Place and response learning of rats in a Morris water maze: differential effects of fimbria fornix and medial prefrontal cortex lesions

The question examined in this study is concerned with a possible functional dissociation between the hippocampal formation and the prefrontal cortex in spatial navigation. Wistar rats with hippocampal damage (inflicted by a bilateral lesion of the fimbria fornix), rats with damage to the medial prefrontal cortex, and control-operated rats were examined for their performance in either one of two different spatial tasks in a Morris water maze, a place learning task (requiring a locale system), or a response learning task (requiring a taxon system). Performance of the classical place learning (allocentric) task was found to be impaired in rats with lesions of the fimbria fornix, but not in rats with damage of the medial prefrontal cortex, while the opposite effect was found in the response learning (egocentric) task. These findings are indicative of a double functional dissociation of these two brain regions with respect to the two different forms of spatial navigation. When the place learning task was modified by relocating the platform, the impairment in animals with fimbria fornix lesions was even more pronounced than before, while the performance of animals with medial prefrontal cortex lesions was similar to that of their controls. When the task was again modified by changing the hidden platform for a clearly visible one (visual cue task), the animals with fimbria fornix lesions had, at least initially, shorter latencies than their controls. By contrast, in the animals with medial prefrontal cortex damage this change led to a slight increase in escape latency.     

Dissociation of Hippocampal and Striatal Contributions to Spatial Navigation in the Water Maze

Two experiments were conducted to compare the effects of fornix/fimbria and caudate-putamen lesions in Long–Evans hooded rats (Rattus norvegicus) trained on two water maze tasks that differed in the type of spatial localization required for optimum solution. In Experiment 1, the lesioned rats and surgical controls were trained on the standard place task in the water maze (Morris, 1981) and given two postacquisition tests (a platform removal probe and platform relocation test). In Experiment 2, rats with similar lesions and control rats were trained on a modified cue navigation task. Fornix/fimbria lesions impaired a late stage of place task acquisition but did not impair acquisition of the cue task. Caudate-putamen lesions resulted in a severe place acquisition impairment and a transient cue acquisition impairment, both of which were characterized by an initial tendency to swim near the wall of the pool. Post-hoc analyses of the direction and angles of departure from the start points suggested that rats with fornix/fimbria lesions used non-allocentric spatial strategies to solve the place task. These rats also demonstrated a significantly weakened spatial bias for the former training quadrant on the platform removal probe and reduced flexibility in navigating to a novel platform location on the platform relocation test. In contrast, rats with caudate-putamen lesions showed a significant spatial bias for the former training quadrant but failed to cross the exact location within the quadrant where the platform was formerly positioned. The results suggest that the hippocampus mediates the allocentric spatial component of the water maze place task while the dorsomedial striatum may play an important role in the acquisition of the procedural aspects of both place and cue versions of the task.     

Effects of dorsal-striatum lesions and fimbria-fornix lesions on the problem-solving strategies of rats in a shallow water maze

In solving a spatial problem, animals can use a place, cue, or response strategy. The present research was designed to evaluate the role of dorsal striatum (DS) in spatial problem solving and to compare it with that of fimbria fornix (FF). Rats were trained with a place + cue task in a shallow pool, then were divided into three groups (DS, FF, control), and lesions were made in the corresponding areas. After retraining, four probe tests were given: Test 1 (start position moved), Test 2 (goal and start positions moved), Test 3 (invisible goal), and Test 4 (curtain test). The test results suggest that the DS and Control groups performed the original task by using the place strategy, whereas the FF group used the cue strategy, which strongly implies that the DS group was impaired in the use of the cue strategy. This research also provides evidence supporting the usefulness of a shallow pool in evaluating animal behavior.     

Rat hippocampus and memory for places of changing significance

Rats were tested once daily on a four-choice delayed match from sample task with a water reward. Each day the correct place changed, and a single exposure to it was provided on information trials. Lesions of the hippocampal formation that involved the fornix, or dorsal hippocampus bilaterally, produced a severe impairment in the performance of previously trained rats. By contrast, lesions of the ventral hippocampus did not preclude reacquisition of the place-memory task. Some otherwise impaired rats with fornical lesions were able to find the water when aided by nonplace cues that consistently signaled reward. Reducing the number of choices from four to two did not aid the impaired rats. Certain lesions of the hippocampal formation in the rat produce a deficit appropriately described as amnesia. The memory deficit is consistent with a role for the hippocampus in processing of place information and shows some parallels to the amnesia seen in persons with temporal lobe lesions.     

ACTH 4-9 analog can retard spatial alternation learning in brain damaged and normal rats

Thirty adult male hooded rats (Long-Evans strain) were assigned randomly to one of three lesion groups (n = 10) and prepared with medial frontal, posterior parietal, or sham neocortical injuries. Following a recovery interval of 10-12 days, access to water was limited to 30 min per day and the rats were shaped to traverse a T-maze for a reward of sweetened water. After a pretraining criterion was attained, osmotic minipumps (Alzet 2002) were installed subcutaneously. The minipumps delivered chronically for the next 14 to 15 days either 0 or 1.2 micrograms of ACTH 4-9 dissolved in bacteriostatic saline per day while the rats were trained on a reinforced spatial alternation task. Analysis of the number of errors made to a criterion of at least 80% correct alternations in two consecutive training sessions, or a ceiling of 62 errors (attained by two rats with parietal lesions), revealed that learning was impaired in the rats with parietal injuries. Contrary to our hypothesis, animals receiving ACTH 4-9 committed more errors than their counterparts receiving only saline.     

Effects of ventral and dorsal CA1 subregional lesions on trace fear conditioning

Recent lines of research have focused on dissociating function between the dorsal and ventral hippocampus along space and anxiety dimensions. In the dorsal hippocampus, the CA1 subregion has been implicated in the acquisition of contextual fear as well as in the trace interval in trace fear conditioning. The present study was designed to test the relative contributions of dorsal (dCA1) and ventral CA1 (vCA1) in trace fear conditioning. Long-Evans rats received ibotenate lesions of the ventral CA1 (n=7), dorsal CA1 (n=9), or vehicle control lesions (n=8) prior to trace fear conditioning acquisition. Results suggest dCA1 and vCA1 groups show no significant deficits during acquisition when compared to control groups. dCA1 and vCA1 both show deficits in the retention of contextual fear when tested 24 h post-acquisition (P<.05 and P<.01, respectively), and vCA1 was impaired relative to dCA1 (P<.05). This is suggestive of a graded involvement in contextual retention between the dorsal and ventral aspects of CA1. dCA1 showed no deficit for retention of conditioned fear to the tone or the trace when tested 48 h post-acquisition, whereas vCA1 did show a significant deficit for the trace interval and a slight, non-significant reduction in freezing to the tone, when compared to the control group (p<.05). Overall the data are suggestive of a graded involvement in retention of fear conditioning between the dorsal and ventral aspects of CA1, but it is likely that vCA1 may be critically involved in retention of trace fear conditioning.     

Task-dependent role for dorsal striatum metabotropic glutamate receptors in memory

The effect of post-training intradorsal striatal infusion of metabotropic glutamate receptor (mGluR) drugs on memory consolidation processes in an inhibitory avoidance (IA) task and visible/hidden platform water maze tasks was examined. In the IA task, adult male Long-Evans rats received post-training intracaudate infusions of the broad spectrum mGluR antagonist α-methyl-4-carboxyphenylglycine (MCPG; 1.0, 2.0 mM/0.5 μL), the group I/II mGluR agonist 1-aminocyclopentane-1,3-carboxylic acid (ACPD; 0.5 or 1.0 μM/0.5 μL), or saline immediately following footshock training, and retention was tested 24 h later. In the visible- and hidden-platform water maze tasks, rats received post-training intracaudate infusions of ACPD (1.0 μM), MCPG (2.0 mM), or saline immediately following an eight-trial training session, followed by a retention test 24 h later. In the IA task, post-training infusion of ACPD (0.5 and 1.0 μM) or MCPG (1.0 and 2.0 mM) impaired retention. In the IA and visible-platform water maze tasks, post-training infusion of ACPD (1.0 μM), or MCPG (2.0 mM) impaired retention. In contrast, neither drug affected retention when administered post-training in the hidden-platform task, consistent with the hypothesized role of the dorsal striatum in stimulus-response habit formation. When intradorsal striatal injections were delayed 2 h post-training in the visible-platform water maze task, neither drug affected retention, indicating a time-dependent effect of the immediate post-training injections on memory consolidation. It is hypothesized that MCPG impaired memory via a blockade of postsynaptic dorsal striatal mGluR's, while the impairing effect of ACPD may have been caused by an influence of this agonist on presynaptic “autoreceptor” striatal mGluR populations.     

Influence of dorsal hippocampal lesions and MMP inhibitors on spontaneous recovery following a habituation/classical conditioning head–shake task

The present investigation combined a classical conditioning paradigm with a head–shake response (HSR) habituation task in order to evaluate the importance of dorsal hippocampal neural plasticity to spontaneous recovery. In the first experiment animals exhibited rapid HSR habituation (air stimulus to the ear) and an 85% level of spontaneous recovery following a 24 h inter-session interval. The addition of a brief tone prior to the air stimulus produced a similar pattern of habituation during the first session, but the level of spontaneous recovery was reduced (44%) during Session II. In a second experiment dorsal hippocampal lesioned rats placed on this tone/HSR paradigm responded with an 87% level of spontaneous recovery during Session II; while neocortex lesioned control rats indicated significantly reduced levels of spontaneous recovery (55%). In a third experiment bilateral injections of a general MMP inhibitor, FN-439, into the dorsal hippocampus resulted in high levels of spontaneous recovery (81%); while control rats injected with artificial cerebrospinal fluid displayed a significant attenuation of spontaneous recovery (45%). Finally, animals bilaterally injected with a specific MMP-3 inhibitor into the dorsal hippocampus indicated very similar results to those obtained following FN-439 injection. These findings indicate that animals prepared with dorsal hippocampal lesions, or injections with an MMP inhibitor, revealed an impaired association between the tone and air stimulus thus maximum spontaneous recovery was present 24 h later. Thus, it appears that the dorsal hippocampus influences habituation by conserving responses and reducing spontaneous recovery when a temporally contingent signaling cue is present.     

The effects of pretraining and reminder treatments on retrograde amnesia in rats: comparison of lesions to the fornix or perirhinal and entorhinal cortices

The present experiment examined the effects of pretraining and reminder treatments on the retention of a nonrelational odor-guided digging task following lesions to the hippocampal formation (i.e., fornix) or parahippocampal region (i.e., perirhinal and entorhinal cortices). The results showed that fornix-lesioned rats and control rats had good retention of the task and did not differ from each other; however, perirhinal- and entorhinal-lesioned rats were severely impaired and differed from fornix and control rats. The present experiment found no attenuation of amnesia following pretraining, which may be due to the lesion technique employed and the size of the resulting lesions. However, the experiment found a significant difference in performance following a reminder treatment, even in the severely impaired perirhinal- and entorhinal-lesioned group.     

Contributions of the dorsal hippocampus and the dorsal subiculum to processing of idiothetic information and spatial memory

It is well established that the dorsal hippocampal formation is crucial for spatial memory in rats. However, little is known about the distinct functions of the dorsal hippocampus and the dorsal subiculum. To examine the role of the dorsal hippocampus and the dorsal subiculum, Long-Evans rats with excitotoxic lesions (NMDA) of the dorsal hippocampus (DH), the dorsal subiculum (DS), or both (DHDS), and controls were trained on a nonmatching-to-place task. Then, to identify the strategy used by each group, they were tested on the same task in the dark with the T-maze being rotated between the sample and the test runs. In the light, rats with combined lesions were impaired. In the dark, groups DH, DS, and controls performed near chance level except in trials without rotation, suggesting the use of a sense of direction. The same rats were trained on a radial-arm maze task. In the light, where proximal visual cues were accessible, combined lesions affected performance whereas in the dark, it was impaired by all lesions. This experiment demonstrated that the dorsal subiculum and the dorsal hippocampus play a crucial role in processing idiothetic information and/or in maintenance of this information in memory.     

Response of the rat brain beta-endorphin system to novelty: importance of the fornix connection

In control rats, a step-down inhibitory avoidance training trial using a 0.8 mA footshock, or simple exposure to the training apparatus without footshock, was followed by a decrease of beta-endorphin-like immunoreactivity measured in the hypothalamus and ventral thalamus. The effect of inhibitory avoidance training was also measured in rats submitted to a brain sham operation, to bilateral transection of the dorsal fornix, to anterior or to posterior hypothalamic deafferentation, to adrenal medullectomy, to an adrenal sham operation, to 16 daily ip injections of 0.2 mg/kg dexamethasone, or to 16 daily ip injections of 1 ml/kg saline. The diencephalic beta-endorphin-like immunoreactivity response to training was abolished by fornix transection and was unaffected by all other treatments. This suggests that the response is not mediated by anterior or posterior neural afferents to the hypothalamus, or by a hypersecretion of epinephrine by the adrenal medullae, or of ACTH by the pituitary gland. The response, instead, appears to require the integrity of the pathway that sends projections from the septo-hippocampal system to the hypothalamus. Previous evidence had suggested that the diencephalic beta-endorphin-like immunoreactivity response to training is a result of novelty, and the septo-hippocampal system has been postulated to play a role in the registration of novelty.     

Locomotor, avoidance,and maze behavior in rats with selective disruption of hippocampal output.

Behavioral correlates of selective disruption of hippocampal output were investigated in a series of five experiments. In two experiments an attempt was made through behavioral investigation to determine whether the CA1 neurons project to the fimbria or to the subiculum. The results supported recent views that the subiculum is the recipient of CA1 axons. Disruption of the CA1 output in the dorsal hippocampus of rats produced increased open-field activity, whereas passive avoidance and spontaneous alternation behaviors remained unchanged. No differentiation was obtained between CA1 damage and neocortical lesions in maze learning. Blocking of the fimbrial CA3 output from the dorsal hippocampus improved passive avoidance performance and impaired active avoidance performance, whereas open-field and spontaneous alternation behaviors were unaffected. Interruption of the CA3 output from the ventral hippocampus improved active avoidance performance and reduced spontaneous alternation behavior. Open-field behavior and passive avoidance performance remained unchanged. Total fimbrial sections increased open-field activity, improved passive and active avoidance, and reduced spontaneous alternation. The results are discussed in terms of functional differentiation between the CA1 and CA3 of the dorsal hippocampus and in terms of functional differences in the fimbrial CA3 output from the dorsal and ventral hippocampus.     

Fimbria/fornix lesions facilitate the learning of a nonspatial response task

The spatial cognitive map theory of O’Keefe and Nadel (1978) predicts that lesions of the hippocampal system should impair learning on spatial tasks but not learning on nonspatial tasks. However, there is evidence that such lesions can facilitate learning on certain nonspatial tasks. Their theory does not predict such facilitation. Nevertheless, it is reasonable to expect that animals possessing a spatial cognitive map would have an inherent bias to engage a mapping strategy and thus be at a disadvantage on certain nonspatial tasks in comparison with animals without the mapping capacity and bias. In the present study, fimbria/fornix lesions impaired learning on a spatial task, but actually facilitated learning on a nonspatial task of equal difficulty. Thus, brain lesions that interfere with map functioning can facilitate learning on tasks for which a mapping strategy interferes with task solution. The results require a modification of the spatial cognitive map theory.     

The hippocampal dentate gyrus is essential for generating contextual memories of fear and drug-induced reward

The hippocampus is believed to play a role in processing information relative to the context in which emotionally salient experiences occur but evidence on the specific contribution of the hippocampal dentate gyrus (DG) to these processes is limited. Here, we have used two classical behavioral paradigms to study the participation of the dorsal DG in context-conditioned reward and context-conditioned fear. Rats received intra-hippocampal vehicle or colchicine injections (4 microg/microl solution; 0.2 microl injections at 10 sites) that damaged the DG but spared other hippocampal subfields. In the first experiment, we used a place conditioning procedure pairing cocaine exposure (20 mg/kg, i.p.) with a specific context and vehicle treatment with another. While rats with sham lesions exhibited preference for the cocaine-paired context following conditioning, rats with lesions of the DG showed no evidence of cocaine-induced place preference. In the second experiment, rats with sham or colchicine lesions received a foot shock in a given context and conditioned freezing was measured upon reexposure to the shock-paired context (2, 24, 48 and 96 h after conditioning). Rats with sham lesions exhibited high levels of conditioned freezing when exposed to the conditioning context but rats with lesions of the DG showed impaired conditioning, behaving as controls that had experienced shock in a different context. These observations indicate that the integrity of the DG is essential for establishing a coherent representation of the context to which emotional experiences, either hedonic or aversive, are bound.     

Intrahippocampal insulin improves memory in a passive-avoidance task in male wistar rats

The main impacts of insulin favor the peripheral organs. Although it functions as a neuropeptide, insulin possesses also some central effects. The aim of this study was to determine the effect of intrahippocampal infusion of insulin on passive avoidance learning in healthy male rats. Thirty male wistar rats were divided into three groups (n=10 each). The experimental group had posttraining insulin infusion into the CA1 region of dorsal hippocampus, after which they were compared with sham (saline) and control (intact) groups. Insulin treated animals had greater latency to enter the dark compartment in compare with saline treated (p=0.023) or control groups (p=0.017). Upon our results, we concluded that intrahippocampal injections of insulin may enhance memory for a simple learning task which supports the concept that insulin possibly plays an endogenous role in memory formation.     

Spatial strategy elaboration in egocentric and allocentric tasks following medial prefrontal cortex lesions in the rat

We evaluated the role of the medial prefrontal cortex (mPFC) in the elaboration of egocentric navigation strategies in a water maze (WM). Lesions of mPFC cell bodies was achieved in 21 rats using bilateral injections of ibotenic acid (IA); 13 control rats were injected with saline. After 17 days, rats had to learn an allocentric (using external cues: 10 lesioned, 7 saline rats) or an egocentric WM (using internal/kinetic cues: 10 lesioned, 6 saline rats) over six trials in a same session. The initial trajectory on the sixth trial was used as an index of the elaboration of a navigation strategy. In the egocentric test, lesioned rats were more rarely located in the target quadrant than control rats. No differences were found between lesioned and control rats in the allocentric test. These results show that lesions of the mPFC impairs the capacity to elaborate an egocentric navigation strategy.     

Memory for Duration: Role of Hippocampus and Medial Prefrontal Cortex

In this task rats had to learn that a three-dimensional object stimulus (a rectangle) that was visible for 2 s would result in a positive (go) reinforcement for one object (a ball) and no reinforcement (no go) for a different object (a bottle). However, if the rectangle stimulus was visible for 8 s then there would be no reinforcement for the ball (no go), but a reinforcement for the bottle (go). After rats learned this conditional discrimination by responding differentially in terms of latency to approach the object, they received large (dorsal and ventral) lesions of the hippocampus, lesions of the medial prefrontal cortex (anterior cingulate and precentral cortex), lesions of the cortex dorsal to the dorsal hippocampus, or served as sham-operated controls. Following recovery from surgery they were retested. The results indicate that there were major impairments following hippocampal lesions, in contrast to cortical control and medial prefrontal cortex lesions, as indicated by smaller latency differences between positive and negative trials on postsurgery tests. In order to ensure that the deficits observed with hippocampal lesions were not due to a discrimination problem, new rats were trained in an object (gray cylinder) duration discrimination task. In this go/no go procedure, the rats were reinforced for a 2-s exposure (duration) of the gray cylinder, but not a 10-s duration, or vice versa. The results indicate that after hippocampal lesions, there was an initial deficit followed by complete recovery. There were no significant changes for the medial prefrontal, cortical control, or sham-operated animals. It appears that the hippocampus, but not the medial prefrontal cortex, is actively involved in representing in short-term memory temporal attribute information based on the use of markers for the beginning and end of the presence (duration) of a stimulus (object).     

Selective fimbria and thalamic lesions differentially impair forms of working memory in rats.

Several series of experiments were designed to compare the effects of selective lesions of the fimbria or of thalamic nuclei on three different tasks involving working memory in rats: object recognition, place recognition, and the radial arm maze test. The main effects of fimbria lesions were as follows: they produced deficits in the radial maze; object recognition was spared or even facilitated, whereas place recognition was impaired. Electrolytic lesions of either centromedian-parafascicularis (CM-Pf) or dorsomedialis (DM) nuclei produced highly significant deficits in the radial maze test but spared object and place recognition. Ibotenate lesions of the CM-Pf had no effect on any test, which means that the critical structure in the effects of the electrolytic lesions of the CM-Pf was the fasciculus retroflexus (FR). These data may contribute two main points to animal models of hippocampal and thalamic amnesia: (1) different forms of working memory in rats might have different neural bases and (2) the FR may be involved in learning and memory processes.     

Rats depend on habit memory for discrimination learning and retention

We explored the circumstances in which rats engage either declarative memory (and the hippocampus) or habit memory (and the dorsal striatum). Rats with damage to the hippocampus or dorsal striatum were given three different two-choice discrimination tasks (odor, object, and pattern). These tasks differed in the number of trials required for learning (~10, 60, and 220 trials). Dorsal striatum lesions impaired discrimination performance to a greater extent than hippocampal lesions. Strikingly, performance on the task learned most rapidly (the odor discrimination) was severely impaired by dorsal striatum lesions and entirely spared by hippocampal lesions. These findings suggest that discrimination learning in the rat is primarily supported by the dorsal striatum (and habit memory) and that rats engage a habit-based memory system even for a task that takes only a few trials to acquire. Considered together with related studies of humans and nonhuman primates, the findings suggest that different species will approach the same task in different ways.     

Scopolamine-induced deficits in spontaneous alternation performance: attenuation with lateral ventricle injections of glucose.

This experiment determined whether centrally administered glucose can attenuate scopolamine-induced deficits in spontaneous alternation performance. All rats were surgically prepared with indwelling cannulae directed at the lateral ventricle. Thirty min prior to alternation tests, rats received systemic (ip) injections of saline or scopolamine (3 mg/kg). Ten or thirty min prior to training, the rats also received a direct injection into the lateral ventricle of either artificial cerebrospinal fluid (CSF) or glucose (3 micrograms in 1 microliter). Scopolamine significantly impaired spontaneous alternation performance relative to controls. Additional treatment with ICV glucose 30 min, but not 10 min prior to testing, significantly attenuated the scopolamine-induced deficit. These results add support to the view that glucose acts directly on brain systems to attenuate behavioral effects of cholinergic antagonists.