In vivo functional imaging and high-resolution manipulations of hippocampal memory circuits

The main aim of this proposal is to understand the cellular and circuit mechanisms that establish spatial coding cellular ensembles in the mammalian hippocampus. The cognitive spatial map theory of the hippocampus posits that internal representations of space are implemented by a sparse subset of 'place cells' that display location-specific firing during spatial navigation, while other neurons remain silent. Moreover, this spatial code is highly dynamic, such that place cells alter their firing properties when the spatial environment changes. The cellular and circuit mechanisms that establish sparsely distributed and dynamic spatial coding schemes in the hippocampus are poorly understood. Longstanding theories posit that the hippocampal inhibitory circuitry plays a central role in the formation and segregation of spatially informative cellular ensembles. If so, the anatomical diversity of local GABAergic interneurons may further promote dynamic organization of place cell assemblies in the population by regulating active dendritic input processing at the subcellular level, which can define the output behavior of principal cells to synaptic excitation in a given environment. Understanding multimodal dynamics in the hippocampus will, therefore, have important consequences for our understanding of how cortical circuits are organized to process and store information. To directly test these hypotheses we will perform multi-level analyses requiring a multidisciplinary approach that brings together experts in neurophysiology, nonlinear optics, molecular genetics and synthetic chemistry. Our research plan is composed of five tightly integrated projects. 1) Functional population imaging in hippocampal CA1 of behaving mice to determine the fine-scale spatial organization of hippocampal spatial coding ensembles and their dynamic reorganization during controlled changes in the spatial environment and spatial learning. 2) Assessment of multimodal organization and dynamics in synaptic microcircuits of genetically-identified interneurons. 3) Implementation of novel cellular-resolution optical, photochemical and pharmacogenetic techniques for manipulating activity of identified inhibitory circuits in vivo. 4) Dissecting multimodal population and microcircuit dynamics of spatial coding CA1 hippocampal neuronal ensembles using cellular-resolution manipulations in vivo. 5) Measurements and manipulation of subcellular integration of excitatory and inhibitory synaptic inputs in functionally-identified hippocampal CA1 pyramidal cells during spatial navigation and learning. This project will yield a detailed understanding of the cellular and circuit mechanisms that establish spatial coding ensembles in the mammalian hippocampus. The complexity of this problem necessitates a multidisciplinary and integrated approach.