The role of the fornix/fimbria and some related subcortical structures in place learning and memory

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 of navigation to a hidden platform. Severe impairment of postoperative 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.     

The topographical organization of the hippocampal projection to the septal area: a comparative neuroanatomical analysis in the gerbil, rat, rabbit, and cat

An experiment was performed to determine the origin of the projection from the hippocampus to the septal area in the subrimate mammalian nervous system. Lesions were made by aspiration or by radio frequency in 4 gerbils, 17 rats, 8 rabbits, and 7 cats. Survival times varied from 2–5 days. Tissues were stained principally with the Fink Heimer I method for identification of degenerating axons and their terminals. Following lesions destroying any one or more of the fields of the dorsal hippocampus of the gerbil, rat, rabbit, or cat, terminal degeneration was observed only in the medial septal area, olfactory tubercle, and adjacent portions of the diagonal band. In addition, lesions producing total destruction of all dorsal hippocampal fields also resulted in the presence of terminal degeneration restricted to the medial septal area. In contrast, superficial lesions of field CA1 of the ventral hippocampus produced terminal degeneration in the lateral septal area, nucleus accumbens, olfactory tubercle, and adjacent portions of the diagonal band. Similar findings were also observed following more widespread lesions of the ventral hippocampus which produced damage to other CA fields as well. Superficial lesions of the posterior crus of the hippocampus (i.e., a position midway between dorsal and ventral hippocampus) resulted in terminal degeneration localized to an intermediolateral region of the septum. Combined lesions of the dorsal hippocampus and fimbria produced widespread terminal degeneration in both the lateral and medial septum indicating that the axons contained within the fimbria arise only from the ventral hippocampus. Finally, lesions of the medial and lateral segments of the fornix of the cat produced terminal degeneration in the medial and lateral regions of the septum, respectively. These findings, collectively, indicate that the origin of the topographical projection to the medial and lateral septum are the dorsal and ventral hippocampus, respectively. This projection is unrelated to cytoarchitectonic fields within the hippocampus and is also invariant among the species considered in this study.     

Long-term spatial memory in rats with hippocampal lesions

In animal models of human amnesia, using lesion methods, it has been difficult to establish the role played by the hippocampus in the formation of long-term spatial knowledge. For example, lesions sustained after acquisition have generally produced a flat retrograde amnesia for spatial information. These results have not made it possible to dissociate the participation of the hippocampus in retrieval/performance processes from its participation in consolidation/retention. The present study was designed to investigate if electrolytic hippocampal lesions made before training lead to a deficit in the long-term retention of spatial knowledge when the rats show equal performance levels during the acquisition. Results show that lesioned rats learn a place response just as well as the control rats when, during the training, an intramaze cue orients the animal in its navigation towards the goal arm. One day after reaching criterion, lesioned and control rats remember the task perfectly during a transfer test in which the intramaze signal used previously is not present. However, 24 days later, the hippocampal animals manifest a profound deficit in the retention of the spatial information. When the spatial task learned during the acquisition phase requires only the use of a guidance strategy, control and lesioned animals show the same level of performance during the training phase and the same degree of retention during the retraining phase 24 days after criterion. Taken together, these results suggest that the hippocampus plays a crucial role in long-term retention of allocentric spatial information.     

Cerebellar nuclear lesions in rats: Subsequent avoidance behavior and ascending anatomical connections

Bilateral lesions of the rat cerebellar dentate and lateral interposed nuclei produced transient deficits in movement and posture, and facilitated acquisition of two-way active avoidance. Bilateral lesions of the fastigial and medial interposed nuclei of the rat cerebellum also produced transient deficits in movement and posture, but impaired acquisition of the avoidance task. Analysis of degeneration patterns after unilateral lesions to either the lateral or medial nuclear region indicated that the lateral area has a denser rostral projection than the medial area, while the medial nuclear region has a heavier caudal projection. It is suggested that these differences in anatomic connections may be related to the observed differences in lesion effect on two-way active avoidance.     

Dorsal hippocampal function in unreinforced spatial learning

This study examined learning about the spatial environment by rats during a single 10 min period of exploration on an eight-arm radial maze. Because no specific behaviors were learned during this procedure, the existence of learned spatial information was inferred from its retarding effect on subsequent conditioned cue preference (CCP) learning on the same maze. Previous experiments have shown that this form of spatial learning, measured in this way, requires an intact fimbriafornix and functional N-methyl-D-aspartate receptors. However, in the present experiments, large neurotoxic lesions of the dorsal hippocampus that impaired win-shift learning failed to eliminate the retarding effect of exploration on CCP learning. This result was obtained in three independent replications. These findings fail to confirm the hypothesis that the hippocampus is involved in spatial learning when that learning occurs in the absence of reinforcers and does not produce any specific learned behaviors. Previous work showed that this form of "pure" spatial learning requires an intact fimbria-fornix for acquisition but not for expression; the present findings suggest that the hippocampus is not required for either of these processes. The fimbria-fornix may interact with other temporal lobe structures in mediating this form of learning. The function of the hippocampus may be limited in some way to situations that involve reinforcers and/or situations in which specific behaviors are learned.     

Medial versus lateral hyperstriatal lesions in pigeons: effects on autoshaping, non-matching-to-sample and spatial discrimination learning at short and long intertrial intervals

Three experiments contrasted the effects of medial and lateral hyperstriatal lesions in pigeons. Expt. 1 found that both types of lesion obtained slower acquisition of autoshaping, compared to unoperated controls. No group differences in maintained rate of autoshaped responding were found. Expt. 2 found that lateral but not medial lesions disrupted choice performance in a non-matching-to-sample (NMTS) task, in which initial preference was for the correct stimulus; birds with lateral lesions responded more slowly to the sample stimulus than did birds with medial lesions. Expt. 3 found that medial but not lateral lesions disrupted both acquisition and reversal of a spatial discrimination at a long, but not at a short intertrial interval (ITI). Medial lesions damage primarily the hyperstriatum accessorium and lateral lesions, the hyperstriatum ventrale; but no significant correlations between the extent of damage to either of these structures and severity of behavioural disruption were obtained. Implications of these findings for theoretical accounts of hyperstriatal involvement in learning processes are discussed.     

A study of hippocampal structure-function relations along the septo-temporal axis

This study examined structural-functional differences along the septo-temporal axis of hippocampus using radial-maze tasks that involved two different memory processes [reference memory (RM) and working memory (WM)], and the use of two kinds of information (spatial vs. nonspatial cue learning). In addition, retention of the nonspatial cue task was tested nine weeks following completion of acquisition, and the rats then underwent discrimination reversal training. Ibotenic acid lesions limited to either the dorsal pole, intermediate area, or ventral pole had minimal effects on acquisition of the complex place and cue discrimination tasks. The one exception was that rats with lesions confined to the dorsal third of hippocampus made more WM errors on the spatial task (but not the cue task) early in training. Selective lesions of the three hippocampal regions had no effects on either long-term retention or reversal of the nonspatial cue discrimination task. In contrast, rats that had all of the hippocampus removed were severely impaired in learning the spatial task, making many RM and WM errors, whereas on the nonspatial cue task, the impairment was limited to WM errors. Further analysis of the WM errors made in acquisition showed that rats with complete lesions were significantly more likely on both the spatial and nonspatial cue tasks to reenter arms that had been baited and visited on that trial compared to arms that had not been baited. A similar pattern of errors emerged for complete hippocampal lesioned rats during reversal discrimination. This pattern of errors suggests that in addition to an impairment in handling spatial information, complete removal of hippocampus also interferes with the ability to inhibit responding to cues that signal reward under some conditions but not under others. The finding that selective lesions limited to the intermediate zone of the hippocampus produce no impairment in either WM ("rapid place learning") or RM in our radial maze tasks serve to limit the generality of the conclusion of Bast et al. (Bast et al. (2009) PLos Biol 7:730-746) that the intermediate area is needed for behavioral performance based on rapid learning about spatial cues.     

Telencephalon and geometric space in goldfish

Neuroanatomical evidence indicates that the lateral pallium (LP) of ray-finned fishes could be homologous to the hippocampus of mammals and birds. Recent studies have found that hippocampus of mammals and birds is critical for learning geometric properties of space. In this work, we studied the effects of lesions to the lateral pallium of goldfish on the encoding of geometric spatial information. Goldfish with telencephalic lesions were trained to search for a goal in a rectangular-shaped arena containing one different wall that served as the only distinctive environmental feature. Although fish with lateral pallium lesions learned the task even faster than sham and medial pallium (MP)-lesioned animals, subsequent probe trials showed that they were insensitive to geometric information. Sham and medial pallium-lesioned animals could use both geometric and feature information to locate the goal. By contrast, fish with lateral palium lesions relied exclusively on the feature information provided by the wall of a different colour. These results indicate that lesions to the lateral pallium of goldfish, like hippocampal lesions in mammals and birds, selectively impair the encoding of geometric spatial information of environmental space. Thus, the forebrain structures of teleost fish that are neuroanatomically equivalent to the mammalian and avian hippocampus also share a central role in supporting spatial cognition. Present results suggest that the presence of a hippocampal-dependent memory system implicated in the processing of geometric spatial information is an ancient feature of the vertebrate forebrain that has been conserved during the divergent evolution of different vertebrate groups.     

Dissociable regulation of instrumental action within mouse prefrontal cortex

Evaluation of the behavioral 'costs', such as effort expenditure relative to the benefits of obtaining reward, is a major determinant of goal-directed action. Neuroimaging evidence suggests that the human medial orbitofrontal cortex (mOFC) is involved in this calculation and thereby guides goal-directed and choice behavior, but this region's functional significance in rodents is unknown despite extensive work characterizing the role of the lateral OFC in cue-related response inhibition processes. We first tested mice with mOFC lesions in an instrumental reversal task lacking discrete cues signaling reinforcement; here, animals were required to shift responding based on the location of the reinforced aperture within the chamber. Mice with mOFC lesions acquired the reversal but failed to inhibit responding on the previously reinforced aperture, while mice with prelimbic prefrontal cortex lesions were unaffected. When tested on a progressive ratio schedule of reinforcement, mice with prelimbic cortical lesions were unable to maintain responding, resulting in declining response levels. Mice with mOFC lesions, by contrast, escalated responding. Neither lesion affected sensitivity to satiety-specific outcome devaluation or non-reinforcement (i.e. extinction), and neither had effects when placed after animals were trained on a progressive ratio response schedule. Lesions of the ventral hippocampus, which projects to the mOFC, resulted in similar response patterns, while lateral OFC and dorsal hippocampus lesions resulted in response acquisition, though not inhibition, deficits in an instrumental reversal. Our findings thus selectively implicate the rodent mOFC in braking reinforced goal-directed action when reinforcement requires the acquisition of novel response contingencies.     

Removal of the hippocampus and transection of the fornix produce comparable deficits on delayed non-matching to position by rats.

Rats with radiofrequency lesions of the fimbria/fornix or with extensive aspiration lesions of the hippocampal region (the hippocampus proper, dentate gyrus, and subicular complex) were tested on their performance of a delayed non-matching to position task which had been learnt before surgery. On a given trial, one of two sample levers was presented in a random manner. Following a response on this lever and a subsequent delay, both levers were presented and reward was now contingent on a response on the lever that was not used as the sample. Both lesions produced equivalent performance deficits on this test of spatial working memory, the pattern of these deficits being consistent with a mnemonic impairment. The lack of difference between these two groups on a variety of performance measures indicates that hippocampal connections passing through the fornix are not only necessary for this test, but that non-fornical hippocampal connections appear unable on their own to maintain accurate responding.     

Perseveration on place reversals in spatial swimming pool tasks: Further evidence for place learning in hippocampal rats

Animals with damage to the fimbria–fornix (FF) or cells of the hippocampus (HIP) can learn a place problem but cannot learn matching-to-place problems, which feature a series of place “reversals.” The two experiments described in the present report were designed to examine the causes of impairment on reversal learning. In experiment 1, control, HIP, and FF groups were trained to asymptote on a place problem, and then the location of the platform was moved. Control rats learned the reversal response more quickly than the initial response; the HIP rats learned both problems at the same rate. Swim analysis showed that the impairment in the lesion group on the reversal response was aggravated by perseverative returns to the first learned place. In experiment 2, control and FF groups were trained on a task in which the platform was visible on three daily trials and hidden on one daily trial. After 10 days, the platforms were moved. In the reversal response, the FF group showed enhanced performance on the cue trials and severely impaired performance on the place trials relative to initial learning and control performance. Swim analysis showed that FF rats perseverated on the initial place response in place trials. These experiments provide further evidence for place learning in hippocampal rats and show that perseverative responses contribute to impairments in new learning. The results are discussed in relation to the idea that the hippocampus mediates spatial mapping and/or uses self-movement cues to solve spatial problems. Hippocampus 7:361–370, 1997. © 1997 Wiley-Liss, Inc.     

On the hippocampus and learned conditional responding: effects of aspiration versus ibotenate lesions.

To study the possible involvement of the hippocampus in learned conditional responding, rats with aspiration lesions of the hippocampus and others that had the hippocampus removed with ibotenic acid were trained on concurrent Pavlovian conditional and nonconditional discriminations. In agreement with the results reported by Ross et al. (1984), animals that had the hippocampus removed with aspiration were unable to learn the conditional discrimination, but learned the simple nonconditional discrimination without difficulty. In contrast, rats that had the hippocampus removed with ibotenic acid did not differ from controls in learning either discrimination. Furthermore, transfer test results were consistent with the hypothesis that ibotenate-lesioned rats performed conditional operations to solve the conditional discrimination problem. Histological analysis indicated that the ibotenate lesions resulted in the removal of the hippocampus and dentate gyrus with minimal involvement of other structures. In aspiration hippocampal animals there was less overall damage to the hippocampus, but there was also extensive damage to the axons passing in alveus and fimbria, together with bilateral loss of cells in the subicular complex, the cingulate gyrus, and the cortex. Since rats with ibotenate lesions had more complete removal of the hippocampus, yet learned both discriminations, the impaired conditional responding found in aspiration hippocampals must be due to extrahippocampal damage.     

The effects of telencephalic pallial lesions on spatial, temporal, and emotional learning in goldfish

In mammals, the pallial amygdala is implicated in emotional learning and memory, whereas the hippocampus is involved in spatial, contextual, or relational memory. This review presents a set of experiments aimed to study the involvement of the dorsomedial and dorsolateral telencephalon of goldfish in spatial and active avoidance learning. Results showed that (1) medial lesions impaired both acquisition and retention of conditioned avoidance response in two-way active avoidance learning experiments with stimuli overlapping (emotional factor) and with an interstimuli gap (temporal and emotional factors), and (2) the medial lesion did not affect spatial learning (spatial, contextual, or relational factors). In contrast, lateral lesions did not impair conditioned avoidance response with stimuli overlapping, but affected conditioned avoidance response with an interstimuli gap and spatial learning. These results support the presence of two differentiated memory systems in teleost fish based on discrete pallial regions: emotional (dorsomedial telencephalon) and spatial/temporal or relational (dorsolateral telencephalon). Furthermore, these functional data support the homology between the medial pallium of the teleost and the pallial amygdala of land vertebrates, and between the teleost lateral pallium and the mammalian hippocampus.     

Effects of partial hippocampal lesions by ibotenic acid on repeated acquisition of spatial discrimination in pigeons

Pigeons were trained on a spatial discrimination task using a repeated acquisition procedure. In this procedure, the pigeons were trained to discriminate between the positions of three keys. One of them was designated the correct key. When the subjects reached the criterion, the discrimination task was changed, with one of two previously incorrect keys now being made the correct key. This procedure was repeated at least 15 times. Then, lesions to the whole hippocampus, the medial hippocampus or to the lateral hippocampus were made by injections of ibotenic acid (Experiment 1). Only the subjects with damage to the whole hippocampus showed deficits in learning after the lesions. The deficits were similar to those caused by aspiration lesions /37/. Knife cuts separating the medial and lateral hippocampi were made in Experiment 2. The subjects did not show deficits in the spatial discrimination task after the sections. Although studies of the connectivity in the avian hippocampus suggested functional differences between the medial and lateral hippocampi, the present results show that pigeons can learn spatial discrimination with the medial and lateral parts of hippocampus separated.     

Selective excitotoxic lesions of the hippocampus and basolateral amygdala have dissociable effects on appetitive cue and place conditioning based on path integration in a novel Y-maze procedure

The hippocampus and amygdala are thought to be functionally distinct components of different learning and memory systems. This functional dissociation has been particularly apparent in pavlovian fear conditioning, where the integrity of the hippocampus is necessary for contextual conditioning, and of the amygdala for discrete cue conditioning. Their respective roles in appetitive conditioning, however, remain equivocal mainly due to the lack of agreement concerning the operational definition of a 'context'. The present study used a novel procedure to measure appetitive conditioning to spatial context or to a discrete cue. Following selective excitotoxic lesions of the hippocampus (HPC) or basolateral amygdala (BLA), rats were initially trained to acquire discrete CS-sucrose conditioning in a Y-maze apparatus with three topographically identical chambers, the chambers discriminated only on the basis of path integration. The same group of animals then underwent 'place/contextual conditioning' where the CS presented in a chamber assigned as the positive chamber was paired with sucrose, but the same CS presented in either of the other two chambers was not. Thus, spatial context was the only cue that the animal could use to retrieve the value of the CS. HPC lesions impaired the acquisition of conditioned place preference but facilitated the acquisition of cue conditioning, while BLA lesions had the opposite effect, retarding the acquisition of cue conditioning but leaving the acquisition of conditioned place preference intact. Here we provide strong support for the notion that the HPC and BLA subserve complementary and competing roles in appetitive cue and contextual conditioning.     

Unreinforced spatial (latent) learning is mediated by a circuit that includes dorsal entorhinal cortex and fimbria fornix

The relationship of the entorhinal cortex (EC) and fimbria-fornix (FF) in unreinforced spatial (latent) learning was studied using the conditioned-cue-preference task on an eight-arm radial maze. The maze was turned before every trial to eliminate the use of local cues. During three pre-exposure sessions, food-deprived rats explored the center platform and two adjacent arms of the maze. Since most of the same cues were visible from both arm locations, discriminating them required spatial learning. The rats were then alternately confined to the end of each arm over several days: one arm always contained food, the other was empty. Finally, the rats were allowed free access to both arms with no food present. Normal rats spent more time in their food-paired than in their unpaired arms showing that they learned to discriminate between the arm locations. Bilateral micro-injections of muscimol into the dorsal, but not into the ventral EC, given before the pre-exposure sessions only, impaired the discrimination. The discrimination was also impaired in rats with unilateral lesions of FF and contralateral injections of muscimol into the dorsal EC given before the pre-exposure sessions. Ipsilateral FF lesions and entorhinal inactivation had no effect. These results indicate that the acquisition of information during unreinforced exploration of a novel environment requires an intact circuit involving the dorsal EC and fimbria fornix. Together with previous reports, that this form of learning does not require a functional hippocampus, (Gaskin et al. (2005) Hippocampus 15:1085-1093) the findings also suggest that the acquisition of certain kinds of unreinforced information by this circuit is independent of the hippocampus.     

The role of the amygdala and the hippocampus in working memory for spatial and non-spatial information

Male rats received either electrolytic or sham lesions bilaterally into the amygdala, hippocampus or amygdala plus hippocampus, or were assigned to an unoperated control group. After the postoperative recovery period all lesioned and control animals were tested for the ability to master a spatial delayed non-matching-to-sample (DNMS), a visual DNMS and a visuo-tactile DNMS. Retention of these paradigms was evaluated 24 h after the last respective training session. Bilateral lesions of the amygdala severely disrupted the acquisition and retention of a DNMS paradigm with visual and visuo-tactile cues as discriminative stimuli and had no effect on the acquisition and retention of a spatial DNMS. On the contrary, bilateral lesions of the hippocampus impaired the acquisition and retention of spatial DNMS, but the animals with these lesions showed an acquisition and retention of the visual and visuo-tactile DNMS paradigms significantly better than those of animals with amygdala lesions. Combined lesions of the amygdala and hippocampus severely disrupted the acquisition and retention of the 3 paradigms. The contribution of the amygdala and the hippocampus in the working memory for spatial and non-spatial information is discussed.     

Behavioral effects of lesions of precommissural and postcommissural fornix

Lesions which sever different parts of precommissural or postcommissural fornix were compared to the effects of control lesions in several behavioral tasks. Spatial learning and avoidance was impaired by lesions of the descending columns, or by lesions which sever the precommissural communications passing to and from medial septum. Damage to precommissural fibers through lateral septum produced a measurable change only on the avoidance task. This pattern of deficits, considered together with the anatomical relationship of the system, suggests a model in which the medial septum relays kinesthetic information to dorsal hippocampus, which in turn serves as a memory system in the performance of spatial habits. It is less clear what kind of information is relayed by lateral septum, but it may communicate with ventral hippocampus regarding the consequences of punishment, and thus serve as part of a system for defensive suppression of behavior.     

Hypothalamic afferent connections mediating adrenocortical responses that follow hippocampal stimulation

This study identified some neural pathways which mediate the adrenocortical responses that follow hippocampal stimulation. The increase in plasma corticosterone following dorsal hippocampus stimulation, in rats with electrodes chronically implanted under pentobarbital anesthesia, was blocked by dorsal fornix and lateral septal lesions and by small posterior hypothalamic deafferentation. Fimbria transection, lateral septal lesions, and posterior hypothalamic deafferentation, but not midbrain reticular formation lesions, also blocked the adrenocortical responses to ventral hippocampus stimulation. Our present and previous studies indicate that the dorsal and ventral hippocampal effects on the hypothalamus, which increase plasma corticosterone concentrations, are mediated by the dorsal fornix and fimbria, respectively, as well as by the lateral septum. A posterior hypothalamic input, which does not involve the medial forebrain bundle or the midbrain reticular formation is also essential for the activation of this response.