Dorsal Hippocampal Lesions Research Articles

Dorsal hippocampal lesions impair appetitive classical conditioning to localized cues

Three experiments examined appetitive classical conditioning in rats with small electrolytic lesions of the dorsal hippocampus. In all the experiments, the reinforcer was food delivery and the conditioned response (CR) entry to the food tray; the three experiments differed in the nature of the conditioned stimulus (CS). When this was a small light located inside the food tray, conditioning was impaired in lesioned animals, but when the CS was a general increase in illumination, they learned at the same rate as controls. With a white noise as the CS, learning was significantly faster in lesioned subjects. These data demonstrate that lesions of the dorsal hippocampus can produce impairments in appetitive delay conditioning, but only with certain types of CS. It is suggested that deficits are found with CSs that are localized in space.

Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function

The Ts65Dn mouse is segmentally trisomic for a part of mouse chromosome 16 and is a genetic model for Down syndrome and Alzheimer's disease. Although many studies have examined the learning and memory processes in Ts65Dn mice, it has yet to be determined if Ts65Dn mice are specifically impaired in learning tasks that require an intact hippocampus. Context discrimination learning is dependent on the dorsal hippocampus in mice. In this task, mice learn to discriminate two similar contexts, one of which is associated with foot shock. In the current study, Ts65Dn mice learned almost identically to what has been reported for mice with dorsal hippocampal lesions, while controls behaved similarly to sham lesioned mice. Therefore, Ts65Dn mice have learning deficits in a hippocampal dependent task that may be related to the loss of cholinergic input to the hippocampus, which occurs after 6 months of age.

Hippocampus and contextual fear conditioning: recent controversies and advances.

Dorsal hippocampal (DH) lesions produce a severe deficit in recently, but not remotely, acquired contextual fear without impairing memory of discrete training stimuli, i.e., DH lesions produce an anterograde and time-limited retrograde amnesia specific to contextual memory. These data are consistent with the standard model which posits temporary involvement of the hippocampus in recent memory maintenance. However, three recent controversies apparently weaken the case for a selective mnemonic role for the hippocampus in contextual fear. First, although retrograde amnesia (from posttraining lesions) is severe, anterograde amnesia (from pretraining lesions) may be mild or nonexistent. Second, a performance, rather than mnemonic, account of contextual freezing deficits in hippocampal-lesioned animals has been offered. Third, damage to the entire hippocampus, including the ventral hippocampus, can produce a dramatic and temporally stable disruption of context and tone fear. These data are reviewed and explanations are offered as to why they do not necessarily challenge the standard model of hippocampal memory function in contextual fear. Finally, a more complete description of the hippocampus' proposed role in contextual fear is offered, along with new data supporting this view. In summary, the data support a specific mnemonic role for the DH in the acquisition and consolidation of contextual representations.

Dissociation of the effects of bilateral lesions of the dorsal hippocampus and parietal cortex on path integration in the rat.

Rodents are able to rely on self-motion (idiothetic) cues and navigate toward a reference place by path integration. The authors tested the effects of dorsal hippocampal and parietal lesions in a homing task to dissociate the respective roles of the hippocampus and the parietal cortex in path integration. Hippocampal rats exhibited a strong deficit in learning the basic task. Parietal rats displayed a performance impairment as a function of the complexity of their outward paths when the food was placed at varying locations. These results suggest that the parietal cortex plays a specific role in path integration and in the processing of idiothetic information, whereas the hippocampus is involved in the calibration of space used by the path integration system.

Dorsal and ventral hippocampus: Same or different?

Previous work has suggested that the hippocampus (HPC) is not a functionally homogenous structure, because lesions of the septal pole have been found to produce more of a deficit in spatial navigation. To investigate whether this dissociation extends to configural-relational learning, we tested rats with dorsal or ventral HPC lesions in a modified version of the Morris water task and in a discriminative context-conditioning paradigm. Results indicated that dorsal HPC lesions were more efficient in impairing performance in the spatial navigation task but that ventral HPC lesions also had some effect. However, no differences between groups were found in the nonspatial context-conditioning task. Both lesion groups acquired discriminative freezing at a rate identical to that of the controls, but lesioned animals could not acquire preference for the safe environment even after three pairings with shock. Thus, comparison of multiple cues with different emotional valence requires integration along the septotemporal axis of the HPC. Reviewing previous studies, we conclude that although the dorsal HPC pole is more efficient than the ventral in supporting spatial navigation, the dissociation is not absolute. We also hypothesize that physiological activity along the longitudinal axis of the HPC might have particular behavioral relevance. Theoretical implications of this hypothesis are considered.

Hippocampal dysfunction during aging II: Deficits on the radial-arm maze☆

Middle-aged and aged rats received dorsal hippocampal lesions before performance was evaluated on the radial-arm maze. The maze task contained simultaneous spatial working memory and visually cued reference memory components. Both middle-aged and aged rats that received lesions committed more errors of both types than sham-operated rats. Moreover, an age-related deficit was found for working and reference memory errors. After 14 sessions of training, a probe session revealed that: (a) middle-aged sham rats relied on spatial cues, (b) middle-aged lesioned rats employed the visual cues at the ends of the maze arms, (c) aged sham rats relied predominately on spatial information, (d) aged lesioned rats could not use spatial information or the visual cues at the ends of the maze arms. The additive effect of lesion and age suggests continued reliance on the hippocampus despite age-related deficits in its functioning. These data are suggestive of reduction in flexible cue utilization during aging, resulting paradoxically in more dependence on the hippocampus for aged rats than younger animals.

Hippocampal dysfunction during aging I: Deficits in memory consolidation☆

Numerous ablation studies indicate a critical role for the hippocampal system in establishing or consolidating certain types of memory. Normal aging manifests by selective neurobiological changes in the hippocampal formation and on performance of tasks that require a functional hippocampus, including retention of contextual fear conditioning. To determine if impairments in the consolidation process contribute to memory dysfunction in aging, middle-aged and aged rats were fear conditioned and subsequently received dorsal hippocampal lesions or sham surgery after a 1, 7, 14, or 28-day interval. During retention tests, middle-aged rats exhibited a temporally graded retrograde amnesia of contextual fear conditioning, whereas aged rats manifested contextual memory impairments at all intervals. We postulate that the lack of consolidation in aged animals relates to previous findings of age-related changes in neuroanatomy and neurophysiological plasticity. The present findings suggest that impaired hippocampal consolidation contributes to age-related learning and memory deficits.

Temporally Graded Retrograde Amnesia of Contextual Fear after Hippocampal Damage in Rats: Within-Subjects Examination

We have shown previously that electrolytic lesions of the dorsal hippocampus (DH) produce a severe deficit in contextual fear if made 1 d, but not 28 d, after fear conditioning (). As such, the hippocampus seems to play a time-limited role in the consolidation of contextual fear conditioning. Here, we examine retrograde amnesia of contextual fear produced by DH lesions in a within-subjects design. Unlike our previous reports, rats had both a remote and recent memory at the time of the lesion. Rats were given 10 tone-shock pairings in one context (remote memory) and 10 tone-shock pairings in a distinct context (with a different tone) 50 d later (recent memory), followed by DH or sham lesions 1 d later. Relative to controls, DH-lesioned rats exhibited no deficit in remote contextual fear, but recent contextual fear memory was severely impaired. They also did not exhibit deficits in tone freezing. This highly specific deficit in recent contextual memory demonstrated in a within-subjects design favors mnemonic over performance accounts of hippocampal involvement in fear. These findings also provide further support for a time-limited role of the hippocampus in memory storage.

The effects of hippocampal and fimbria-fornix lesions on prepulse inhibition.

The present experiments tested the effects of conventional (dorsal aspiration and electrolytic) and excitotoxic (N-methyl-D-aspartate [NMDA]) hippocampal lesions and fimbria-fornix (FF) transection on prepulse inhibition (PPI) of startle response and on open-field activity. Activity was increased by FF transection and by conventional but not excitotoxic hippocampal lesions; complete NMDA lesion increased amphetamine-induced activity. Whereas dorsal hippocampal aspiration lesion disrupted PPI, the phenomenon was not affected by dorsal hippocampal electrolytic lesion, partial or complete excitotoxic (NMDA) hippocampal lesions, or complete FF transection, which interrupted the cholinergic input to the hippocampus as well as the hippocampal-subicular input to the nucleus accumbens. Systemic apomorphine disrupted PPI in both FF-transected rats and their controls. It is suggested that the hippocampus is essential for PPI disruption rather than for PPI expression.

Dissociating context and space within the hippocampus: Effects of complete, dorsal, and ventral excitotoxic hippocampal lesions on conditioned freezing and spatial learning.

Dissociating context and space within the hippocampus: Effects of complete, dorsal, and ventral excitotoxic hippocampal lesions on conditioned freezing and spatial learning.

Role of vasopressin in learning and memory in the hippocampus

The involvement of arginine8-vasopressin (VP) in learning and memory in the hippocampus is examined in mice using a discriminative learning task. Bilateral dorsal hippocampal lesion blocks the enhancing effect of intracerebroventricular (i.c.v.) injection of VP on retrieval and relearning processes. An additional study showed that immunoneutralization of dorsal hippocampal endogenous VP inhibited the facilitating effect of i.c.v. injection of VP, suggesting that hippocampus is essential for the expression of VP's behavioral effects. Using in situ microinjection, a greater sensitivity of the ventral part of the hippocampus to the memory enhancing effects of VP has been reported. This effect is mediated by vasopressin V1 type receptors and oxytocin receptors. Then, we examined the effects on behavior of VP applied to the ventral hippocampus, in relation to the time of treatment during learning. When the animals have no previous information about the task to learn, a deleterious effect of VP appears (pre-first session treatment). Regarding memory consolidation, the effects of VP may depend upon the previous level of performance acquired by the animals since, when injected after the first learning session, the peptide slightly delayed performance, whereas when the injection took place after the second learning session, it enhanced learning. Concerning memory retrieval, the effects of VP depend on the quality of the previously stored information. The fact that VP did not generate the same behavioral effects when the treatment was performed at the beginning or in the middle of the learning processes, suggests that mnemonic context is an important factor in understanding the effect of VP on memory in the ventral hippocampus. Finally, the role of hippocampal adrenergic receptors in the enhancing VP effects on memory retrieval has been examined. The facilitatory effects of VP seem to depend upon the functional state of both alpha- and beta-adrenergic receptors, but further studies will be necessary to clarify the role played by each receptor type in retrieval processes, and to determine the relationships that might exist between them.

Effect of a Prolyl Endopeptidase Inhibitor, JTP-4819, on Radial Maze Performance in Hippocampal-Lesioned Rats

The effect of a novel prolyl endopeptidase (PEP) inhibitor, (S)-2-2[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (JTP-4819), on spatial learning deficits in rats with dorsal hippocampal (DH) lesions was examined using an eight-arm radial maze. The correct performance remained at chance levels even after 18 acquisition trials in rats with DH lesions. JTP-4819 (3.0 mg/kg, p.o.) significantly ameliorated this learning impairment after 34–41 days of treatment. When DH lesions were created in rats after achievement of learning, postoperative performance deteriorated prominently, but gradually recovered with the repetition of trials. JTP-4819 (3.0 mg/kg, p.o.) significantly decreased the number of trials needed to reattain learning criterion. After the behavioral experiment, the choline acetyltransferase (ChAT) activity and [ 3H]-pirenzepine binding ( K d, B max) in the residual hippocampus and cerebral cortex were analyzed. Neither parameter was significantly affected by JTP-4819. In conclusion, JTP-4819 can improve both learning and relearning deficits of spatial memory in DH-lesioned rats, postulating that enhancement of neuropeptide activity via PEP inhibition may be involved in the mechanism of action of JTP-4819.

Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats

Electrolytic lesions of the dorsal hippocampus (DH) produce deficits in both the acquisition and expression of conditional fear to contextual stimuli in rats. To assess whether damage to DH neurons is responsible for these deficits, we performed three experiments to examine the effects of neurotoxic N-methyl- d-aspartate (NMDA) lesions of the DH on the acquisition and expression of fear conditioning. Fear conditioning consisted of the delivery of signaled or unsignaled footshocks in a novel conditioning chamber and freezing served as the measure of conditional fear. In Experiment 1, posttraining DH lesions produced severe retrograde deficits in context fear when made either 1 or 28, but not 100, days following training. Pretraining DH lesions made 1 week before training did not affect contextual fear conditioning. Tone fear was impaired by DH lesions at all training-to-lesion intervals. In Experiment 2, posttraining (1 day), but not pretraining (1 week), DH lesions produced substantial deficits in context fear using an unsignaled shock procedure. In Experiment 3, pretraining electrolytic DH lesions produced modest deficits in context fear using the same signaled and unsignaled shock procedures used in Experiments 1 and 2, respectively. Electrolytic, but not neurotoxic, lesions also increased pre-shock locomotor activity. Collectively, this pattern of results reveals that neurons in the DH are not required for the acquisition of context fear, but have a critical and time-limited role in the expression of context fear. The normal acquisition and expression of context fear in rats with neurotoxic DH lesions made before training may be mediated by conditioning to unimodal cues in the context, a process that may rely less on the hippocampal memory system.

Fetal hippocampal transplants restore conditioned blocking in rats with dorsal hippocampal lesions: effect of age

Previous studies have shown that conditioned blocking of taste aversion learning in 3-month-old Wistar rats depends on the hippocampal system integrity. Thus, the aim was to demonstrate that enough connectivity would develop after a graft to support the attention mechanism required for conditioned blocking. In the first experiment, bilateral homotopic grafts of 16–17 day-old hippocampal fetal tissue applied to 3-month-old male Wistar rats after electrolytical lesions of the dorsal hippocampus reinstated conditioned blocking tested 5 months after the transplantation. Unexpectedly, an early age-dependent impairment of conditioned blocking, similar to that induced by hippocampal lesions, was found in the 8-month-old control group. This finding was further supported by the results of the second experiment. Non-operated 3-month-old but not 8-month-old Wistar rats showed conditioned blocking. The results are discussed in terms of early hippocampal vulnerability, prevented by fetal grafts.

Electrolytic Lesions of the Fimbria/Fornix, Dorsal Hippocampus, or Entorhinal Cortex Produce Anterograde Deficits in Contextual Fear Conditioning in Rats

Recent data indicate that dorsal hippocampal (DH) lesions disrupt Pavlovian fear conditioning to contextual cues in rats. In the present study, we examined the effects of electrolytic lesions of the fimbria/fornix (FX) or entorhinal cortex (EC), the primary afferent projection systems to the DH, on contextual fear conditioning in rats. Conditioning consisted of the delivery of unsignaled footshocks in a novel observation chamber, and freezing served as the measure of conditional fear. Electrolytic lesions of the FX, DH, or EC made 1 week before training produced anterograde impairments in both immediate postshock freezing on the conditioning day and freezing during the context extinction test 24 h following training. The deficits in conditional freezing produced by FX, DH, and EC lesions were not statistically different, although the deficits in rats with FX or EC lesions tended to be more severe than those in rats with DH lesions. In addition to producing deficits in conditional freezing, FX, DH, or EC lesions produced a pronounced locomotor hyperactivity. Within the lesion and sham groups, however, locomotor activity was not significantly correlated with conditional freezing. These results indicate that contextual fear deficits in rats with hippocampal formation damage are equivalent following either FX, DH, or EC lesions. The relationship of freezing deficits and locomotor hyperactivity in rats with hippocampal formation lesions is discussed.

Spatial and visual discrimination learning in CD1 mice: Partial analogy between the effect of lesions to the hippocampus and the amygdala

CD1 mice with dorsal hippocampal and central amygdaloid lesions were submitted to three radial eight-arm maze tasks requiring various degrees of spatial and nonspatial information processing. The results show that, on the standard version of the radial maze, only hippocampal lesions disrupted performance. In the spatial four-baited path task, both hippocampal and amygdaloid lesions increased the errors and modified the patterns of arm choice. Finally, on the visually cued four-baited path task, the two lesions did not affect any quantitative aspect of performance but a strong and unexpected effect of amygdaloid lesions on the patterns of arm choice was found. Taken together, the results indicate i) an effect of hippocampal lesions in all situations that require performing a spatial discrimination, and ii) an effect of amygdaloid lesions in all situations that require distinguishing between baited and unbaited arms, whatever the modality—spatial or visual—being relevant for discriminating the two sets of arms. The analogy between the effects of hippocampal and amygdaloid lesions specifically observed in the spatial four-baited path task suggests that these two limbic areas can exert a similar control on performance in tasks involving mapping operations based upon the discrimination of rewarded and nonrewarded reinforced locations.

Contextual control of conditioned responding in rats with dorsal hippocampal lesions.

The control exerted by contextual cues over classically conditioned responding was assessed for rats with electrolytic lesions of the dorsal hippocampus and sham-operated controls. In 3 experiments the rats received initial training with 2 reinforced cues, each presented in its own distinctive context, followed by a nonreinforced test in which the cues were presented in the other context. Both control and operated subjects showed context specificity, as evidenced by less vigorous responding to these cues than to cues presented on test in their original contexts. The groups did not differ in their ability to learn an explicit discrimination in which a given cue was reinforced in one context and nonreinforced in a different context (although the groups did differ on a simple autoshaping task). It is concluded that a special role for the hippocampus in the contextual control of conditioned responding still remains to be demonstrated.

Contextual control of conditioned responding in rats with dorsal hippocampal lesions.

Contextual control of conditioned responding in rats with dorsal hippocampal lesions.

Prefrontal cortex and working memory for spatial response, spatial location, and visual object information in the rat.

In the first experiment, rats were trained on a working memory task for a spatial response (right-left turn) information using a delayed matching-to-sample procedure. Following lesions of the medial prefrontal cortex (MPF), which includes anterior cingulate and medial precentral cortex, there was a profound working memory deficit even at the shortest delay. In the second experiment, rats were trained on a working memory task for spatial location information using a delayed matching-to-sample procedure. Following lesions of the MPF, there was only a mild working memory deficit, whereas following dorsal hippocampal lesions there was a profound working memory deficit even at the shortest delay. In the third experiment, rats were trained on a working memory task for visual object information using a delayed nonmatching-to-sample procedure. Following lesions of the MPF, there were no working memory deficits, whereas following lesions of the prelimbic and infralimbic cortex there was a profound working memory deficit even at the shortest delay. The results suggest that different neural subregions of the prefrontal cortex mediate working memory for specific attribute information.

Dorsal hippocampal lesions impair blocking but not latent inhibition of taste aversion learning in rats.

The aim of the present experiments was to study the effect of nonselective electrolytic lesions of the rat dorsal hippocampus on 2 learning phenomena: the L.J. Kamin (1969) blocking effect and latent inhibition of taste aversion learning. Bilateral dorsal hippocampal lesions selectively impaired blocking induced by 1 saccharin-lithium chloride pairing previous to 1 serial compound (saccharin-cider vinegar)-lithium pairing, but lesions had no effect on latent inhibition of a saline aversion, induced by 6 saline preexposures, in the same group of animals. Moreover, dorsal hippocampal lesions did not affect latent inhibition of saccharin-conditioned aversion induced by 1 or 6 preexposures. It is argued that blocking and latent inhibition of taste aversion learning do not share a common neural mechanism.