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Behavioral Neuroscience 1993, Vol. 107, No. 4, 565-574

Medial Septal Lesions Disrupt Spatial, but Not Nonspatial, Working Memory in Rats

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John E. Kelsey and Hannah Vargas In Experiment 1, rats with small medial septal lesions were less able than were control rats to remember the location of the arm of a Y maze they had been forced to enter on the preceding sample run. Moreover, as the retention interval between the sample and choice runs on this spatial delayed nonmatching-to-sample (DNMTS) task was increased to 1 and 2 min, the magnitude of the deficit increased. In contrast, these same lesioned rats were not deficient in Experiment 2 in their ability to remember the object they had encountered in the straight alley on the sample run. In fact, when the retention interval was increased to 1 min on this nonspatial DNMTS task, the rats with medial septal lesions were more accurate than were the controls. This pattern of results did not appear to be due to task difficulty, recovery of function, or sequence of training. Rather, these results indicate that damage to the septohippocampal system disrupts spatial working memory more than it disrupts nonspatial working memory.

alternative hypothesis that suggests that the role of the hippocampal system is not to code working memory but to form a cognitive or spatial map of one's environment (O'Keefe & Nadel, 1978). In this view, damage to such a system would disrupt performance in a radial arm maze or T maze, not because the animal cannot remember where it has just been (working memory), but because it does not know where it is now (spatial mapping). A seemingly compelling test of these two competing hypotheses would be to examine the effects of damage to this system on a nonspatial (i.e., spatially irrelevant) working memory task such as a delayed nonmatching-to-sample task (DNMTS) that requires the memory of objects rather than locations (e.g., Rothblat & Hayes, 1987). On such a task, the rat would encounter a single object on the sample run and then, when faced with a choice between that and another object on the subsequent choice run, be required to choose the other object. Because this task clearly requires working memory, that is, the capacity to remember the object just encountered, Olton et al. (1979) would predict that damage to the hippocampal system would disrupt performance on such a nonspatial task as much as it does on more traditional spatial working memory tasks. On the other hand, O'Keefe and Nadel (1978) would predict less disruption on the nonspatial task than on the spatial task because the nonspatial task requires little or no spatial mapping. Unfortunately, there are few studies that examine the performance of rats with damage to the hippocampal system on nonspatial working memory tasks and fewer yet that compare the performance of such rats on both spatial and nonspatial working memory tasks. Consistent with their view, Olton and Feustle (1981) found that large fimbria-fornix lesions, which damage many of the afferent and efferent projections of the hippocampus, disrupted the ability of rats to select the arms of a four-arm radial maze that were different in color and texture, but not necessarily spatial location, from arms they had already entered on that trial. Similarly, Raffaele and Olton (1988) found that large, but not small, fimbria-fornix lesions impaired the ability of rats to select the goal box, irrespective of location, that was visibly

Considerable evidence implicates the hippocampal projection system in memory (e.g., Squire, 1992). However, substantial controversy still exists about the precise role this system plays in mediating memory. Olton, Becker, and Handelmann (1979) have argued that the role of this system is to mediate trial-dependent or working memory. As examples of support for this view, Olton and Papas (1979) found that damage to this system disrupts the ability of rats in a radial arm maze to avoid reentry into baited arms previously entered on that trial. Similarly, Hepler, Olton, Wenk, and Coyle (1985) found that damage to this system in rats disrupts delayed nonmatching to position in a T maze when a retention interval of more than a few seconds exists between the sample and choice runs. Olton et al. (1979) argued that these deficits occur because the rats with damage to the hippocampal system cannot remember which baited arm(s) they had already visited on that trial. A serious problem for this working memory hypothesis is the consistent finding that damage to the hippocampal system disrupts the ability to find a platform hidden in a fixed location in a circular Morris water tank, a task that requires little or no working memory (e.g., Kelsey & Landry, 1988; Morris, Garrud, Rawlins, & O'Keefe, 1982). This observation, coupled with the finding that the hippocampus contains neurons ("place cells") that respond best to a particular location in the environment (O'Keefe, 1976; O'Keefe & Dostrovsky, 1971), led to an John E. Kelsey, Department of Psychology, Bates College; Hannah Vargas, Department of Psychology, Bates College (now at University of Vermont College of Medicine). Partial support for this work was provided by the National Science Foundation College Science Instrumentation Program through Grant CSI-8650267 and the National Science Foundation Instrumentation and Laboratory Improvement Program through Grant CSI-8750377. This study was based on research submitted to Bates College by Hannah Vargas as partial fulfillment for a Bachelor of Science degree in biopsychology. These data were presented at the Society for Neuroscience Convention in St. Louis, 1990. Correspondence concerning this article should be addressed to John E. Kelsey, Department of Psychology, Bates College, Lewiston, Maine 04240.

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identical to the goal box they had most recently entered. Finally, Jagielo, Nonneman, Issac, and Jackson-Smith (1990) found that rats with large hippocampal lesions failed to learn to select the goal box in a T maze that was the same color as the start box, even when there was no working memory requirement. On the other hand, Aggleton, Hunt, and Rawlins (1986) found that large hippocampal lesions failed to disrupt the ability to select the visibly novel goal box irrespective of location, even at retention intervals of 60 s. However, these same lesions severely disrupted the ability of rats in a Y maze to choose the goal box that was in the location least recently visited, even with a minimal delay between choices. Similarly, Peinado-Manzano (1990) found that lesions of the dorsal hippocampus that disrupted the ability of rats to select the arm in a T maze spatially opposite the arm most recently entered failed to affect the ability to select the arm with visual cues unlike those of the arm most recently entered. Rothblat and Kromer (1991) also found that large fimbria-fornix lesions that disrupted the ability of rats to acquire and perform spatial DNMTS in a T maze did not disrupt the ability to select the object that was different from the object encountered on the previous sample run even when the retention interval was 30 s. Finally, Mumby, Wood, and Pinel (1992) found that hippocampal lesions failed to disrupt the ability of rats to select the novel object until the retention interval between sample and choice runs was greater than 600 s, and Otto and Eichenbaum (1992) found that lesions of the fornix failed to disrupt the ability of rats to respond to an odor when it did not match the preceding odor, regardless of the delay (retention interval) between odor presentations. No satisfactory explanation has yet been offered to account for the differences between those studies that find deficits on nonspatial working memory tasks following hippocampal damage and those that do not. However, it is interesting to note that of the three studies that reported a deficit, all used extensive preoperative training and two used matching-tosample tasks. On the other hand, of the five studies that reported little or no deficits, three used only postoperative training and all five used nonmatching-to-sample tasks. Whatever the appropriate explanation, the latter five studies indicate that damage to the hippocampal system, which readily disrupts working memory in a variety of spatial tasks, often has less of an effect on performance in nonspatial tasks. The intent of the present study was to determine if lesions of the medial septum/diagonal band of Broca, the area that gives rise to the major cholinergic input to the hippocampus (Wainer, Levey, Mufson, & Mesulam, 1984), would produce a similar pattern of results. Like direct damage to the hippocampus, damage to the medial septum of rats has been shown to disrupt spatial mapping in the Morris water tank (Kelsey & Landry, 1988), acquisition of the radial arm maze task (Hepler, Wenk, Cribbs, Olton, & Coyle, 1985), spatial DNMTS in a T maze (Hepler, Olton, Wenk, & Coyle, 1985), and spatial delayed alternation in a two-lever operant chamber (Numan & Quaranta, 1990). However, to our knowledge, the effects of medial septal lesions have not been examined on a task of nonspatial working memory. Consequently, in the present study, we examined the effects of lesions of the medial septal/diagonal

band of Broca area of rats on acquisition and performance of both a spatial and nonspatial DNMTS task within the same Y maze. The major difference between the two tasks was what occurred on the sample run and, thus, what the rats were required to remember on the subsequent choice run. In the initial spatial DNMTS task, the rats were required to demonstrate their memory of the location of the arm of the Y maze they had been forced to enter on the sample run by selecting the spatially opposite arm on the subsequent choice run. In contrast, on the nonspatial DNMTS task, the rats were required to demonstrate their memory of which of two objects they had encountered in the straight alley on the sample run by subsequently selecting the arm that now contained the other object. Following acquisition, the accuracy of working memory jn both tasks was further assessed by increasing the retention interval between the sample and choice runs of each trial. If medial septal lesions have effects on working memory that arc similar to those postulated for hippocampal lesions by Olton et al. (1979), then increasing the retention interval, by increasing the demand on working memory (Honig, 1978), should increase the magnitude of the lesion-induced deficit.

Experiment 1: Spatial DNMTS In this experiment, the rats were required to demonstrate their memory of the location of the arm of the Y maze they had been forced to enter on the initial sample run of each trial by subsequently entering the spatially opposite arm on the choice run. Insofar as medial septal lesions have effects on memory that are similar to those produced by hippocampal damage, then both of the major hypotheses discussed predict that medial septal lesions will produce deficits on this task. Method Subjects Seventeen naive, male Sprague-Dawley rats, weighing between 360 and 460 g at the start of testing, were housed individually in clear, plastic cages with wood shavings as bedding. The colony was lit from 7:00 a.m. until 7:00 p.m. each day, and the rats had ad-lib access to food and water except during testing, when they were 13-18-hr water deprived.

Apparatus The wooden Y maze was 13 cm wide and 30 cm high with a 66-cm-long start alley and two 50-cm-long goal arms separated by 120° from each other and from the start alley. Three Masonite guillotine doors divided the maze into a 23-cm-long start box and two 30-cm-long goal boxes. Mounted on the floor 1 cm from the end of each goal box was a 2.5-cm-diameter, 2-cm-high, concave, steel water cup. The maze was housed in an illuminated room supplied with 76 dB white noise.

Surgery All rats were anesthetized with an i.p. injection of 1.1 cc/kg sodium pentobarbital (50 mg/cc Nembutal). Electrolytic lesions were made in the ventromedial septum of 10 rats by passing 1.0 mA of anodal DC current for 15 s through a Number 1 insect pin that was completely

MEDIAL SEPTAL LESIONS DISRUPT SPATIAL WORKING MEMORY insulated with Epoxylite except for the flattened tip. The electrode was stereotaxically implanted at a 10° angle at the following coordinates: AP = 8.4, H = 0.2, and L = 0.0 (Pellegrino, Pellegrino, & Cushman, 1979). Sham lesions in which the electrode was lowered 1.0 mm above the septum and no current was passed were performed on three rats, and sham lesions in which holes were drilled in the skull but no electrode was lowered were performed on two rats. Two additional rats served as anesthetized controls. Because there were no behavioral differences between any of these three groups, these seven rats were combined into a single control group.


Procedure Preliminary training. Beginning 2-3 weeks following surgery, all rats were habituated to the maze for 2-3 days. On the first day, the rats

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were allowed to explore the open maze and drink 8% sucrose water from the water cups. On subsequent days, the rats were allowed to leave the start box and enter a goal box to receive 0.5 cc sucrose and were gradually habituated to the guillotine doors. To ensure that the rats had equivalent experience with both goal boxes, we occasionally blocked the entrance to one of the goal boxes by lowering the door. Training continued in this fashion until the rats were reliably traversing the maze in less than 2 min. Acquisition. The rats were brought in pairs, usually a lesioned and a control rat, to the maze room in their home cages and trained for 10 trials/day for 6 days. Each trial consisted of two runs. On the initial sample run, access to one goal box was blocked by lowering the door to that box. The rat was placed into the start box, and after 5 s the door from the start box was opened, enabling the rat to enter the open goal box to receive 0.5 cc of 8% sucrose. The door to that goal box was then lowered behind the rat. After the rat had finished drinking, it was

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Figure 1. Reconstructions of a smaller (solid) and a larger (stippled) medial septal lesion. (Sections are taken from A Stereotaxic Atlas of the Rat Brain (pp. 14, 16, 18, 20, 22, and 24) by L. J. Pellegrino, A. S. Pellegrino, and A. J. Cushman, 1979, New York: Plenum Press. Copyright 1979 by Plenum Press. Adapted by permission.)

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The septal lesions were rather small and produced bilateral damage that was generally confined to the medial septal nucleus and diagonal band of Broca (see Figure 1). Seven of the lesions were similar in size and location to the smaller lesion depicted in Figure 1, and two were more similar to the larger lesion. Six lesions extended anteriorally into the medial paraolfactory area, four lesions produced unilateral damage to the lateral septal nuclei, and two lesions extended ventrally into the anterior commissure. One rat with an intended lesion was eliminated from the data analysis because no lesion was detected.

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returned to the start box for a 5-s retention interval. On the subsequent choice run, all three doors were raised, and the rat was rewarded with 0.5 cc sucrose only for entering the goal box in the location opposite that of the box it had been forced to enter on the preceding sample run. An entry was judged to have occurred when all four legs were in the goal box, at which point the door to that box was lowered behind the rat. The time required to leave the start box and enter a goal box was measured to the nearest 0.1 s with a stopwatch. If the rat entered the incorrect goal box, it received no sucrose and was required to spend 25 s in that goal box. The rat was then returned to its home cage for the 3-min intertrial interval (ITI), during which the second rat received its trial. The goal box the rats were forced to enter on the sample run was selected randomly each day with the requirement that each goal box be selected on half of the 10 trials each day, but on no more than 3 trials in a row. Although the maze was cleaned of feces and urine between trials, the maze was not explicitly cleaned between rats. Retention. Beginning 1-4 days following acquisition, the rats were tested for nine trials/day for 4 days as during acquisition with the exception that the retention interval between the sample and choice runs was varied between 0.5, 1.0, and 2.0 min. The rats were placed in white plastic cages during the retention intervals. The sequence of intervals was selected randomly with the requirement that each interval occurred once within each block of three trials.

Histology Following completion of Experiment 2, the rats with lesions were sacrificed with an overdose of ether and perfused intracardially with isotonic saline followed by 10% formol-saline. A cryostat was used to cut 64-n.m-thick coronal sections through the area of the lesion. Every fourth section was mounted on slides, stained with cresyl violet, and examined through a dissecting microscope.

Data Analysis The number of correct choices during both acquisition and retention and the latency to respond on choice runs during acquisition were separately analyzed by two-way Group (2) x Day (6 or 2) analyses of variance (ANOVAs) with repeated measures on days.

Behavioral Acquisition. The rats increased the accuracy of their choices during the 6 days of acquisition of this spatial DNMTS task, F(5, 70) = 3.90, p < .01, and both groups of rats increased their accuracy at the same rate (see Figure 2). However, the rats with medial septal lesions made fewer correct choices than did the control rats during acquisition, F(\, 14) = 5.56, p < .05. The rats also decreased their latency to respond on choice trials during acquisition, F(5, 70) = 9.99,p < .001, and the two groups did not differ from each other on this measure. By the 6th day of acquisition, the control rats had reached asymptote, the rats with septal lesions were no longer making more errors than were the controls, F(l, 70) = 1.04, p > .30, and all but one rat with a lesion had made at least 70% of their responses correctly for 2 consecutive days. Because this latter lesioned rat was still performing at chance levels by the end of acquisition, its subsequent retention data were excluded from the analysis. Retention. There was substantial variability in the performance of the rats during the first 2 days of retention testing as they became accustomed to the changing retention intervals. Consequently, only the more stable data from the last 2 days were analyzed. During the last 2 days of retention testing, the accuracy of choices decreased as the retention interval between the initial sample run and the subsequent choice run was increased from 0.5 min to 2.0 min, F(2, 26) = 23.54, p < .001 (see Figure 3). Moreover, the rats with medial septal lesions made fewer correct choices, F(l, 13) = 18.48,p < .001, and decreased their accuracy more rapidly than did the control rats as the retention interval increased, F(2, 26) = 3.29, p = .05. Subsequent simple effects tests indicated that the rats in both groups were equivalently accurate at the 0.5-min interval, F(l, 39) = 0.58, p > .45. However, the rats with medial septal lesions made fewer correct choices than did the control rats when the retention interval was increased to 1 min, F(l, 39) = 15.11,p < .001, and 2 min, F(\, 39) = 11.86,p < .01, as the accuracy of the rats with medial septal lesions fell to chance. Discussion As expected, small medial septal lesions impaired the ability to both acquire and perform this spatial DNMTS task. The rats

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with medial septal lesions were less likely than were the control rats to correctly choose the arm that was in the location opposite the arm they were forced to enter on the preceding sample run. This finding is consistent with findings that damage to the hippocampal system in general (Dunnett, 1985; Markowska, Olton, Murray, & Gaffan, 1989; PeinadoManzano, 1990) and the medial septum in particular (Hepler, Olton, Wenk, & Coyle, 1985) disrupts spatial DNMTS in rats. This expected finding is, of course, consistent with both major hypotheses under consideration, the working memory hypothesis (Olton et al., 1979) and the spatial mapping hypothesis (O'Keefe & Nadel, 1978). The additional finding that the rats with medial septal lesions were performing as accurately as were the controls by the end of acquisition and during retention testing at the shortest retention interval (30 s) indicates that these rats can learn this spatial task. This is consistent with findings that the initial severe deficits in spatial tasks following septohippocampal damage are sometimes reduced with practice (e.g., Hepler, Olton, Wenk, & Coyle, 1985; Morris, Schenk, Tweedie, & Jarrard, 1990). Although this improvement may represent the efficient use of nonspatial strategies to solve a spatial problem (Harrell, Barlow, & Parsons, 1987; Schenk & Morris, 1985), it may also indicate that small medial septal lesions do not completely eliminate the capacity for spatial mapping. Whatever the appropriate explanation for this apparent recovery of function, recovery was far from complete. The initial deficit in choice accuracy was reinstated by increasing the retention interval to 1 and 2 min. This finding that the lesion-induced deficit in this spatial working memory task increased as the retention interval and, thus, the demand on working memory increased is also consistent with the findings of others (Dunnett, 1985; Hepler, Olton, Wenk, & Coyle, 1985; Numan & Quaranta, 1990). This finding is also quite consistent with the hypothesis that damage to the septohippocampal system produces a deficit in spatial working memory, that is, the ability to remember the location of the arm they had entered on the preceding sample run (Olton et al., 1979).

Experiment 2: Nonspatial DNMTS The intention of this experiment was to determine if medial septal lesions that disrupt performance in a spatial DNMTS task would similarly disrupt performance in a nonspatial (i.e., spatially irrelevant) DNMTS task in the same Y maze that required them to remember which object they had encountered on the sample run. Insofar as medial septal and hippocampal lesions have similar effects on memory and insofar as Olton et al. (1979) are correct in postulating that damage to the hippocampal system disrupts working memory in general, then medial septal lesions would also be expected to disrupt acquisition and performance of this nonspatial DNMTS task. On the other hand, if O'Keefe and Nadel (1978) are correct in arguing that damage to the hippocampal system selectively disrupts spatial mapping, then medial septal lesions would be expected to have little if any effect on this nonspatial task.

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Method Subjects The 17 rats used in Experiment 1 served as subjects.

Apparatus and Stimuli The Y maze used in Experiment 1 was placed in the same location in the same room as in Experiment 1. An additional moveaWe water cup, 0.75-cm high and 2.5-cm in diameter, was placed at the end of the start alley during sample runs. Two objects—a 7-cm-high, 1.25-cm-wide, and 7.5-cm-long wooden horse and a 12-cm-high and 2.5-cm-wide blue plastic Statue of Liberty—were used as the discriminative stimuli.

Procedure Acquisition. Acquisition was begun approximately 2 weeks after the termination of Experiment 1. All rats were trained in pairs for 10 trials/day for 12 days. As in the spatial DNMTS task of Experiment 1, each trial consisted of a sample run followed by a choice run. On the sample run, access to both goal boxes was blocked by lowering the guillotine doors. One of the two stimulus objects was placed 5 em from the end of the start alley, and the moveable water cup containing 0.5 cc of 8% sucrose was placed behind it. After 5 s in the start box, the door was raised, enabling the rat to run to the object and displace it in order to drink the sucrose. After the rat had finished drinking, it was returned to the start box for its 15-s retention interval. On the subsequent choice run, one of the stimulus objects was placed in a goal arm just in front of the guillotine door and the other object was placed in front of the door of the other arm such that both objects were visible from the choice area. All three doors were then raised, and the rat was required to enter the goal box behind the object not encountered on the preceding sample run in order to receive 0.5 cc of 8% sucrose in the goal box. The door to that box was then lowered behind the rat. If the rat selected the incorrect object/box, it received no sucrose and was confined in that goal box for 25 s, as in Experiment 1. The rat was then returned to its home cage for the 3-min ITI. The object used on each sample run was randomly selected with the requirement that each object be selected on half of the 10 trials each

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changing intervals. Consequently, only the more stable data from the last 2 days were analyzed. During the last 2 days of retention testing, the accuracy of choices decreased as the retention interval between the sample and choice runs increased from 0.5 min to 2.0 min, F(2, 26) = 15.76, p < .001 (see Figure 5). Although the rats with medial septal lesions made more correct choices during testing than did the controls, F(l, 13) = 7.99,p < .02, subsequent simple effects tests indicated that this was significant only at the 1-min retention interval, F(\, 37) = 9.95,p < .01.


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day, but on no more than 3 trials in a row. Similarly, the goal arm into which that object was placed on the subsequent choice run was randomly selected with the requirements that each object be placed in each arm on half the trials and that the left (and right) arm contain the correct object on half the trials. Following the 12 days of formal acquisition, training was continued as before until each rat made at least 70% of its choices correctly for 2 consecutive days. Retention. As in Experiment 1, the rats were then tested for nine trials/day for 4 days as during acquisition except that retention intervals of 0.5,1.0, and 2.0 min were inserted between the sample and choice runs. The rats were placed in white plastic cages during the retention intervals. The retention intervals were randomly selected such that each interval appeared once in each block of three trials. Data Selection and Analysis One control rat was eliminated from the analysis of the retention data because it did not achieve the acquisition criterion of 70% correct for 2 consecutive days. The remaining data were analyzed as in Experiment 1. Results Acquisition As anticipated, acquisition of this nonspatial DNMTS task was more difficult than acquisition of the spatial DNMTS task in Experiment 1 (cf. Figures 4 and 2). Nevertheless, the rats did increase the accuracy of their choices as training progressed, F(ll, 154) = 5.19,p < .001 (see Figure 4). In contrast to Experiment 1, there were no differences between the two groups in the number of correct choices made during acquisition of this task. There were also no differences between the two groups in their latency to respond on choice trials or in their preference for either object or either arm. Retention As in Experiment \, performance during the first 2 days of retention testing was variable as the animals adjusted to the

In contrast to the clear deficit produced on the spatial DNMTS task of Experiment 1, medial septal lesions produced no deficit on this nonspatial DNMTS task. During acquisition, the rats with medial septal lesions were as accurate as the control rats in selecting the arm containing the object not encountered on the preceding sample run. In fact, when the retention interval was increased to 1 min, the rats with medial septal lesions were significantly more accurate than were the control rats. This demonstration that small medial septal lesions do not disrupt nonspatial (spatially irrelevant) DNMTS is consistent with the reports of Aggleton et al. (1986), Peinado-Manzano (1990), Rothblat and Kromer (1991), Mumby et al. (1992), Otto and Eichenbaum (1992), and Sutherland and McDonald (1990) that nmbria-fornix and hippocampal damage also have little or no effect on nonspatial DNMTS tasks. Thus, these data fail to support the contention of Olton et al. (1979) that septohippocampal damage should disrupt working memory similarly in both spatial and nonspatial tasks. It cannot be claimed that the medial septal lesions failed to disrupt nonspatial DNMTS because the task was too easy. On the contrary, acquisition of this nonspatial DNMTS task was more difficult than was acquisition of the spatial DNMTS task. Having the capacity and apparently the propensity to preferen100 O

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MEDIAL SEPTAL LESIONS DISRUPT SPATIAL WORKING MEMORY daily use spatial information (Gaffan & Davies, 1981; Olton & Schlosberg, 1978), these rats probably found it more difficult to pay attention to and remember objects. Moreover, this tendency of normal rats to use spatial information in preference to other cues may have been initially exacerbated in the present experiment by the prior training on the spatial DNMTS task in Experiment 1 in which only spatial cues were relevant. Consequently, it might be argued that this task was so difficult for the control rats that a lesion-induced deficit could not be observed. However, our control rats were able to acquire this task and perform at 80% correct even when the sample-choice retention interval was 30 s. This high degree of accuracy in the controls certainly allowed ample opportunity for the rats with medial septal lesions to demonstrate deficient working memory. Our lesions were small, and Raffaele and Olton (1988) reported that only large, and not small, fimbria-fornix lesions disrupted nonspatial matching to color/texture. Perhaps larger medial septal lesions would have produced a deficit on this task. Nevertheless, although our medial septal lesions failed to disrupt nonspatial DNMTS, they were certainly large enough to dramatically impair acquisition and performance of the spatial DNMTS task in Experiment 1. It could be argued that our failure to find a lesion-induced deficit in this experiment was due to the sequence of training. Perhaps if our rats had been trained on the nonspatial task first, a deficit would have been observed on nonspatial DNMTS. In this view, the failure to find a deficit on the second task could be due to recovery of function or some carryover effect of prior training on the initial task, such as perseveration of spatial strategies by the controls. Our pattern of results is unlikely to be due to recovery of function. First, most neural recovery of function occurs within the first few weeks following surgery (e.g., Braun, 1978), before the onset of Experiment 1. Second, although there was improvement in the performance of the lesioned rats in Experiment 1, perhaps indicative of recovery, increasing the retention interval to 1 and 2 min effectively reinstated the deficit; that is, recovery was, at best, incomplete. Third, Markowska et al. (1989) found that an initial deficit on a spatial DNMTS task produced by hippocampal lesions was still apparent after several weeks of intervening training on conditional discriminations; that is, the initial deficit did not disappear with time. Although there may have been some carryover effects from prior training on the spatial DNMTS task, the possibility that our failure to find a lesion-induced deficit in the nonspatial DNMTS task is due to such carryover effects is also not well supported. First, Mumby et al. (1992) and Otto and Eichenbaum (1992) found that hippocampal and fornix lesions, respectively, failed to alter nonspatial DNMTS in naive rats. Similarly, Aggleton et al. (1986) and Rothblat and Kromer (1991), who also found that hippocampal damage disrupted spatial, but not nonspatial, DNMTS, trained their rats on the nonspatial task first. Most relevantly, Peinado-Manzano (1990) found that the order of training did not alter the ability of hippocampal lesions to disrupt spatial, but not nonspatial, DNMTS. Thus, these data indicate that the findings that damage to the septohippocampal system disrupts performance on spatial working memory tasks more than it disrupts perfor-

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mance on nonspatial working memory tasks are robust and do not depend on task sequence. Nevertheless, it is noted that those data were collected in different tasks following different lesions than those used in the present experiment. Consequently, we cannot be completely certain that our data do not reflect carryover effects until the effects of medial septal lesions are examined on the nonspatial DNMTS task without prior training on a spatial task. The most obvious remaining difference between our two experiments was what the rats were required to remember about the sample run. Consequently, it seems likely to us that it is that difference that accounts for the difference in outcome. In particular, because the rats were required to remember spatial locations in Experiment 1 and nonspatial objects in Experiment 2, our data and the similar data summarized earlier all suggest that septohippocampal damage disrupts spatial working memory more than it does nonspatial working memory. An explanation for the surprising outcome that medial septal lesions actually improved choice accuracy at the 1-min retention interval on this nonspatial DNMTS task assumes differential use of irrelevant spatial information. As discussed above, control rats are apparently biased toward using and remembering spatial information, even when it is irrelevant (e.g., Gaffan & Davies, 1981; Olton & Schlosberg, 1978). The rats with medial septal lesions, on the other hand, apparently having a diminished capacity to use and remember spatial information, may have found it easier to pay attention to and remember the relevant objects. Similar explanations have been offered for the findings that rats with hippocampal damage are superior to controls on a win-stay version of the radial maze (Packard, Hirsh, & White, 1989), on a conditional discrimination (Gallagher & Holland, 1992), and in finding a nonstationary but visible platform in a circular water tank (Gallagher & Holland, 1992).

General Discussion In Experiment 1, rats with small medial septal lesions were markedly deficient in the acquisition and performance of a spatial DNMTS task in which the rats were required to demonstrate their memory of the location of the arm of a Y maze they had been forced to enter on the sample run by subsequently selecting the opposite arm on the choice run. Although with practice, the rats with medial septal lesions were able to choose as accurately as did the control rats when the retention interval between the sample and choice runs was short (30 s), increasing the interval to 1 and 2 min reinstated the deficit. In contrast, in Experiment 2, these same rats with medial septal lesions were not deficient in acquiring or performing a nonspatial (spatially irrelevant) DNMTS task that required them to demonstrate their memory of which object they had encountered in the straight alley on the sample run by subsequently entering the arm that now contained the other object. In fact, when the retention interval was increased to 1 min on this task, the rats with medial septal lesions were more accurate than were the controls. The finding that the rats with medial septal lesions learned and performed the nonspatial DNMTS task as well as or better


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than the controls indicates that the lesion-induced deficit in the spatial DNMTS task was not due to an effect on motivation, discrimination, attention, or reference memory. We have also argued that the failure to find a deficit in the nonspatial task was not likely to be due to task difficulty, recovery of function, or the sequence of testing. Thus, this pattern of results would seem to reflect differential effects of medial septal lesions on the most obvious remaining difference between Experiments 1 and 2: the requirement for spatial versus nonspatial working memory. The finding that medial septal lesions, which damage the major cholinergic input to the hippocampus (Wainer et al, 1984), disrupt spatial but not nonspatial DNMTS is consistent with the findings of others following damage to the other aspects of the septohippocampal system (Aggleton et al., 1986; Peinado-Manzano, 1990; Rothblat & Kromer, 1991). Together, these and related findings (Jarrard, 1983; Mumby et al., 1992; Otto & Eichenbaum, 1992) strongly suggest that damage to the septohippocampal system typically has a larger effect on tasks of spatial working memory than on tasks of nonspatial working memory. Clearly this pattern of results is not predicted by Olton et al. (1979), who argued for a more general effect on working memory of all kinds. Nor is this pattern explained by Rawlins (1985), who argued that septohippocampal damage should disrupt performance on all tasks in which there is marked temporal discontinuity. Although this pattern is more consistent with the hypothesis of O'Keefe and Nadel (1978) that septohippocampal damage disrupts cognitive or spatial mapping, their hypothesis does not easily explain why the rats with medial septal lesions learned to perform as accurately as did the control rats on the spatial DNMTS task when the retention interval was short (30 s). However, these data are quite consistent with an amalgam of the different hypotheses of Olton et al. (1979) and O'Keefe and Nadel (1978): that the major deficit caused by medial septal lesions and presumably other kinds of septohippocampal damage is on spatial working memory (Markowska et al., 1989; Thomas, Brito, Stein, & Berko, 1982). We do not argue that damage to this system affects only tasks of spatial working memory. It is clear that such damage can produce deficits in tasks requiring spatial mapping but little working memory (e.g., Jarrard, 1983; Kelsey & Landry, 1988; Morris et al., 1982). It is also clear that such damage can produce deficits in tasks requiring working memory but little spatial mapping (e.g., Meek, Church, & Olton, 1984; Olton & Feustle, 1981; Raffaele & Olton, 1988). However, the bulk of the data indicates that the largest effects of damage to the septohippocampal system occur on tasks that require both spatial mapping and working memory, that is, spatial working memory. Although the present data can thus be attributed to a disruption of two relatively independent memorial systems— spatial and working—other investigators have argued that all effects of damage to the septohippocampal system can be attributed to disruption of a unitary system. For example, several theorists have argued that damage to the septohippocampal system disrupts the ability to learn and remember the configural relations between multiple stimuli and events, including, but not limited to, spatial relations (Eichenbaum, Pagan, & Cohen, 1986; Eichenbaum, Pagan, Mathews, &

Cohen, 1988; Hirsh, 1980; Sutherland & Rudy, 1989). In this view, deficits would be expected on most spatial tasks because such tasks usually require learning the relationship between many stimuli. On the other hand, large deficits in nonspatial DNMTS tasks such as ours might not be expected because all that is required is the memory of a single object, not its configural relationship to other stimuli (although it is interesting to note that Sutherland & Rudy, 1989, argued that nonspatial DNMTS tasks do require some degree of configural learning). A serious problem with this intriguing view is that it seemingly predicts lesion-induced deficits on tasks requiring nondelayed conditional discriminations, that is, tasks in which stimulus A in context B requires response X, whereas the same stimulus A in different context C requires response Y. Although deficits following hippocampal damage have been seen in some conditional discriminations (Ross, Orr, Holland, & Berger, 1984; Sutherland & McDonald, 1990), several investigators have found no effect of such damage on a variety of conditional discriminations (Davidson & Jarrard, 1989; Gallagher & Holland, 1992; Jarrard & Davidson, 1990; Markowska et al., 1989; Thomas & Gash, 1988). Perhaps in response to these latter findings, Eichenbaum and his colleagues (Eichenbaum, Mathews, & Cohen, 1989; Eichenbaum, Stewart, & Morris, 1990) and Squire (1992) have more recently argued that the septohippocampal system is particularly required for flexible use of such relational representations. Thus, according to this view, animals with damage to this system should be deficient primarily when they are required to demonstrate they understand the relation among the elements of a configuration, for example, when they are asked to respond to an element isolated from its usual configuration (e.g., Sutherland & McDonald, 1990). On the other hand, this view suggests that these animals should be less or minimally deficient if allowed to respond consistently to a configuration as an entity (e.g., Eichenbaum et al., 1990). In their view, DNMTS tasks require flexible use because they require "making a response inconsistent with the behavior performed during acquisition of the material" (Eichenbaum et al., 1990, p. 3541). Thus, because spatial DNMTS also involves memory of a relationship between multiple stimuli, these authors would presumably predict that septohippocampal damage would produce deficits on such a task. On the other hand, Eichenbaum and his colleagues may not expect such damage to produce consistent deficits on nonspatial DNMTS tasks, because, although efficient performance presumably still requires flexible use, the stimuli to be remembered are not usually highly relational. Given these assumptions, this attempt to develop a unitary hypothesis may account for our data in a parsimonious manner and is, therefore, compelling. However, until this unitary hypothesis is more adequately tested, the possibility that septohippocampal damage disrupts multiple memory systems remains viable. Whatever the outcome of this debate, recent evidence suggests that although the analyses offered in the preceding paragraphs may help us understand the functions of the hippocampus proper and its projections through the fimbriafornix, they are apparently less appropriate for understanding the functions of the parahippocampal areas, including the perirhinal, parahippocampal, and entorhinal cortices, all of

MEDIAL SEPTAL LESIONS DISRUPT SPATIAL WORKING MEMORY


which also interact extensively with the hippocampus. On the basis of a variety of evidence, including findings that lesions to these latter areas disrupt performance on nonspatial, as well as spatial, working memory tasks in both rats (e.g., Olton, Walker, & Wolf, 1982; Otto & Eichenbaum, 1992) and monkeys (e.g., Gaffan & Murray, 1992; Zola-Morgan, Squire, Amaral, & Suzuki, 1989), it has been suggested that these latter areas are more extensively or differently involved in working memory than is the hippocampus proper (Otto & Eichenbaum, 1992; Squire, 1992). Further research is required to more precisely delineate the memorial function of all the hippocampal projections.

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Received July 16,1992 Revision received February 18, 1993 Accepted March 5,1993 •