PROJECT 1-Neural encoding based on lateral and medial entorhinal information processing streams in behaviorally-characterized aged rats

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The hippocampus and medial temporal lobe structures play critical roles in the formation and maintenance of declarative memories. A consensus is emerging that the hippocampus receives a self-motion-based, spatial signal from the medial entorhinal cortex (MEC) and an external sensory signal about objects and items in the world from the lateral entorhinal cortex (LEC). It combines these inputs to create conjunctive representations of discrete experiences within their spatiotemporal contexts. Because memory loss is one of the hallmark characteristics of both normal and pathological aging, a key challenge is to understand the physiological changes that occur in the hippocampus with aging. Recent results suggest that the LEC is particularly susceptible to age-related dysfunction. Moreover, treatment with the antiepileptic drug, levetiracetam, can ameliorate some of the physiological and cognitive impairments associated with aging. This project proposes a number of experiments to test specific hypotheses about how LEC and MEC inputs affect hippocampal function with aging. Place cells of aged rats with impaired memory show a reduced control by local sensory cues (associated with neural representations of the LEC), whereas they continue to be controlled by global spatial cues (associated with representations of the MEC). Place cells of the CA3 region will be recorded from young rats and from aged rats (with and without memory impairments) in the following experiments. (a) Local and global spatial reference frames will be placed in conflict. It is hypothesized that aged impaired rats will show an abnormal lack of control by the local reference frame, and that this abnormal condition will be ameliorated by treatment with levetiracetam. (b) The geometry and location of a recording chamber will be altered. It is hypothesized that aged impaired rats will show an abnormal stability of their place fields when only the geometry is altered (due to a hypothesized loss of LEC input) but will show normal place field changes when the location is altered (due to a hypothesized normal MEC input). The abnormal stability patterns will be ameliorated with levetiracetam treatment. (c) The formation of new place fields associated with an investigatory behavior known as head-scanning will be investigated It is hypothesized that aged impaired rats will show a reduction in the formation of new place fields associated with this behavior. Treatment with levetiracetam will restore this neural plasticity phenomenon. (d) Recordings from the MEC and LEC will test the hypothesis that grid cells, border/boundary cells, and nonspatial cells of aged impaired rats will be normal, compared to young and aged unimpaired rats. These experiments will provide robust tests of the general hypothesis that LEC neural processing is particularly susceptible to age-related dysfunction, and that levetiracetam treatment is a potential therapy to restore hippocampal function in aged-impaired animals.