My career goal is to lead an independent research group to investigate the cellular and circuit mechanisms underlying normal operation of the hippocampal CA3 circuit and the role of CA3 in neuropsychiatric disorders, such as depression and schizophrenia. To achieve this goal, I propose a project that will provide me with significant training by investigating the dorsoventral divergence of hippocampal CA3 function. The CA3 area of the hippocampus is traditionally viewed as a homogeneous autoassociative network crucial for rapid associative learning and memory. However, my recent work and others have demonstrated a remarkable transverse heterogeneity in intrinsic excitability, synaptic connectivity, and behavior in dorsal CA3. This proposal follows up and expands on these previous studies to test a central hypothesis that the dorsal and ventral CA3 are differentially involved in contextual learning and anxiety-related behavior. Specifically, I propose to differentiate the behavioral role of dorsal versus ventral CA3 using channelrhodopsin2 (ChR2)-based optogenetic and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)-based chemogenetic approaches to bidirectionally manipulate dorsal versus ventral CA3 activity. Next, I will employ an immediate early gene Arc-based memory tagging strategy to test whether activation of memory engram cells in dorsal or ventral CA3 is sufficient to recall a fear memory. Finally, I will utilize in vivo miniature microscope imaging technology to examine whether the dorsal and ventral CA3 display distinctive network dynamics that underlie their specific behavioral function. Taken together, the proposed experiments will provide new insight into the diversity of in vivo operation and behavioral function of CA3 circuit. Moreover, as certain neuropathological conditions, such as chronic stress, depression, and schizophrenia, preferentially impair dorsal or ventral hippocampus, this proposal is highly relevant to clinical research. As my primary expertise has been in neurophysiology, the proposed studies represent a significant change of my research and will enable me to acquire essential new training in mouse behavior, in vivo imaging, and large-scale data analysis. My career goal is to combine these technique and scientific insights gained through this K01 to provide a better understanding of how CA3 circuit operates under physiological condition and how a dysfunctional CA3 circuit leads to behavioral deficits in CA3-related neuropsychiatric disorders, such as depression and schizophrenia.
Although the CA3 area in the hippocampus is traditionally thought to act as an autoassociative network crucial for associative learning and memory, recent genomic evidence reveals a remarkable heterogeneous pattern in gene expression in CA3. This proposal aims to address the dorsoventral diversity of CA3 circuit at the functional and behavioral level. The proposed studies will provide new insight into functional diversity of CA3, and will contribute to a better understanding of the etiology of neuropsychiatric disorders that are associated with CA3, including depression and schizophrenia.