Inhibitory Network Dynamics Supporting Hippocampal Spatial Representations

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Project Abstract The hippocampus is a mammalian brain structure critical for various cognitive functions, including spatial navigation and episodic memory. Hippocampal area CA1, the output node of the hippocampus, is composed of a relatively homogenous population of excitatory pyramidal cells and a smaller, yet diverse, population of GABAergic interneurons (INs). Remarkably, individual pyramidal cells in CA1 (CA1PCs) can integrate thousands of excitatory and inhibitory synaptic inputs to respond specifically to various features of the external environment (“feature selectivity”). One prominent example of feature selectivity is the location-specific increases in firing rate that pyramidal cells exhibit (“place cells”) as an animal traverses its environment. Although place cells might provide the link between the cognitive functions of the hippocampus and the activity patterns of individual cells, the circuit-level mechanisms responsible for their formation and stability remain unknown. In particular, it remains unknown whether INs influence place cell dynamics, as there is a lack of information about the in vivo activity patterns of molecularly-defined INs and synaptic connectivity between INs and pyramidal cells remains difficult to establish in vivo. The goal of this proposal is to characterize the in vivo dynamics of the major IN subtypes at the population level and their relationship to the spatially tuned activity of postsynaptic CA1PCs during spatial navigation and learning. In Aim 1, I will perform AOD-based two-photon functional calcium imaging and retrospective molecular characterization of the imaged cells with post-hoc immunohistochemistry to characterize the collective dynamics of the major CA1 IN subtypes during behavior. In Aim 2, I will combine these techniques with single-cell-initiated monosynaptic, retrograde viral tracing to determine the relationship between the functional dynamics of presynaptic INs and the formation and stability of spatially tuned activity in postsynaptic CA1PCs during spatial navigation and learning. These experiments will lead to a better understanding of the local inhibitory dynamics that support hippocampal spatial representations to guide behavior.