Inah Lee

A behavioral assessment of hippocampal function based on a subregional analysis.

The purpose of this review is to determine whether specific subregions (dentate gyrus [DG], CA3, and CA1) of the hippocampus provide unique contributions to specific processes associated with intrinsic information processing exemplified by novelty detection, encoding, pattern separation, pattern association, pattern completion, retrieval, short-term memory and intermediate-term memory. Based on anatomical neural network organization, electrophysiology of cellular activity, lesions, early gene activation, and computational modeling, it can be shown that there exists extensive cooperation among the three subregions of the hippocampus, but there also exists reliable specificity of function for each of the subregions of the hippocampus. The primary process supported by the DG subregion of the hippocampus can be characterized by orthogonalization of sensory inputs to create a metric spatial representation. Furthermore the DG participates in conjunction with CA3 in supporting spatial pattern separation. The CA3 subregion of the hippocampus supports processes associated with spatial pattern association, spatial pattern completion, novelty detection, and short-term memory. The CA1 subregion of the hippocampus supports processes associated with temporal pattern association, temporal pattern completion, and intermediate-term memory. Furthermore, the CA3 in conjunction with CA1 supports temporal pattern separation. All the above-mentioned processes are assumed to reflect intrinsic processing of information within the hippocampus. The diversity of functions associated with the different subregions of the hippocampus suggests that one should not treat the hippocampus as a single entity, but rather that one should concentrate on elucidating further the functions of both dorsal and ventral subregions of the hippocampus and pathways that directly connect each of the subregions as well as their connections with the entorhinal cortex.

Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3

The hippocampus, a critical brain structure for navigation, context-dependent learning and episodic memory, is composed of anatomically heterogeneous subregions. These regions differ in their anatomical inputs as well as in their internal circuitry. A major feature of the CA3 region is its recurrent collateral circuitry, by which the CA3 pyramidal cells make excitatory synaptic contacts on each other. In contrast, pyramidal cells in the CA1 region are not extensively interconnected. Although these differences have inspired numerous theoretical models of differential processing capacities of these two regions, there have been few reports of robust differences in the firing properties of CA1 and CA3 neurons in behaving animals. The most extensively studied of these properties is the spatially selective firing of hippocampal ‘place cells’. Here we report that in a dynamically changing environment, in which familiar landmarks on the behavioural track and along the wall are rotated relative to each other, the population representation of the environment is more coherent between the original and cue-altered environments in CA3 than in CA1. These results demonstrate a functional heterogeneity between the place cells of CA3 and CA1 at the level of neural population representations.

The role of hippocampal subregions in detecting spatial novelty.

Previous literature suggests that the hippocampus subserves processes associated with the encoding of novel information. To investigate the role of different subregions of the hippocampus, the authors made neurotoxic lesions in different subregions of the dorsal hippocampus (i.e., CA1, dentate gyrus [DG], or CA3) of rats, followed by tests using a spontaneous object exploration paradigm. All lesion groups explored normally an object newly introduced in a familiar location. However, when some of the familiar objects were moved to novel locations, both DG and CA3 lesion groups were severely impaired in reexploring the displaced objects, whereas the CA1 lesion group was only mildly impaired in reexploration. The results suggest that the DG-CA3 network is essential in detecting novelty for spatial, but not for individual object, information.

Differential contribution of NMDA receptors in hippocampal subregions to spatial working memory

N-methyl-d-aspartate (NMDA) receptor–dependent synaptic plasticity in the mammalian hippocampus is essential for learning and memory. Although computational models and anatomical studies have emphasized functional differences among hippocampal subregions, subregional specificity of NMDA receptor function is largely unknown. Here we present evidence that NMDA receptors in CA3 are required in a situation in which spatial representation needs to be reorganized, whereas the NMDA receptors in CA1 and/or the dentate gyrus are more involved in acquiring memory that needs to be retrieved after a delay period exceeding a short-term range. Our data, with data from CA1-specific knockout mice, suggest the possibility of heterogeneous mnemonic function of NMDA receptors in different subregions of the hippocampus.

Differential roles of dorsal hippocampal subregions in spatial working memory with short versus intermediate delay

In order to determine the role of subregions of the hippocampus in spatial working memory, this study combined selective neurotoxic lesions of the hippocampal subregions with a simple delayed nonmatching-to-place task on a radial maze in rats. Lesions of the dentate gyrus or the CA3, but not the CA1, subregion of the hippocampus induced a deficit in the acquisition of the task with short-term delays (i.e., 10 sec) and impaired performance of the task in a novel environment. All subregional lesions produced sustained impairment in performing the task with intermediate-term delays (i.e., 5 min) when rats were tested in a familiar environment. The results suggest a dynamic interaction among the dorsal hippocampal subregions in processing spatial working memory, with the time window (i.e., delay) of a task recognized as an essential controlling factor.

Disruption of delayed memory for a sequence of spatial locations following CA1- or CA3-lesions of the dorsal hippocampus

Axon-sparing neurotoxic lesions of CA1 or CA3 were produced in the dorsal hippocampus to test dissociative lesion effects on spatial working memory for sequential items. Rats were required to remember four different sections sequentially presented on a newly devised maze (i.e., Tulum maze) during a study phase. Each section was cued by a unique object that was specifically associated with each location within the section during the study phase. Following a 15-s delay and during the test phase, rats were required to revisit the location within a section randomly chosen among the previously visited sections in the absence of the cued object. Both CA1 and CA3 lesions similarly disrupted accurate relocation of a previously visited place. However, differential effects of the CA1 and CA3 lesions were observed in serial position curves. CA3-lesions disrupted performance for the first three serial positions, but did not disrupt performance for the last serial position (recency). In contrast, CA1-lesions disrupted performance for all serial positions. The results suggest that temporal separation of spatial memory may depend on the conjoint function of CA1 and CA3 of the hippocampus with a disruption of a spatial pattern completion process following CA3 lesions and a disruption of a temporal pattern separation process following a CA1 lesion.

Patterns of hippocampal cell loss based on subregional lesions of the hippocampus

It is widely accepted that the hippocampus plays an essential role in memory. Furthermore, studies have suggested that subregions within the hippocampus contribute differentially to specific behavioral components of memory. These studies typically rely on lesions produced by localized injections of neurotoxins (e.g., ibotenic acid or colchicine) into targeted subregions of the hippocampus. In the present study, the specificity of ibotenic acid lesions into areas CA1 and CA3 and colchicine lesions into the dorsal dentate gyrus (DG) was tested. Specifically, the effects of lesions within the dorsal hippocampus, the ventral hippocampus, and areas outside the hippocampus (e.g., lateral septum and entorhinal cortex) were evaluated using Fluoro-Jade, a histofluorescent stain for degenerating neurons. The results show that cell loss is relatively uniform after ibotenic acid injections into areas CA1 and CA3 and variable after colchicine injections into DG. CA1 and CA3 lesions appeared mostly localized to those relative subregions, and DG lesions appeared highly localized to the DG. Using these lesion procedures, little cell loss was apparent in the ventral hippocampus, and no cell loss was apparent in the entorhinal cortex. It is suggested that the lesion procedures described in this study produce relatively selective lesions of neurons within specific subregions of the hippocampus and should be useful for studies examining possible differential contributions of hippocampal subregions to memory processes.

Simulating place field dynamics using spike timing-dependent plasticity

Spatial firing fields (place fields) of rat hippocampal cells undergo changes when the rat runs stereotyped routes. Previously, Mehta et al. [Experience-dependent asymmetric shape of hippocampal receptive fields, Neuron 25 (2000) 700-715] indicated that spike timing-dependent plasticity (STDP) might explain the observed shift of the place field center of mass and the development of skewness. In this study, by using simulations of spiking neurons with STDP, we demonstrate that STDP may cause a shift and negative skewness in the synaptic weights vector; however, we explain why these changes do not necessarily result in negative skewness of place fields. We further explore the parameters and additional mechanisms that favor the development of skewness.