Dorsoventral functional divergence of the hippocampal CA3 circuit

项目总结/摘要 我的职业目标是领导一个独立的研究小组，研究细胞和电路机制， 海马CA 3回路的基本正常运作和CA 3在神经精神疾病中的作用， 如抑郁症和精神分裂症。为了实现这一目标，我提出了一个项目， 通过研究海马CA 3功能的背腹向差异来进行有意义的训练。CA 3区 海马体传统上被视为一个同质的自联想网络， 联想学习和记忆。然而，我最近的工作和其他人已经证明了一个显着的 在背侧CA 3内在兴奋性、突触连接性和行为的横向异质性。这 建议跟进和扩大这些以前的研究，以测试一个中心的假设，背和 腹侧CA 3参与情境学习和焦虑相关行为的差异。我特别 建议使用通道视紫红质2（ChR 2）区分背侧与腹侧CA 3的行为作用- 基于光遗传学和设计师受体的设计师药物独家激活（DREADD） 化学遗传学方法双向操纵背侧与腹侧CA 3活性。接下来，我将雇用 一种基于即时早期基因弧的记忆标记策略， 背侧或腹侧CA 3中的神经元足以回忆起恐惧记忆。最后，我将利用体内微型 显微镜成像技术，以检查背侧和腹侧CA 3是否显示独特的网络 它们特定的行为功能背后的动力学。总的来说，拟议的实验将 为CA 3回路的体内操作和行为功能的多样性提供了新的见解。而且随着 某些神经病理状况，如慢性应激、抑郁症和精神分裂症， 损伤背侧或腹侧海马，该提议与临床研究高度相关。作为我的主要 由于我的专长是神经生理学，因此所提出的研究代表了我的研究的重大变化 并将使我能够获得在小鼠行为、体内成像和大规模数据方面的基本新培训 分析.我的职业目标是联合收割机结合这些技术和科学的见解，通过这个K 01， 更好地了解CA 3回路在生理条件下如何工作，以及 功能失调的CA 3回路导致CA 3相关神经精神障碍中的行为缺陷，例如 抑郁症和精神分裂症。

PROJECT SUMMARY/ABSTRACT 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.