The capacity for memory is one of the most profound features of the mammalian brain, and the proper encoding and retrieval of information are the processes that form the basis of learning. The centrality of learning and memory to all aspects of mammalian life underscores the devastating nature of degenerative neurological disorders, such as Alzheimer's disease and schizophrenia that impair the hippocampus and compromise these processes. Although the hippocampal formation is one of the most extensively studied structures in the brain, the circuit mechanisms underlying its normal function remain elusive. Hippocampal principal cells form complex representations of the external environment, but in stark contrast to the diversity of inhibitory interneurons catalogued and despite the apparent need for functional segregation, they are largely considered a homogeneous population. The goal of this proposed research is to investigate functional segregation within the pyramidal cell population at the output node of the hippocampus, area CA1. In particular, given known developmental, genetic, and connectivity differences between superficial and deep cells in this region, we aim to explore the functional differences between these subpopulations and their relative contributions to learning and memory. This proposal implements numerous recent advances in optical imaging and genetic perturbation methods in the mouse, allowing us to longitudinally monitor and manipulate the activity of large populations of hippocampal neurons with submicron spatial resolution over days to weeks as the animal engages in various learning paradigms. In area CA1 principal cells form representations of the external world through their coordinated firing patterns. While spatial representations of static environments persist over long time periods, firing patterns in the CA1 principal cell population change dramatically over the course of learning. This proposal will test the hypothesis that superficial and deep CA1 principal cells demonstrate different coding dynamics during spatial navigation behaviors and learning tasks. Preliminary data from a head-fixed spatial navigation task suggests that spatial representations in the superficial CA1 pyramidal cell population are highly stable over many days, while firing patterns in the deep population are far more variable, suggesting a functional difference between these subpopulations and perhaps satisfying the need for both stability and flexibility in hippocampal codes. This proposal will also implement pharmacogenetic manipulations to test the hypothesis that coding differences between these subpopulations are the causal basis for differential contributions to learning and memory. In summary this work will use chronic head-fixed two- photon imaging of different subpopulations of CA1 pyramidal cells during learning in the awake rodent to further our understanding of functional subdivision in the hippocampal circuit.
Normal development and circuit function within the hippocampal formation are crucial for the processes of learning and memory. Although these functions are impaired in a variety of neurological disorders, such as Alzheimer's disease and schizophrenia, we know little about their precise circuit mechanisms and about functional subdivisions within the hippocampal output node more generally. By working to better understand the differential contributions to learning and memory of developmentally- related subpopulations of neurons in the hippocampus, this proposal will shed light on the means by which aberrant development and circuit function contributes to pathology.
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