Dorsoventral functional divergence of the hippocampal CA3 circuit

海马 CA3 回路的背腹功能分歧

• 批准号: 9932690
• 负责人: Qian Sun
• 金额: $ 14.9万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9932690
• 关键词: Address; Anterior; Antidepressive Agents; Anxiety Disorders; Area; Behavior; Behavioral; Bilateral; Cells; Chronic stress; Clinical; Clinical Research; Cues; Data Analyses; Dependovirus; Dorsal; Electrophysiology (science); Etiology; Foundations; Fright; Gene Expression; Genetic; Genomics; Goals; Heterogeneity; Hippocampus (Brain); Human; Image; Imaging technology; Immediate-Early Genes; Impairment; In Vitro; Lead; Learning; Measures; Membrane; Memory; Mental Depression; Microscope; Mus; Neurons; Pathway interactions; Pattern; Physiological; Play; Population; Process; Property; Research; Resistance; Resolution; Rodent; Role; Schizophrenia; Solid; Synapses; Tamoxifen; Techniques; Testing; Training; Translating; Virus; Work; anxiety-related behavior; base; behavior test; calmodulin-dependent protein kinase II; career; classical conditioning; conditioned fear; conditioning; dentate gyrus; designer receptors exclusively activated by designer drugs; electrical property; entorhinal cortex; experimental study; fear memory; field study; genome-wide analysis; granule cell; hippocampal pyramidal neuron; in vivo; in vivo imaging; insight; learned behavior; light gated; memory encoding; memory recall; microscopic imaging; mossy fiber; neurophysiology; neuropsychiatric disorder; novel; operation; optogenetics; programs; segregation; time interval

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.

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 海马CA 3回路正常运作的机制以及CA 3在 神经精神障碍，如抑郁症和精神分裂症。为了实现这一目标，我提出了一个 该项目将通过调查背腹分歧为我提供重要的培训， 海马CA 3区功能。海马体的CA 3区传统上被认为是一个 同构自联想网络对于快速联想学习和记忆至关重要。然而，在这方面， 我最近的工作和其他人已经证明了内在的横向异质性， 兴奋性、突触连接性和背侧CA 3中的行为。这一建议是继 这些先前的研究，以测试一个中心假设，即背侧和腹侧CA 3是不同的 参与情境学习和焦虑相关行为。具体来说，我建议区分 使用基于通道视紫红质2（ChR 2）的光遗传学和 设计师受体专门由设计师药物激活（DREADDs） 双向操纵背侧与腹侧CA 3活性的方法。接下来，我将聘请一位 基于即时早期基因弧记忆标记策略检测记忆是否激活 背侧或腹侧CA 3中的印迹细胞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检查背腹侧CA 3是否显示 独特的网络动力学是其特定行为功能的基础。综合起来， 提出的实验将提供新的见解的多样性，在体内的运作和行为 CA 3电路的功能。此外，作为某些神经病理学条件，如慢性应激， 抑郁症和精神分裂症，优先损害背侧或腹侧海马，这一建议是 与临床研究高度相关。由于我的主要专长是神经生理学， 拟议的研究代表了我的研究的重大变化，将使我能够获得 在小鼠行为、体内成像和大规模数据分析方面进行必要的新培训。我的职业生涯 目标是联合收割机将这些技术和通过K 01获得的科学见解结合起来，以提供更好的 了解CA 3回路在生理条件下如何运作，以及功能失调的 CA 3回路导致CA 3相关神经精神疾病（如抑郁症）的行为缺陷 和精神分裂症