The role of the hippocampus in object recognition in rats: examination of the influence of task parameters and lesion size

Studies examining the effects of hippocampal lesions on object recognition memory in rats have produced conflicting results. The present study investigated how methodological differences and lesion size may have contributed to these discrepancies. In Experiment 1 we compared rats with complete, partial (septal) and sham hippocampal lesions on a spontaneous object recognition task, using a protocol previously reported to result in deficits following large hippocampal lesions . Rats with complete and partial hippocampal lesions were unimpaired, suggesting the hippocampus is not required for object recognition memory. However, rats with partial lesions showed relatively poor performance raising the possibility that floor effects masked a deficit on this group. In Experiment 2, we used a second spontaneous object recognition protocol similar to that used by the two other studies that have reported deficits following hippocampal lesions . Rats with complete hippocampal lesions were significantly impaired, whereas rats with partial lesions were unimpaired. However, the complete lesion group showed less object exploration during the sample phase. Thus, the apparent recognition memory deficit in Experiment 2 may be attributable to differential encoding. Together, these findings suggest that the hippocampus is not required for intact spontaneous object recognition memory. These findings suggest that levels of object exploration during the sample phase may be a critical issue, and raise the possibility that previous reports of object recognition deficits may be due to differences in object exploration rather than deficits in object recognition per se.     

Object recognition memory in the rat: the role of the hippocampus.

Object recognition memory of rats with fimbria-fornix or ventral temporal lesions was evaluated with a behavioral protocol (delayed non-matching-to-sample task with trial-unique stimuli) similar to that used to test recognition functions in primates. Animals with damage to the hippocampal system showed no evidence of lasting impairment on the object recognition task with retention intervals up to 30 s. In contrast, rats with fimbria-fornix lesions displayed severe and enduring deficits on a test of spatial memory, i.e. rewarded alternation, with but 5 s delays. These results provide further evidence that a dissociation exists between the types of memory that are and are not lost following damage to the hippocampus. Whereas the hippocampus is necessary for some types of mnemonic processes, other types of recognition functions (e.g. perceptual recognition) may be fully mediated in regions of sensory and/or association neocortex without the involvement of the hippocampus.     

Associative recognition and the hippocampus: Differential effects of hippocampal lesions on object‐place,object‐context and object‐place‐context memory

The hippocampus is thought to be required for the associative recognition of objects together with the spatial or temporal contexts in which they occur. However, recent data showing that rats with fornix lesions perform as well as controls in an object‐place task, while being impaired on an object‐place‐context task (Eacott and Norman ( 2004 ) J Neurosci 24:1948–1953), suggest that not all forms of context‐dependent associative recognition depend on the integrity of the hippocampus. To examine the role of the hippocampus in context‐dependent recognition directly, the present study tested the effects of large, selective, bilateral hippocampus lesions in rats on performance of a series of spontaneous recognition memory tasks: object recognition, object‐place recognition, object‐context recognition and object‐place‐context recognition. Consistent with the effects of fornix lesions, animals with hippocampus lesions were impaired only on the object‐place‐context task. These data confirm that not all forms of context‐dependent associative recognition are mediated by the hippocampus. Subsequent experiments suggested that the object‐place task does not require an allocentric representation of space, which could account for the lack of impairment following hippocampus lesions. Importantly, as the object‐place‐context task has similar spatial requirements, the selective deficit in object‐place‐context recognition suggests that this task requires hippocampus‐dependent neural processes distinct from those required for allocentric spatial memory, or for object memory, object‐place memory or object‐context memory. Two possibilities are that object, place, and context information converge only in the hippocampus, or that recognition of integrated object‐place‐context information requires a hippocampus‐dependent mode of retrieval, such as recollection. © 2009 Wiley‐Liss, Inc.     

Lateral entorhinal cortex is critical for novel object‐context recognition

Episodic memory incorporates information about specific events or occasions including spatial locations and the contextual features of the environment in which the event took place. It has been modeled in rats using spontaneous exploration of novel configurations of objects, their locations, and the contexts in which they are presented. While we have a detailed understanding of how spatial location is processed in the brain relatively little is known about where the nonspatial contextual components of episodic memory are processed. Initial experiments measured c‐fos expression during an object‐context recognition (OCR) task to examine which networks within the brain process contextual features of an event. Increased c‐fos expression was found in the lateral entorhinal cortex (LEC; a major hippocampal afferent) during OCR relative to control conditions. In a subsequent experiment it was demonstrated that rats with lesions of LEC were unable to recognize object‐context associations yet showed normal object recognition and normal context recognition. These data suggest that contextual features of the environment are integrated with object identity in LEC and demonstrate that recognition of such object‐context associations requires the LEC. This is consistent with the suggestion that contextual features of an event are processed in LEC and that this information is combined with spatial information from medial entorhinal cortex to form episodic memory in the hippocampus. © 2013 Wiley Periodicals, Inc.     

Dorsal hippocampal lesions boost performance in the rat sequential reaction time task

It is commonly accepted that the hippocampus plays a major role in declarative memory across species and that it is of particular relevance for spatial memory in rodents. However, the interplay between hippocampal function and nondeclarative memory systems, such as procedural stimulus-response (S-R) or sequential learning, is less clear: depending on task requirements, an interaction, dissociation or interference between hippocampal function and other memory systems may occur. This study was conducted to investigate the influence of dorsal ibotenic hippocampal lesions on learning and performance of sequential behavior in a rat version of the serial reaction time task (SRTT). Magnetic resonance imaging (MRI) analyses of the lesions revealed a bilateral volume reduction of ≈ 46% (histological analyses: ≈ 59%) of the total hippocampus. They were largely confined to its dorsal part and led to an expected spatial memory deficits in an object place recognition test as compared to healthy controls, even though sham lesions had the same effect. Our earlier studies on sequential learning had revealed substantial impairments in case of dorsal striatal dopaminergic lesions. In the present study, however, hippocampal lesioned animals unexpectedly showed superior performance throughout SRTT testing and training as compared to controls, which resulted in a higher degree of subsequent automated sequential behavior. Thus, our data reveal the infrequent case where hippocampal lesions lead to long-term improvements in test performance of a type of rather complex procedural behavior. One possible explanation for this effect is that hippocampal activity in rodents can interfere with other memory systems during the acquisition of procedural tasks with very low spatial requirements, as used here. Alternative explanations for the observed superior SRTT performance in lesioned animals, such as hyperactivity or increased exploratory drive are also topic of the discussion.     

The effects of hippocampal lesions upon spatial and non-spatial tests of working memory

A series of experiments examined the proposal that the primary effect of hippocampal damage in rats is to disrupt working memory. Although extensive hippocampal lesions produced a severe impairment in forced-choice alternation--a test of spatial working memory--the same lesions did not impair the acquisition of a non-spatial test of working memory--delayed non-matching-to-sample. This test of object recognition required the rats to select that arm in a Y-maze which contained unfamiliar stimuli. Rats with hippocampal lesions were able to learn and perform this task at normal rates, even with retention delays of as long as 60 s. Two additional experiments helped confirm that the animals had indeed learnt a non-spatial test of working memory. The final experiment examined whether hippocampal lesions resulted in an increased sensitivity to proactive interference. It was found that repetition of test stimuli within a session, which increased interference, did attenuate recognition performance but there was no evidence that the animals with hippocampal lesions were differentially affected.     

Equivalent impairment of spatial and nonspatial memory following damage to the human hippocampus.

The hippocampus has sometimes been proposed to function as a cognitive map, a memory system that stores information about allocentric space. Work with experimental animals and memory-impaired patients has raised difficulties with this view by showing that the hippocampus is not performing an exclusively spatial function. However, the possibility has remained that the hippocampus plays a special role in spatial memory or a disproportionately large role in spatial memory compared to other kinds of memory. This study compared spatial and nonspatial memory in amnesic patients with lesions of the hippocampal formation or diencephalon. Subjects studied an array of 16 toy objects and were subsequently tested for object recall, object recognition, and memory for the location of the objects. Control subjects were tested after long retention intervals in order to equate their object memory performance with that of the patients. The main finding was that, when the performance of amnesic patients on the object memory tests was matched to the object memory performance of control subjects, spatial memory performance of the amnesic patients also matched the spatial memory performance of the control subjects. The results were the same for the two groups of patients. These findings suggest that the hippocampus is not especially involved in spatial memory. Spatial memory is simply one instance of a broader category of memory that requires the hippocampus. While cognitive mapping in its most abstract sense may describe hippocampal function, our results support alternative formulation, suggesting that the hippocampus is necessary for the rapid acquisition of relational, configural, or declarative (as opposed to purely spatial) information.     

Spared place and object-place learning but limited spatial working memory capacity in rats with selective lesions of the dentate gyrus

We studied the cognitive performance of rats with colchicine-induced lesions of the hippocampal dentate gyrus (DG) on a range of spatial, non-spatial and mixed spatial/procedural tasks. Rats were assigned to three experimental groups receiving large colchicine lesions (7 microg per hippocampus), small colchicine lesions (1.75 microg per hippocampus) or sham lesions. Stereological estimates of cell density indicated that the colchicine treatments induced dose-dependent damage to the DG, while sparing in large part other hippocampal subfields. Remarkably, the behavioural results showed that the colchicine lesions did not affect the performance of rats in an object discrimination task, in an object-place associative task in which a familiar object was displaced from a given position nor in a spontaneous spatial discrimination task performed in the T-maze. However, rats in both lesion groups were severely impaired in a reinforced non-matching-to-position working memory task conducted in the T-maze. Importantly, performance in the working memory task correlated strongly with cell density in the DG but not with cell density in the CA1 and CA3 areas. Only rats with large-lesions showed a transient deficit in a reinforced rule-based conditional discrimination task. These data demonstrated that rats with selective lesions of the DG readily acquire and retain neural representations relative to objects and places but are specifically impaired in their ability to update rapidly and flexibly spatial information that is essential to guide goal-directed actions.     

Hippocampal lesioned rats are able to learn a spatial position using non-spatial strategies

In the last two decades, many experiments have demonstrated that the hippocampus plays a role in the learning and processing of spatial and contextual information. Despite these demonstrations, some recent publications have indicated that the hippocampus is not the only structure involved in spatial learning and that even after hippocampal lesions, rats can perform spatial tasks. However, it is not well established whether animals with hippocampal dysfunction still have some spatial learning capacities or develop non-spatial solutions; these may require lengthier acquisition training. We now report the effects of conventional, dorsal hippocampal ablation on rats' performance on the water maze. We tested rats using a short (4 days) versus a long (16 days) acquisition period. We demonstrated that animals with dorsal hippocampal lesions have some residual capacity for learning the localization of a hidden escape platform in a pool during both a reference memory task and a working memory task. The animals with dorsal hippocampal lesions learned to escape at a fixed location, but only with extended training. It is suggested that these animals used non-spatial strategies to compensate for a spatial memory impairment. The results are discussed with respect to the experimental procedure and the strategy applied by the lesioned rats.     

Disconnecting hippocampal projections to the anterior thalamus produces deficits on tests of spatial memory in rats

A disconnection procedure was used to test whether projections from the hippocampus to the anterior thalamic nuclei (AT), via the fimbria-fornix (FX), form functional components of a spatial memory system. The behavioural effects of combined unilateral lesions in the AT and FX were compared when they were either in contralateral hemispheres (AT-FX Contra) or the same hemisphere (AT-FX Ipsi). Other groups received bilateral FX lesions and Sham surgeries. Expt 1 demonstrated that none of these lesions affected performance of an object recognition task, while performance of an object location task, which tests the subjects' preference for an object that has changed location, was impaired in the AT-FX Contra and FX groups. In a T-maze alternation task, however, the FX group was severely impaired while both the AT-FX Ipsi and AT-FX Contra lesion groups showed only a mild impairment. In order to test whether spared crossed projections might support spatial performance in the AT-FX Contra group we then examined the effects of a combined AT-FX Contra lesion coupled with transection of the hippocampal commissure. This combination of lesions produced a severe disruption in spatial memory performance in the water maze, radial arm maze and T-maze, which was significantly greater than that produced by ipsilateral and contralateral AT-FX lesions alone. These results support the notion that disconnection of the AT from their hippocampal inputs produces impairments on a range of spatial memory tasks, but indicate that there are an array of different routes that can subserve this function.     

A comparison of egocentric and allocentric spatial memory in a patient with selective hippocampal damage

The spatial memory of a single patient (YR) was investigated. This patient, who had relatively selective bilateral hippocampal damage, showed the pattern of impaired recall but preserved item recognition on standardised memory tests that has been suggested by Aggleton and Shaw [Aggleton JP, Shaw C. Amnesia and recognition memory: a reanalysis of psychometric data. Neuropsychologia 1996;34:51-62] to be a consequence of Papez circuit lesions. YR was tested on three recall tests and one recognition test for visuospatial information. The initial recall test assessed visuospatial memory over very short unfilled delays and YR was not significantly impaired. This test was then modified to test recall of allocentric and egocentric spatial information separately after filled delays of between 5 and 60 s. YR was found to be more impaired at recalling allocentric than egocentric information after a 60 s interval with a tendency for the impairment to increase up to this delay. Recognition of allocentric spatial information was also assessed after delays of 5 and 60 s. YR was impaired after the 60 s delay. The results suggest that the human hippocampus has a greater involvement in allocentric than egocentric spatial memory, and that this most likely concerns the consolidation of allocentric information into long-term memory rather than the initial encoding of allocentric spatial information. The findings also suggest that YR's item recognition/free recall deficit pattern reflects a problem retrieving or storing certain kinds of associative information.     

Vestibular loss promotes procedural response during a spatial task in rats

Declarative memory refers to a spatial strategy using numerous sources of sensory input information in which visual and vestibular inputs are assimilated in the hippocampus. In contrast, procedural memory refers to a response strategy based on motor skills and familiar gestures and involves the striatum. Even if vestibular loss impairs hippocampal activity and spatial memory, vestibular‐lesioned rats remain able to find food rewards during complex spatial memory task. Since hippocampal lesions induce a switch from declarative memory to procedural memory, we hypothesize that vestibular‐lesioned rats use a strategy other than that of hippocampal spatial response to complete the task and to counterbalance the loss of vestibular information. We test, in a reverse T‐maze paradigm, the types of strategy vestibular‐lesioned rats preferentially uses in a spatial task. We clearly demonstrate that all vestibular‐lesioned rats shift to a response strategy to solve the spatial task, while control rats use spatial and response strategies equally. We conclude that the loss of vestibular informations leading to spatial learning impairments is not offset at the hippocampus level by integration process of other sense mainly visual informations; but favors a response strategy through procedural memory most likely involving the striatum, cerebellum, and motor learning. © 2014 Wiley Periodicals, Inc.     

Rats with lesions of the hippocampus are impaired on the delayed nonmatching-to-sample task

Rats with ibotenic acid lesions of the hippocampus (H-IBO) were trained on the trial-unique delayed nonmatching-to-sample task (DNMS) using a short delay of 4 s. The H-IBO group learned the nonmatching rule as quickly as control animals. However, performance was impaired on the DNMS task when the delay between the sample and choice phase was increased to 1 or 2 min. The use of 4-s delay (probe) trials indicated that the H-IBO animals retained the nonmatching-to-sample rule throughout testing. In a second experiment, using the same groups of rats, extended training at the 1-min delay did not ameliorate the deficit produced by H-IBO lesions. The finding of impaired recognition memory in rats after hippocampal lesions is consistent with findings from humans and monkeys. Several methodological issues are considered that have complicated the interpretation of earlier studies of recognition memory in rats following hippocampal lesions. The capacity for recognition memory in humans, monkeys, and rodents is discussed as a straightforward example of hippocampus-dependent (declarative) memory.     

Cooperation between the hippocampus and the entorhinal cortex in spatial memory: a disconnection study

It has been recently shown that lesions of parahippocampal areas including the entorhinal cortex do not disrupt place learning in the water maze, suggesting that the hippocampo-cortical circuitry is not important for spatial memory [Burwell RD, Saddoris MP, Bucci DJ, Wiig KA. Corticohippocampal contributions to spatial and contextual learning. J Neurosci 2004;24:3826-36]. The aim of the present study was to tax more directly the cooperation between the hippocampus and entorhinal cortex in two different spatial tasks, a place navigation task and a spontaneous object exploration task, using a disconnection procedure. Damaging the entorhinal-hippocampal system induced impairments in the two tasks but only in the spatial object exploration task rats with contralateral lesions displayed a greater deficit than rats with ipsilateral lesions. The results suggest that the cooperation between the hippocampus and the entorhinal cortex is modulated by the nature of the task and the cognitive processes involved in formation of spatial memory.     

Effects of discrete kainic acid-induced hippocampal lesions on spatial and contextual learning and memory in rats

Substantial information is available concerning the influence of global hippocampal lesions on spatial learning and memory, however the contributions of discrete subregions within the hippocampus to these functions is less well understood. The present investigation utilized kainic acid to bilaterally lesion specific areas of the rat hippocampus. These animals were subsequently tested on a spatial orientation task using a circular water maze, and on an associative/contextual task using passive avoidance conditioning. The results indicate that both the dorsal CA1 and the ventral CA3 subregions play important roles in learning. Specifically, CA1 lesions produced a deficit in the acquisition of the water maze task and a significant memory impairment on the passive avoidance task. CA3 lesions also caused learning deficits in the acquisition of the water maze task, and produced even greater impairments in performance on the passive avoidance task. We conclude that CA1 and CA3 hippocampal subregions each play significant roles in the overall integration of information concerning spatial and associative learning.     

Hippocampal lesions produce both nongraded and temporally graded retrograde amnesia in the same rat

Rats were administered contextual fear conditioning and trained on a water‐maze, spatial memory task 28 days or 24 h before undergoing hippocampal lesion or control surgery. When tested postoperatively on both tasks, rats with hippocampal lesions exhibited retrograde amnesia for spatial memory at both delays but temporally graded retrograde amnesia for the contextual fear response. In demonstrating both types of retrograde amnesia in the same animals, the results parallel similar observations in human amnesics with hippocampal damage and provide compelling evidence that the nature of the task and the type of information being accessed are crucial factors in determining the pattern of retrograde memory loss associated with hippocampal damage. The results are interpreted as consistent with our transformation hypothesis (Winocur et al. (2010a) Neuropsychologia 48:2339–2356; Winocur and Moscovitch (2011) J Int Neuropsychol Soc 17:766–780) and at variance with standard consolidation theory and other theoretical models of memory. © 2013 Wiley Periodicals, Inc.     

Effects of hippocampal lesions on patterned motor learning in the rat

Motor skill learning in rats has been linked to cerebellar function as well as to cortical and striatal influences. The present study evaluated the contribution of the hippocampus to motor learning. Adult male rats received electrolytic lesions designed to selectively destroy the hippocampus; a sham-lesioned group of animals served as a control. The animals with hippocampal lesions acquired a patterned motor learning task as well as sham controls. In contrast, rats with hippocampal lesions were impaired in spatial, but not cued, learning in the Morris water maze. In addition, lesioned rats showed profound impairment in the novel object recognition memory task, when a 1-h delay was used between training and testing. Taken together, these results suggest that the hippocampus is not necessary during acquisition of the motor learning task.     

A single early-life seizure impairs short-term memory but does not alter spatial learning,recognition memory,or anxiety

The impact of a single seizure on cognition remains controversial. We hypothesized that a single early-life seizure (sELS) on rat Postnatal Day (P) 7 would alter only hippocampus-dependent learning and memory in mature (P60) rats. The Morris water maze, the novel object and novel place recognition tasks, and contextual fear conditioning were used to assess learning and memory associated with hippocampus/prefrontal cortex, perirhinal/hippocampal cortex, and amygdala function, respectively. The elevated plus maze and open-field test were used to assess anxiety associated with the septum. We report that sELS impaired hippocampus-dependent short-term memory, but not spatial learning or recall. sELS did not disrupt performance in the novel object and novel place recognition tasks. Contextual fear conditioning performance suggested intact amydgala function. sELS did not change anxiety levels as measured by the elevated plus maze or open-field test. Our data suggest that the long-term cognitive impact of sELS is limited largely to the hippocampus/prefrontal cortex.     

A single early-life seizure impairs short-term memory but does not alter spatial learning, recognition memory, or anxiety

The impact of a single seizure on cognition remains controversial. We hypothesized that a single early-life seizure (sELS) on rat Postnatal Day (P) 7 would alter only hippocampus-dependent learning and memory in mature (P60) rats. The Morris water maze, the novel object and novel place recognition tasks, and contextual fear conditioning were used to assess learning and memory associated with hippocampus/prefrontal cortex, perirhinal/hippocampal cortex, and amygdala function, respectively. The elevated plus maze and open-field test were used to assess anxiety associated with the septum. We report that sELS impaired hippocampus-dependent short-term memory, but not spatial learning or recall. sELS did not disrupt performance in the novel object and novel place recognition tasks. Contextual fear conditioning performance suggested intact amydgala function. sELS did not change anxiety levels as measured by the elevated plus maze or open-field test. Our data suggest that the long-term cognitive impact of sELS is limited largely to the hippocampus/prefrontal cortex.     

Dentate gyrus mediates cognitive function in the Ts65Dn/DnJ mouse model of down syndrome

In the Ts65Dn/DnJ mouse model of Down syndrome (DS), hippocampal deficits of learning and memory are the most robust features supporting this mouse as a valid cognitive model of DS. Although dentate gyrus (DG) dysfunction is suggested by excessive GABAergic inhibition, its role in perturbing DG functions in DS is unknown. We hypothesize that in the Ts65Dn/DnJ mouse, the specific role of the DG is disturbed in its support of contextual and spatial information. Support for this hypothesis comes from rats with DG lesions that show similar deficits. In order to test this hypothesis, we have developed a novel series of spontaneous exploratory tasks that emphasize the importance of recognizing spatial and contextual cues and that involve DG function. The results with this exploratory battery show that Ts65Dn/DnJ mice are impaired in DG‐dependent short‐term recognition tests involving object recognition with contextual cues, in place recognition and in metric distance recognition relative to wild type littermate controls. Further, whereas Ts65Dn/DnJ mice can recognize object novelty in the absence of contextual cues after a 5‐min delay, they cannot do so after a delay of 24 h, suggesting a problem with CA1‐mediated consolidation. The results also show that Ts65Dn/DnJ mice are not impaired in tasks (object recognition and configural object recognition) that are mediated by the perirhinal cortex (PRh). These results implicate the DG as a specific therapeutic target and the PRh as a potential therapeutic strength for future research to ameliorate learning and memory in DS. © 2013 Wiley Periodicals, Inc.