., Johnson, R., Ellenberger, J., & Davis, H. P. (1986). Performance of rats with either ischemic hippocampal injury, or bilateral radiofrequency lesions of the hippocampus or caudate on a 12 arm radial maze. Society for Neuroscience Abstracts, 12, 745. Volpe, B. T., Pulsinelli, W. A., Tribuna, J., & Davis, H. P. (1984). Behavioral performance of rats following transient forebrain ischemia. Stroke, 15, 558-562. Walker, J. A., & Olton, D. S. (1984). Fimbria-fornix lesions impair spatial working memory but not cognitive mapping. Behavioral Neuroscience, 98, 226-242. Whishaw, I. Q., & Kolb, B. (1984). Decortication abolishes place but not cue learning in rats. Behavioral Brain Research, 11, 123-134. Whishaw, I. Q., Mittlemann, G., Bunch, S. T., & Dunnett, S. B. (1987). Impairments in the acquisition, retention, and selection of spatial navigation strategies after medial caudate-putamen lesions in rats. Behavioral Brain Research, 24, 125-138. Whishaw, I, Q., O'Conner, W. T., & Dunnett, S. B. The contributions of motor cortex, nigrostriatal dopamine and caudate-putanTen to skilled forelimb use in the rat. Brain, 109, 805-843. Winocur, G. (1974). Functional dissociation within the caudate nucleus of rats. Journal of Comparative and Physiological Psychology, 86, 432-439.