Place learning and memory were assessed in rats with selective damage to the fornix/fimbria or to subcortical structures which have a major connection with the ...
265
Behavioural BraOz Research, 32 (1989) 265-277 Elsevier BBR 00905
The role of the fornix/fimbria and some related subcortical structures in place learning and memory R.J. S u t h e r l a n d and A.J. R o d r i g u e z Department of Psychology, The University of Lethbridge, Lethbridge, Alta. (Canada) (Received 17 June 1988) (Revised version received 27 July 1988) (Accepted 3 August 1988)
Key words: Fornix fimbria; Nucleus accumbens; Anterior thalamus; Mammillary complex; Medial septum; Spatial learning; Spatial memory; Amnesia; Place navigation
Place learning and memory were assessed in rats with selective damage to the fornix/fimbria or to subcortical structures which have a major connection with the hippocampal formation via the fornix/fimbria. Navigation to a hidden or visible platform in a fixed location was studied in the Morris water task in rats who were preoperatively trained in the task or who were preoperatively naive. All rats learned to navigate accurately to a visible platform. Only complete transection of the fornix/fimbria abolished both acquisition and retention ofnavigation to a hidden platform. Severe impairment ofpostoperative acquisition was produced by bilateral damage to the medial nucleus accumbens or bilateral damage to the anterior thalamic area. Nucleus accumbens or anterior thalamic damage produced little effect on retention of preoperatively acquired place navigation. Damage to medial septum or mammillary complex produced modest impairments evident only in postoperative acquisition.
INTRODUCTION
Damage to the hippocampal formation (hippocampus, dentate gyrus, and subicular cortex) produces a variety of deficits in memory abilities. In rats, monkeys, and humans with bilateral hippocampal formation damage there is a profound impairment of learning some types of new information (anterograde amnesia), as well as an impairment of retaining information acquired during an interval of time prior to damage (retrograde .amnesia) 17"32"4s. Many experiments have demonstrated a long-lasting disruption of behaviour in tasks requiring place learning following electrolytic, aspiration, and neurotoxin lesions of the hippocampal f o r m a t i o n 1'8'9'19'21'22"28,36.39.44. Of equal importance are studies recording from
single units in the hippocampal formation and closely related structures in freely-moving rats. Very clear and robust relationships have been demonstrated between unit discharge rate and the rat's position in an environment and between discharge rate and the direction in which the rat's head is oriented in an environment 14'16'2~176 Although hippocampal neurons display other robust unit discharge-behaviour correlations, the high proportion of spattally selective neurons nicely complements the aforementioned lesion experiments and forms a solid basis for the suggestion that the hippoeampal formation plays a central role in the construction and storage of spatial maps of environments24. The specific contributions to spatial memory of structures directly or indirectly connected to the I
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Correspondence: R.J. Sutherland, Department of Psychology, The University of Lethbridge, Lethbridge, Alta., Canada T I K 3M4. 0166-4328/89]503.50 9 1989 Elsevier Science Publishers B.V. (Biomedical Division)
266 hippocampal formation are less clear. There are two major routes of communication between the hippocampal formation and the rest of the forebrain. One route is the well-described fornix system; the other route passes through the retrohippocampal area. Bilateral damage to the latter route appears to impair acquisition and retention of place learning. Entorhinal cortex damage produces a long-lasting disruption ofplace learning in the radial arm maze9'27 and the Morris water task 3~. Similarly, damage to the posterior cingulate/retrosplenial area (area 29), which occupies an important position in conveying information to and from the hippocampal formation, impairs acquisition and retention of performance in the Morris water task (see ref. 40 for a more complete discussion). One simple interpretation of these results is that the cortical afferents to the hippocampal formation convey essential perceptual and movement-related information and/or hippocampal output relevant to place learning is conveyed through the retrohippocampal routes 33. The fornix connects the hippocampal formation with diverse subcortical areas including the medial and lateral septal areas, nucleus accumbens, anterior thalamus, mammillary nuclei, and monoamine-containing cell groups in the brainstem. On'the basis of available data, very little can be concluded about the relationship of the majority of these structures to place learning and memory. Neither the noradrenergic nor dopaminergic innervation of the hippocampal formation is necessary for normal place navigation 37"45. Damage to the medial septal area significantly impairs acquisition of place navigation TM, although by the end of training these rats show a clear preference for swimming in the correct region of the pool on probe tests 5. Although these lesions would deprive the hippocampal formation of cholinergic and some non-cholinergic inputs, the pat.tern of results is consistent with the effects on place navigation of administering muscarinic receptor blockers 38'43. Medial septal lesions have also been shown to retard acquisition of spatial alternation in a T-maze TM, impair retention of place learning in a circular maze 46, and to disrupt performance in the 8-arm radial maze26. Complete transection of the fornix seems .to produce a
greater impairment. Place learning is abolished in the circular maze 25 and in a conditional T-maze task 7, and retention of place learning is disrupted in the uncued, 8-arm radial maze 8"9. Variations in behavioural tasks among studies, however, preclude a direct comparison of the magnitude of the deficits in place learning after fornix or medial septal lesions. The contribution to place learning and memory of the remaining structures which have afferents or efferents travelling through the fornix is unknown. The present experiment evaluates postoperative acquisition and retention of place learning in rats with fornix/fimbria, medial septum, nucleus accumbens, anterior thalamus, partial cingulate cortex, or mammillary body lesions. The effect of each lesion on navigation to a hidden platform and to a visible platform in the Morris water task 's was assessed in preoperatively trained and naive rats, thereby allowing direct comparison of the magnitude of the deficits in place learning and memory. MATERIALS AND METHODS
Animals Ninety-five male Long-Evans hooded rats were used. They were individually housed in hanging wire mesh cages with continual access to food and water. A 12:12 light-dark cycle was maintained throughout the experiment and at the time of surgery and testing the rats weighed 300-450 g. Surgery All rats were injected with atropine methyl nitrate (20 mg/kg, i.p.) and were anesthetized with sodium pentobarbital (65 mg/kg, i.p.) prior to surgery. All lesions were made electrolyticallyt using stainless steel insect pins (size 000), insulated except for the cross-section at the tip. An uninsulated rectal electrode served as the cathode for the lesion circuit. The control rats were treated similarly except that only the skin on the head was incised and reclosed. Table I presents the number of rats in each of the treatment conditions who received accurate lesion placements and who were included in the statistical analysis. Fornix/
267 fimbria damage was produced using 5 lesions sites (1.0 mA for 15 s) at 1.3 mm posterior to the bregma, 4.3 mm ventral to the skull at bregma, and between 0.0 and 1.75 mm lateral to the midline. Lesions were made in each hemisphere in the cingulate cortex overlying the fornix/fimbria in a separate group of rats as a control for the unintended damage to this tissue produced in some fornix/fimbria lesion rats. The coordinates were 1.3 mm posterior to the bregma, 1.2 mm from the midline, and 2.1 mm below the surface ofthe skull at the bregma. Each hemisphere received one cingulate lesion at 1.0 mA for 10 s. One lesion (1.5 mA for 20 s) in the nucleus accumbens in each hemisphere was placed at 1.2 mm anterior to the bregma, 1.25 mm lateral to the midline, and 7.5 mm below the surface of the skull at the bregma. One lesion (1.5 mA for 20 s) was placed in the anterior thalamic area in each hemisphere at 1.3 m m posterior to the bregma, 1.2 mm lateral to the midline, and 6 mm below the surface of the skull at the bregma. One lesion (1.0 mA for 10 s) was placed in the mammillary bodies in each hemisphere at 4.6 mm posterior to the bregma, 0.5 mm lateral to the midline, and 9.4 mm below the surface of the skull at the bregma. A single lesion was placed in the medial septum on the midline at 0.2 mm anterior to the bregma and 6.4 mm below the surface of the skull at the bregma.
Apparatus The swimming pool was circular (1.4 m diana.) and the sides were 48 cm high. The pool was filled with milky water (19 ~ to a level 23 cm below the top ofthe wall. The hidden platform was made ofclear Plexiglas (13 x 13 cm) and its top surface was submerged 1.5 cm below the surface of the water. The visible platform (13 x 13 cm) was black and protruded 5 cm above the surface of the water..Several large objects (counters, shelves, wall posters, etc.) were visible around the room by a viewer in the pool. A video camera was mounted above the centre of the pool and the output of the camera was brought to a VPII2 target scanner (HVS Image Analyzing). The sequence of positions of the rat's head (20/s) during each trial was stored using an APPLE II+ computer and later
analyzed. The analysis of each trial included the latency to find the platform, swim path length, and proportion of swim path length in each of 4 quadrants of the pool 35. Each of these measurements was made using the automated tracking system.
Behavioural testing Two weeks following surgery, all rats received 8 trials per day during the light phase of their daily cycle for 9 consecutive days. Starting locations (north, south, east, or west) were randomly selected without replacement within each block of 4 trials. If a rat did not find the platform within 90 s, the trial was terminated and the rat was lifted by hand from the water and returned to its intertrial holding cage. The intertrial interval was approximately 5 min. The hidden platform was located in the centre of the northwest quadrant for trial blocks 1-11 and in the centre ofthe southeast quadrant on trial block 12. During trial blocks 13-16 a black visible platform, protruding 5 cm above the water surface, was placed in the centre of the northwest quadrant. In the final phase of testing (trial blocks 17 and 18) the hidden platform was again placed in the centre of the northwest quadrant. Rats in the pretrained groups received 8 trials per day for 5 consecutive days with the hidden platform positioned in the centre of the northwest quadrant using procedures identical to those in postoperative training. The pretraining was completed 2-7 days before surgery.
Histology After behavioural testing the rats were deeply anesthetized with sodiu m pentobarbital and intracardially perfused with physiological saline followed by 10~ formal-saline. The brains were extracted and stored in a 10~o formal:saline, 30~o sucrose solution. They were sectioned at 40 l~m using a cryostat. Every third section through the lesions was mounted on microscope slides and stained using Cresyl violet. The outline of each lesion was drawn using a microscope projector and lesion extent was estimated.
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Statbrtical analysis Analysis of variance with repeated measures was carried out on the escape latency, swim path length, and swim path length in the 4 quadrants using the BMDP statistical package on a DEC 20 computer. The performance of animals that were naive or preoperatively trained was assessed in separate analyses. All follow-up comparisons were performed using Fisher's LSD method with a criterion P = 0.05.
B
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RESULTS
Lesions Fig. 1 presents representative lesions at their maximal extent from each group based upon histology from the rat with median performance for the group in the Morris water task. Rats were not included in the fornix/fimbria lesion groups (Fig. IA) if the fornix/fimbria was not completely interrupted or if there was damage to the underlying dorsal portion of the thalamus. The behaviour of rats with fornix/fimbria transection and additional clear damage to overlying cingulate cortex (Fig. 1B) was analyzed separately. A separate group ofrats with bilateral small lesions in the deep cingulate cortex (Fig. 1C) was analyzed. In the case of the nucleus accumbens lesion groups (Fig. 1D), only rats with complete bilateral destruction of the medial half of nucleus accumbens were included. The behaviour of rats with asymmetrical nucleus accumbens lesions which unilaterally spared the medial portion of that nucleus, but which included unilateral damage to the medial septum and vertical limb of the diagonal band of Broca (Fig. 1E) was analyzed separately. The anterior thalamic lesions (Fig. IF) included damage to the anteromedial, anteroventral, and anterodorsal nuclei and in some rats the most dorsal portion of the anteroventral nucleus was spared. The mammillary complex lesion (Fig. 1G) included the medial and lateral nuclei and in some rats the supramammillary nucleus was bilaterally destroyed. The septal lesion (Fig. IH) included the medial nucleus (except its most anterior part), the dorsal portion of the vertical limb of the diagonal band
Fig. !. Representation lesions at their maximal extent from rats with median performance in the Morris water task: A: fornix/fimbria lesion. B" fornix/fimbria + cingulate cortex lesion. C: cingulate cortex lesion. D: nucleus accumbens lesion. E: asymmetrical nucleus accumbens lesion. F: anterior thalamus lesion. G" mammillary complex lesion. It: medial septal lesion.
of Broca, and approximately the medial halfofthe lateral nucleus.
Behaviour The analysis of variance on the latency to find the platform for the naive groupsrevealed a significant effect oflesion (F8,54 = 9.54, P < 0.0001), trial block ( F 1 7 . 9 1 8 = 7 8 . 8 , P', 50 0 t~.l
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Fig. 10. Mean percentage of swim distance for the naive groups in each quadrant of the pool during the block of 4 trials (trial block 12) when the platform was rcpositioned. The previously correct quadrant was in the northwest (NW) quadrant.
hidden or visible platforms. When the platform was repositioned, the naive lesion rats swam significantly more in the previously correct quadrant than in the others, very similar to the naive control rats (see Fig. 10). The latency to reach the hidden platform was significantly longer for the pretrained lesion rats than for the pretrained control rats only for the first block oftrials (Fig. 9). For the remaining trial blocks with hidden or visible platforms there were no significant differences. The pretrained septum lesion rats showed a significant preference for swimming in the previously correct quadrant when the hidden platform was repositioned (Fig. 1 i).
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Pretrainedgroups Fig. 11. Mean percentage ofswim distance for the pretrained groups in each quadrant of the pool during the block of 4 trials (trial block 12) when the platform was repositioned. The previously correct quadrant was in the northwest (NW) quadrant.
273 TABLE I
Summary of behavioural results 'X' indicates transient but statistically significant impairment relative to controls; ' X X ' indicates statistically significant impairment relative to controls throughout testing; 'C' designates the cingulate cortex lesion group; 'n.t.' indicates that the lesion group was not tested. The q u a d r a n t preference measure is based upon w h e t h e r the group s w a m significantly more in the previously correct q u a d r a n t c o m p a r e d to each o f the o t h e r quadrants during the first block o f trials after the platform was repositioned. The number o f subjects in each group includes only those rats with satisfactory lesion locations who were included in the statistical analyses.
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Summary of results Table I presents a summary of the pattern of deficits with each of the lesion groups swimming to the hidden and visible platforms and when the hidden platform was repositioned. Swimming to the visible platform was not reliably affected by any of the lesions. Each of the lesions produced at least an initial impairment in learning to swim to the hidden platform; however clear differences in the severity of the impairments are evident. Only the naive rats with fornix/fimbria, bilateral nucleus accumbens, and anterior thalamic lesions were impaired throughout testing with the hidden platform and did not preferentially swim in the previously correct quadrant when the hidden platform was repositioned. In the case of the pretrained rats, only those with fornix/fimbria transection were consistently impaired in swimming to the hidden platform and did not show a preference for the previously correct quadrant when the hidden platform was moved. DISCUSSION
Transection of the fornix/fimbria or lesions in structures which are directly connected with the
X X
Latency (visible)
m
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hippocampal formation through the fornix/ fimbria can produce significant impairments in place learning and memory in the Morris water task. None of the lesions prevented the rats from readily learning to swim to a visible platform. Thus, the observed impairments in swimming to the hidden platform cannot be attributed to some general deficit in sensorimotor processes or motivational processes. The rats with fornix/fimbria lesions did not learn to navigate to the location of the hidden platform nor did they retain place navigation that had been acquired preoperatively. Their failure was evident in the longer latencies to reach the hidden platform, the lack of effect on latencies following repositioning of the hidden platfornl, and the lack of preference for swimming in the previously correct quadrant of the pool when the platform was repositioned. The performance of rats with fornix/fimbria lesions who had received preoperative training was superior to those who were naive, particularly during the initial trial blocks of postoperative testing. This superiority was not reflected in an increased preference for the correct quadrant of the pool when the hidden platform was moved. There was no evidence that
274 they had learned or remembered the location of the hidden platform relative to the available distal cues in the room. The performance of rats with fornix/fimbria lesions in the Morris water task is very similar to animals with extensive damage to the hippoeampal formation 34. Damage to other structures, such as cingulate cortex or dorsal anterior thalamus which are immediately adjacent to the fornix/fimbria, failed to produce this pattern of results. Thus, the interruption of hippocampal input and/or output probably underlies the deficit in place learning and memory after fornix/fimbria transection. We note that the fornix/fimbria lesion rats did show a significant decline in latency to find the hidden platform across trial blocks. It is likely that this improvement in performance reflects the adoption of a strategy other than spatial mapping (see for example ref. 35) which led to progressively m o r e efficient searching patterns, although we also note that it has proven difficult to characterize precisely what these strategies entail in the hidden platform version of this task. The rats with anterior thalamie damage or nucleus accumbens damage exhibited clear impairments in postoperative acquisition of place navigation. They consistently took longer to find the hidden platform than control rats. When the hidden platform was repositioned, their latencies were unaffected and they did not preferentially swim in the previously correct quadrant of the .pool. This is the first demonstration that either of these two areas which receive major direct and indirect projections from the hippocampal formation make an important contribution to place learning. The non-specific lesion used in the present study probably also interrupted connections between mediodorsal thalamus and frontal cortex. It is unlikely that interruption of this connection substantially affected performance because we have previously shown that large bilateral lesions in themediodorsal thalamus do not affect acquisition of place navigation in this same task ~2. The comparison of performance of rats with bilateral damage to the medial portion of nucleus accumbens with that of rats with similarly extensive damage but with the medial nucleus accumbens spared in one hemisphere.(Figs. 5 and
6), provides support for the conclusion that it is specifically damage to nucleus accumbens that is associated with the impairment in place navigation. Definitive evidence in support of this conclusion must await the evaluation of place navigation by rats with selective cellular neurotoxic damage in nucleus accumbens. The nucleus accumbens may be more important in new learning than has been realized previously and its degeneration could be important in the amnesic syndrome which follows anterior communicating artery rupture z9. It is clear from the present results that the contributions of anterior thalamic nuclei and nucleus accumbens are qualitatively different from the contribution of the fornix/fimbria (or of the hippocampal formation). Neither of these subcortical lesions produced important impairments in performance by rats that had been preoperatively trained. Thus, based upon the present data their contribution may be limited to processes involved in the initial acquisition of place navigation. Although the present experiment does not directly address the issue, it is interesting to consider in what way nucleus accumbens and anterior thalamic areas contribute to place navigation. The medial portion of nucleus accumbens receives extensive projections from the hippocampal formation and associated cortical a r e a s 4"1~ There are data which show that at least some of the effects on locomotion produced by direct manipulations of the hippocampal formation may be mediated by connections with the nucleus accumbens 6"47. Several authors have suggested that the information represented in hippocampal circuitry interfaces with the motor system via nucleus accumbens4:s,47. Since it is established that an intact hippocampal formation is essential for new and recent place learning, the present results with nucleus accumbens lesions argue against it being a necessary output structure for controlling movements in respect to places. The rats that were trained to navigate to the hidden platform before the nucleus accumbens was damaged were able to navigate accurately. By the same argument, the anterior thalamic area cannot be a necessary output structure for
275 hippocampal control of spatially-guided movements. Based upon the present results, the reciprocal connections between anterior thalamic nuclei and cingulate cortical areas, a portion of which form an integral part of the traditional Papez circuit, may play an important role during the initial acquisition of place information, but are not necessary for the expression in behaviour of previously acquired place information. This relationship to place learning is clearly different from the postulated role for the anterior thalamic nuclei in simple discrimination learning (3). According to Gabriel et al. 3, activity in anterior thalamus plays an important role after a behavioural discrimination has been acquired, not during the initial stages of acquisition. Also, Gabriel et al. 3 have demonstrated accelerated acquisition of simple discriminative performance following damage to the hippocampal formation. The possibility should be considered that the role in acquisition and retention of new information of both the anterior thalamic area and hippocampal formation depends critically upon the nature of the behavioural task. In the case of acquisition of simple discrimination tasks (those involving straightforward S - R associations), according to Gabriel et al.'s 3 data, the output of the hippocampal formation indirectly suppresses the development of discriminative activity in the anterior thalamus, whereas, in place learning, there appears to be a synergistic relationship between the hippocampal formation and anterior thalamus. Based upon neuroanatomical and electrophysiological identification of pathways, the most likely point of convergence between anterior thalamic and hippocampal 'output is in the posterior cingulate cortex. (area 29). Thus, lesions in this area should also disrupt place navigation in the same task. Consistent with this interpretation is our finding that selective removal of area 29 also produces substantial impa!rments in acquisition and retention of place learning in the Morris water task 4~ Intei'estingly, a case of profound anterograde amnesia with limited retrograde amnesia associated with area 29 damage in a human patient has been described in a recent report 42. Mammillary or medial septal lesions produced
a more modest impairment of acquisition of place navigation. Both groups attained a level of performance that was not significantly different from the control group and they had clearly learned to navigate to the correct region of the pool. Thus, although place learning does not proceed as rapidly as in normal rats, neither of these structures makes a necessary contribution to the acquisition of place navigation. An impairment of place navigation produced by mammillary or medial septal lesions in preoperatively trained rats was not demonstrated in the present study. In almost all respects these animals behaved like control rats. Both of these structures have direct connections with structures that do appear to be important for acquisition and/or retention of place learning. The medial septal area damaged in the present experiment has projections to the hippocampal formation, entorhinal cortex, and posterior cingulate cortex. The mammillary complex has a massive projection to anterior thalamus. The loss of these projections may influence, but does not block, processing in the hippocampal formation and anterior thalamus which is necessary for acquisition of place navigation. It may appear paradoxical that transection of the fornix/fimbria blocks place navigation in naive and preoperatively trained rats, but that damage to each of the subcortical structures whose afferents or efferents make a major contribution to the fornix/fimbria rats produces only transient impairments in place navigation in preoperatively trained rats. Two explanations suggest themselves. The first is that some combination or all of these structures must be damaged to affect retention of place navigation. Thus fornix/fimbria transection produces its anterograde and retrograde effects because it destroys many different projections, none of which is individually necessary for navigation in a familiar environment. Straightforward tests of this explanation are possible. The second possibility is that the critical feature oftransecting the fornix/fimbria is not the loss of the information represented in the activity of these projections per se, but rather a nonspecific suppression of activity of hippocampal formation neurons brought about by the massive loss of input and severing of efferent axons
276 (diaschisis). The fact that direct damage to the hippocampal formation affects both acquisition and retention of place navigation 34 is consistent with this suggestion. If diaschisis is critical then simply allowing a lengthy postoperative recovery interval following fornix/fimbria damage should permit superior place navigation in preoperatively trained rats. In summary, the present experiment suggests that the nucleus accumbens and anterior thalamic nuclei, together with the hippocampal formation and posterior cortex (including area 29 and primary and secondary visual cortex) are essential components of the neural circuitry for the acquisition of place navigation. Unlike the hippocampal formation and posterior neocortex, none of the major terminal fields of the fornix makes an essential contribution to the expression of previously acquired place information in behaviour. Thus, either the terminal fields of the fornix are redundantly involved in the expression of previously acquired place information, in such a way that they a r e conjointly necessary, or the critical circuitry for place information to be expressed in behaviour involves hippocampal projections through the retrohippocampal area to neoc o r t e x 33. ACKNOWLEDGEMENTS
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