Effects Of Hippocampal Lesions Research Articles

Behavior is movement only but how to interpret it? Problems and pitfalls in translational neuroscience-a 40-year experience.

Translational research in behavioral neuroscience seeks causes and remedies for human mental health problems in animals, following leads imposed by clinical research in psychiatry. This endeavor faces several problems because scientists must read and interpret animal movements to represent human perceptions, mood, and memory processes. Yet, it is still not known how mammalian brains bundle all these processes into a highly compressed motor output in the brain stem and spinal cord, but without that knowledge, translational research remains aimless. Based on some four decades of experience in the field, the article identifies sources of interpretation problems and illustrates typical translational pitfalls. (1) The sensory world of mice is different. Smell, hearing, and tactile whisker sensations dominate in rodents, while visual input is comparatively small. In humans, the relations are reversed. (2) Mouse and human brains are equated inappropriately: the association cortex makes up a large portion of the human neocortex, while it is relatively small in rodents. The predominant associative cortex in rodents is the hippocampus itself, orchestrating chiefly inputs from secondary sensorimotor areas and generating species-typical motor patterns that are not easily reconciled with putative human hippocampal functions. (3) Translational interpretation of studies of memory or emotionality often neglects the ecology of mice, an extremely small species surviving by freezing or flight reactions that do not need much cognitive processing. (4) Further misinterpretations arise from confounding neuronal properties with system properties, and from rigid mechanistic thinking unaware that many experimentally induced changes in the brain do partially reflect unpredictable compensatory plasticity. (5) Based on observing hippocampal lesion effects in mice indoors and outdoors, the article offers a simplistic general model of hippocampal functions in relation to hypothalamic input and output, placing hypothalamus and the supraspinal motor system at the top of a cerebral hierarchy. (6) Many translational problems could be avoided by inclusion of simple species-typical behaviors as end-points comparable to human cognitive or executive processing, and to rely more on artificial intelligence for recognizing patterns not classifiable by traditional psychological concepts.

Scalar timing in memory: A temporal map in the hippocampus

Many essential tasks, such as decision making, rate calculation and planning, require accurate timing in the second to minute range. This process, known as interval timing, involves many cortical areas such as the prefrontal cortex, the striatum, and the hippocampus. Although the neurobiological origin and the mechanisms of interval timing are largely unknown, we have developed increasingly accurate mathematical and computational models that can mimic some properties of time perception. The accepted paradigm of temporal durations storage is that the objective elapsed time from the short-term memory is transferred to the reference memory using a multiplicative “memory translation constant” K*. It is believed that K* has a Gaussian distribution due to trial-related variabilities. To understand K* genesis, we hypothesized that the storage of temporal memories follows a topological map in the hippocampus, with longer durations stored towards dorsal hippocampus and shorter durations stored toward ventral hippocampus. We found that selective removal of memory cells in this topological map model shifts the peak-response time in a manner consistent with the current experimental data on the effect of hippocampal lesions on time perception. This opens new avenues for experimental testing of our topological map hypothesis. We found numerically that the relative shift is determined both by the lesion size and its location and we suggested a theoretical estimate for the memory translation constant K*.

Environmental Anchoring of Head Direction in a Computational Model of Retrosplenial Cortex.

The activity of head direction cells signals the direction of an animal's head relative to landmarks in the world. Although driven by internal estimates of head movements, head direction cells must be kept aligned to the external world by sensory inputs, which arrive in the reference frame of the sensory receptors. We present a computational model, which proposes that sensory inputs are correctly associated to head directions by virtue of a conjunctive representation of place and head directions in the retrosplenial cortex. The model allows for a stable head direction signal, even when the sensory input from nearby cues changes dramatically whenever the animal moves to a different location, and enables stable representations of head direction across connected environments.

The effects of hippocampal lesions on MRI measures of structural and functional connectivity.

ABSTRACTFocal lesions can affect connectivity between distal brain regions (connectional diaschisis) and impact the graph‐theoretic properties of major brain networks (connectomic diaschisis). Given its unique anatomy and diverse range of functions, the hippocampus has been claimed to be a critical “hub” in brain networks. We investigated the effects of hippocampal lesions on structural and functional connectivity in six patients with amnesia, using a range of magnetic resonance imaging (MRI) analyses. Neuropsychological assessment revealed marked episodic memory impairment and generally intact performance across other cognitive domains. The hippocampus was the only brain structure exhibiting reduced grey‐matter volume that was consistent across patients, and the fornix was the only major white‐matter tract to show altered structural connectivity according to both diffusion metrics. Nonetheless, functional MRI revealed both increases and decreases in functional connectivity. Analysis at the level of regions within the default‐mode network revealed reduced functional connectivity, including between nonhippocampal regions (connectional diaschisis). Analysis at the level of functional networks revealed reduced connectivity between thalamic and precuneus networks, but increased connectivity between the default‐mode network and frontal executive network. The overall functional connectome showed evidence of increased functional segregation in patients (connectomic diaschisis). Together, these results point to dynamic reorganization following hippocampal lesions, with both decreased and increased functional connectivity involving limbic‐diencephalic structures and larger‐scale networks. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

The hippocampus

The hippocampus

Evidences of the role of the rodent hippocampus in the non-spatial recognition memory

The hippocampus is a key region responsible for processing spatial information. However, the role of the hippocampus in non-spatial recognition memory is still controversial. In the present study, we performed hippocampal lesioning to address this controversy. The hippocampi of mice were disrupted with bilateral cytotoxic lesions, and standard object recognition (non-spatial) and object location recognition (spatial) were tested. In the habituation period, mice with hippocampal lesions needed a significantly longer time to fully habituate to the test box. Interestingly, after 4 days of habituation (insufficient habituation), the recognition index was similar in the sham and hippocampal lesion groups. However, exploration time was significantly shorter in mice with hippocampal lesions compared with that in control mice. Interestingly, if mice were subjected to a 10-days-long period of habituation (full habituation), the recognition index was significantly lower in mice with hippocampal lesions compared with that in control mice; however, total exploration time was similar in both groups. Furthermore, the object recognition test after full habituation occluded hippocampal long-term potentiation, a cellular model of memory. These results indicate that sufficient habituation is required to observe the effects of hippocampal lesions on object recognition memory.

Hippocampal lesion and transitive inference: dissociation of inference-based and reinforcement-based strategies in pigeons.

A typical nonverbal transitive inference task (TI) consists of several overlapping discriminations (A+ B-, B+ C-, C+ D-, D+ E-, where letters indicate stimuli and pluses and minuses denote reinforcement and nonreinforcement). A choice of stimulus B in a novel pair BD is interpreted as indicative of a TI (if B > C and C > D, then B > D). Although hippocampus has been implicated in nonverbal TI, it is not clear whether it simply maintains memory of associative values or stores an ordered representation of stimuli. We investigated the effect of hippocampal lesion on TI in pigeons while controlling reinforcement history so that reliance on associative values would lead to a choice of a stimulus D in the pair BD instead of a choice of a stimulus B expected by inferential mechanisms. Prior to the lesion, some of the pigeons (relational group; n = 4) have selected B over D indicating TI, while other birds (associative group; n = 6) chose D over B suggesting reliance on associative values. Hippocampal lesion had no effect on postlesion performance in associative group. In contrast, the relational group that preferred stimulus B in a pair BD before lesion showed a near-chance performance after the lesion. Our results demonstrate that hippocampus may be involved in creating a representation of an ordered series of the stimuli instead of maintaining reinforcement history of each stimulus. In addition, we provide a behavioral procedure suitable for dissociating different behavioral strategies used to solving TI task. Finally, we show for the first time the involvement of avian hippocampus in the task that is not explicitly spatial in nature. These results further confirm the notion that avian hippocampus is functionally analogous to mammalian hippocampus despite the significant differences in their anatomy.

Inhibition, the final frontier: The impact of hippocampal lesions on behavioral inhibition and spatial processing in pigeons.

Two commonly accepted functions of the mammalian hippocampus are the processing of spatial information and behavioral inhibition. Although there is clear evidence that the avian hippocampus is also critical for the processing of spatial information, there is a dearth of evidence that it plays a role in behavioral inhibition. In Experiment 1, the effect of hippocampal lesions on behavioral inhibition in pigeons was assessed. Control and hippocampal lesioned pigeons were trained to peck stimuli that were associated with one of three probabilities of reinforcement (40%, 70%, or 100%). The number of pecks that control pigeons distributed to each stimulus was directly related to its respective probability of reinforcement. In contrast, hippocampal lesioned pigeons distributed their pecks evenly across the three stimuli. In Experiment 2, we tested whether these pigeons also displayed the well-accepted spatial deficit. Consistent with previous work, control pigeons acquired the radial arm maze in significantly fewer trials than the hippocampal lesioned pigeons. Together, Experiments 1 and 2 demonstrate that, much like the mammalian hippocampus, the avian hippocampus is critical to behavioral inhibition and spatial processing.

Crossmodal object recognition in rats with and without multimodal object pre-exposure: No effect of hippocampal lesions

The neural mechanisms and brain circuitry involved in the formation, storage, and utilization of multisensory object representations are poorly understood. We have recently introduced a crossmodal object recognition (CMOR) task that enables the study of such questions in rats. Our previous research has indicated that the perirhinal and posterior parietal cortices functionally interact to mediate spontaneous (tactile-to-visual) CMOR performance in rats; however, it remains to be seen whether other brain regions, particularly those receiving polymodal sensory inputs, contribute to this cognitive function. In the current study, we assessed the potential contribution of one such polymodal region, the hippocampus (HPC), to crossmodal object recognition memory. Rats with bilateral excitotoxic HPC lesions were tested in two versions of crossmodal object recognition: (1) the original CMOR task, which requires rats to compare between a stored tactile object representation and visually-presented objects to discriminate the novel and familiar stimuli; and (2) a novel ‘multimodal pre-exposure’ version of the CMOR task (PE/CMOR), in which simultaneous exploration of the tactile and visual sensory features of an object 24h prior to the sample phase enhances CMOR performance across longer retention delays. Hippocampus-lesioned rats performed normally on both crossmodal object recognition tasks, but were impaired on a radial arm maze test of spatial memory, demonstrating the functional effectiveness of the lesions. These results strongly suggest that the HPC, despite its polymodal anatomical connections, is not critically involved in tactile-to-visual crossmodal object recognition memory.

The Hippocampus of Food-Storing Birds

when we examined sections from our control birds we saw something very striking. The hippocampus was clearly much larger in chickadees than shown in the atlas. Where the canary atlas showed a smooth curve as the dorsal surface of the brain travelled medially and descended between the hemispheres, the chickadees had a large bump. Previous work by many researchers on the songbird brain had prepared us for the idea that regions of the bird brain could vary between species. Song control nuclei vary in relative size between species and it seemed a likely hypothesis that food-storing birds, which can remember the spatial location of thousands of scattered food caches, might have a hippocampus that was bigger than the hippocampus of non-storing birds. With help from the Long Point Bird Observatory in Ontario, Anthony and I began collecting food-storing and nonstoring birds, sectioning the brains and measuring the relative size of the hippocampus. I contacted my former postdoctoral supervisor at Oxford, John Krebs, and John proposed that his team would collect European species in a parallel project. In Canada, Anthony and I, with help from George Wallace and the banders at Long Point, were able to collect individuals of 23 species from 3 food-storing families (chickadees, nuthatches and jays) and 10 non-food-storing families and subfamilies (wrens, kinglets, thrushes, mimids, starlings, warblers, cardinals, buntings, finchIn 1984–1985, Anthony Vaccarino and I performed a number of experiments on the effects of hippocampal lesions on the accuracy of cache recovery in food-storing black-capped chickadees [Sherry and Vaccarino, 1989]. Like most research, the genesis of this project involved many people. I presented a poster on memory for cache sites at the Neurobiology of Learning and Memory meeting in Irvine, Calif. in 1984 and Larry Squire pointed out to me that the obvious next experiment was to test for hippocampal involvement. I mentioned this idea to my friend Michael Leon at the same meeting, noting that I had no experience doing neurosurgery on 11-gram passerine birds and Michael, with his usual aplomb said that was no problem, there were colleagues at my own institution, the University of Toronto, like Alison Fleming, who could easily teach me the surgical skills. Alison introduced me to Anthony, who was working in Alison’s lab as an undergraduate, and we were on our way. We found that hippocampal lesions severely disrupted the ability of chickadees to find their caches. Fortunately for us, the birds continued to make caches and search for them, they just searched in the wrong places. This work formed part of Anthony’s undergraduate thesis and we published the paper in Behavioral Neuroscience in 1989 [Sherry and Vaccarino, 1989]. We had used the Stokes, Leonard and Nottebohm canary brain atlas [Stokes et al., 1974] as a guide to lesion placement but Published online: August 26, 2011

Hippocampus lesions induced deficits in social and spatial recognition in Octodon degus

Previous studies of rodents reported that the hippocampus plays an important role in social behavior as well as spatial behavior. However, there are inconsistencies between reports of the effects of hippocampal lesions on social behavior. The present study sought to clarify the aspects of social behavior in which the hippocampus plays a role in the degu, Octodon degus, a social rodent. We examined the effects of hippocampal lesions on social behavior in the degu using familiar and novel partners. When placed in a familiar environment with a familiar partner after surgery, sham operation control (S.Cont) degus exhibited affinitive behavior longer compared with hippocampal lesioned (HPC) degus. In a novel environment, S.Cont degus exhibited longer aggressive behavior toward novel partners, and longer affinitive behavior with familiar partners compared with HPC degus. HPC degus did not show evidence of differentiation in social behavior, regardless of partner's novelty. The results of an anxiety test confirmed that these findings could not be attributed to changes in emotional state. We conducted an object-recognition test with the same subjects. HPC degus showed an impairment in spatial recognition but not object recognition. Taken together, these results suggest that the degu hippocampus plays an important role not only in spatial recognition but also social recognition. The changes in social behavior resulting from hippocampal lesions were interpreted as due to an impairment of social recognition rather than an impairment in novelty detection.

Pattern memory involves both elemental and configural processes: Evidence from the effects of hippocampal lesions.

The formation of an integrated memory for a pattern of stimulation could be based on the elements of that pattern becoming directly linked to one another, or by each of the elements becoming linked to a shared separate configural representation. These 2 accounts have proven difficult to discriminate between. Here, rats received exposure to four patterns of stimulation, each consisting of an auditory stimulus, a visual context, and a time of day; and we examined whether pre-training lesions to the hippocampus influenced memory for the patterns. These lesions abolished pattern memory that required configural processes (Experiments 1A and 1B) but had no effect on pattern memory that could be supported by elemental processes (Experiment 2). This dissociation provides support for the views that elemental and configural processes ordinarily support pattern memory and that rats with lesions to the hippocampus are left reliant on elemental processes. (

An investigation of the effects of hippocampal lesions in rats on pre‐ and postoperatively acquired spatial memory in a complex environment

In previous work, we showed that adult rats that were reared socially for 3 months in a complex (village) environment retained allocentric spatial memory for that environment following hippocampal lesions (Winocur et al., (2005) Nat Neurosci 8:273–275). In the present series of experiments, we showed that 3 months of postoperative rearing did not confer the same benefits (Experiment 1), although hippocampal groups, with or without rearing experience, exhibited spatial learning after extensive training (Experiments 1 and 2). Experiment 3 showed that as little as 2 weeks of preoperative rearing in the village was sufficient to retain acquired spatial memories after hippocampal lesions. Probe testing revealed that, although rats with hippocampal lesions exhibited remarkably good memory for preoperatively learned locations in the village, they were impaired when changes in task demands required flexible use of existing spatial representations. In a direct test of flexibility (Experiment 4), preoperatively reared rats were administered a blockedroutes task in the original learning environment, in which on designated trials, a barrier was placed across one of the direct paths to the goal compartment. On encountering the barrier, control rats consistently selected the next most direct route, whereas rats with hippocampal lesions, despite using spatial strategies, made more errors and took longer to find the goal. The present results confirm that allocentric spatial memories can survive hippocampal damage but they are schematic in nature and less cohesive than those associated with cognitive maps in intact brains. As well, there was evidence that, although different processes are involved in their formation, the schematic memories that were acquired preoperatively and survived hippocampal lesions are essentially the same as those laboriously formed postoperatively after extensive training.

Hippocampal lesion effects on occasion setting by contextual and discrete stimuli

Three experiments examined the role of the dorsal hippocampus (dHIPP) in occasion setting with diffuse contextual and discrete light stimuli serving as occasion setters in classical fear conditioning with rats. Both sham-operated and dHIPP-lesioned animals readily learned a L→T+, T− serial feature-positive discrimination in which a light (L) “set the occasion” for reinforcement of a tone (T+). dHIPP-lesioned animals were deficient, however, in acquiring a similar discrimination in which different contexts (A and B) served as occasion setters, i.e., A(T+) and B(T−). The lesioned animals also failed to discriminate between a context in which a tone had been partially reinforced and a context in which no conditioning had taken place, whereas sham-operated animals froze more to the tone in the conditioned context than in the novel context. Collectively, the data indicate that the dorsal hippocampus is important in processing information about the signaling value of contextual, but not discrete, stimuli.

Object recognition memory and the rodent hippocampus.

In rodents, the novel object recognition task (NOR) has become a benchmark task for assessing recognition memory. Yet, despite its widespread use, a consensus has not developed about which brain structures are important for task performance. We assessed both the anterograde and retrograde effects of hippocampal lesions on performance in the NOR task. Rats received 12 5-min exposures to two identical objects and then received either bilateral lesions of the hippocampus or sham surgery 1 d, 4 wk, or 8 wk after the final exposure. On a retention test 2 wk after surgery, the 1-d and 4-wk hippocampal lesion groups exhibited impaired object recognition memory. In contrast, the 8-wk hippocampal lesion group performed similarly to controls, and both groups exhibited a preference for the novel object. These same rats were then given four postoperative tests using unique object pairs and a 3-h delay between the exposure phase and the test phase. Hippocampal lesions produced moderate and reliable memory impairment. The results suggest that the hippocampus is important for object recognition memory.

Changes in context-specificity during memory reconsolidation: Selective effects of hippocampal lesions

After acquisition, memories associated with contextual fear conditioning pass through a labile phase, in which they are vulnerable to hippocampal lesions, to a more stable state, via consolidation, in which they engage extrahippocampal structures and are resistant to such disruption. The process is accompanied by changes in the form of the memory from being context-specific to context-general. However, when revived by a reminder, stable memories once again become labile and susceptible to hippocampal disruption, and memory reconsolidation is needed to stabilize them. This study addressed two questions with respect to this reconsolidation phenomenon: (1) How do reminders reinstate a hippocampally dependent memory trace? (2) As the memory changes from a stable to a labile state after a reminder, does its form remain invariant, or does it also change? Using contextual manipulations at retrieval in a test of contextual fear conditioning, we showed that when the fear-conditioning environment served as a reminder, the reinstated memory regained its context specificity and, as a result, became vulnerable again to the effects of hippocampal lesions. By comparison, exposure to a different environment during the reminder session reinstated a version of the original memory that was dependent primarily on general features of the original context and, consequently, was less affected by hippocampal lesions. These findings, which relate loss of reactivated memories after hippocampal destruction (or inactivation) to changes in memory representation, are interpreted as consistent with the transformation hypothesis of memory processing.

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.

Hippocampal Lesions Impair Rapid Learning of a Continuous Spatial Alternation Task

The hippocampus is essential for the formation of memories for events, but the specific features of hippocampal neural activity that support memory formation are not yet understood. The ideal experiment to explore this issue would be to monitor changes in hippocampal neural coding throughout the entire learning process, as subjects acquire and use new episodic memories to guide behavior. Unfortunately, it is not clear whether established hippocampally-dependent learning paradigms are suitable for this kind of experiment. The goal of this study was to determine whether learning of the W-track continuous alternation task depends on the hippocampal formation. We tested six rats with NMDA lesions of the hippocampal formation and four sham-operated controls. Compared to controls, rats with hippocampal lesions made a significantly higher proportion of errors and took significantly longer to reach learning criterion. The effect of hippocampal lesion was not due to a deficit in locomotion or motivation, because rats with hippocampal lesions ran well on a linear track for food reward. Rats with hippocampal lesions also exhibited a pattern of perseverative errors during early task experience suggestive of an inability to suppress behaviors learned during pretraining on a linear track. Our findings establish the W-track continuous alternation task as a hippocampally-dependent learning paradigm which may be useful for identifying changes in the neural representation of spatial sequences and reward contingencies as rats learn and apply new task rules.

Does the cingulate cortex contribute to spatial conditional associative learning in the rat?

Rats with lesions to the anterior or posterior (retrosplenial) region of the cingulate cortex and rats with lesions that included both the anterior and posterior cingulate cortex were tested on a visual-spatial conditional task in which they had to learn to approach one of the two objects depending on the spatial context within which they were embedded. Lesions restricted to either the anterior or the retrosplenial cingulate region did not impair learning of this task which is known to be very sensitive to the effects of hippocampal lesions. Complete lesions of the cingulate cortex gave rise to only a minor retardation in learning. In contrast, lesions to the retrosplenial cortex impaired performance on a spatial navigation task and the classic radial maze. These results suggest that the retrosplenial portion of the cingulate region forms part of a hippocampal circuit underlying learning about spatial responses. The dissociation between the effects of lesions of the cingulate region on different classes of behavior known to be associated with hippocampal function suggests that, although this neural structure does play a role in an extended hippocampal circuit underlying spatial learning, its role in such learning may be a selective one.

Additional evidence for intact appetitive trace conditioning in hippocampal-lesioned rats.

Hippocampal lesions impair aversive trace conditioning but do not interfere with appetitive Pavlovian trace conditioning of the licking response (LR). This experiment examined whether learning to discriminate the events occurring in the home cage and in the training chamber could account for the differential effects of hippocampal lesions on aversive and appetitive trace conditioning. Performance of rats with excitotoxic lesions of the hippocampus was compared to that of sham-operated rats in LR trace conditioning. The unconditional stimulus (US) "cola soft drink" was delivered only in the training chamber. Thus, as in aversive conditioning procedures, the hedonic properties of the US and the resulting behaviors and motivational states occurred only in that environment. The results failed to reveal learning differences between lesioned rats and controls. Our findings and those of other reports concur that trace conditioning with an appetitive US is independent of the hippocampal system.