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Neural circuit organization and function of hippocampal CA1 and the subiculum


The hippocampal formation is a brain region that plays critical roles in memory and spatial navigation. A mechanistic understanding of hippocampal circuit organization and function is fundamental for determining how this brain region contributes to memory and cognition. Although the general anatomy and circuit organization of the hippocampal CA1 has been well-studied, most of our understanding of hippocampal circuits comes from the conventional anatomical tracing studies which lack cell-type specificity and quantitative measurements of connectional strengths. New advances in virology and genetics complement traditional approaches and are powerful tools for mapping cell-type-specific circuit connectivity and function. Herein, through a series of extensive studies using cutting-edge viral and genetic techniques, novel hippocampal circuits and their functions are elucidated. In Chapter 1, a Cre-dependent, genetically modified rabies-based tracing system was developed to map local and long-range monosynaptic connections to specific excitatory and inhibitory CA1 neuron types in the mouse. Our data show the different input sources of varying strengths are distributed onto each specific CA1 cell type, providing insight into differential circuit mechanisms of hippocampal functional operations. In Chapter 2, quantitative re-evaluation of intra- and para- hipppocampal input connections to excitatory neurons in different CA1 proximodistal subfields was performed using monosynaptic rabies tracing. The results provide a new topographic circuit basis for functional considerations of CA1-associated memory and cognition. For the studies reported in Chapters 3 and 4, a detailed analysis of synaptic circuit organization and function of the subiculum to CA1 back-projection pathway was performed using state-of-the-art techniques including combinatorial viral tracing, genetically targeted manipulation of neural activity, and behavioral analysis. Building on the results from chapter 1 that provide unambiguous anatomical evidence for non-canonical subicular back-projections to CA1, global circuit input and output connections of CA1-projecting and other subicular neurons were mapped and compared. These studies establish that CA1-projecting subicular neurons are a distinct neuronal group with unique circuit properties within the subiculum. To link circuit mapping to function and behavior, I investigated how DREADDs-mediated inactivation of CA1-projecting subicular neurons modulates spatial learning and memory, and found that inactivating CA1-projecting subicular neurons specifically impairs animal’s object location memory. This study has, for the first time, implicated the non-canonical subicular projections in hippocampus-associated spatial memory behavior. Together, this dissertation has provided novel, cell-type-specific anatomical and functional insights for hippocampal CA1 and the subiculum, and addressed the circuit organization and function of the under-appreciated bidirectional connections of subiculum and hippocampal CA1. This study may also lead to a better understanding of the neural circuit mechanisms that underlie hippocampal-related neurological disorders such as Alzheimer's disease.

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