Optogenetic dissection of dentate gyrus circuitry underlying anxiety

描述（由申请人提供）：我的职业目标是培养研究生、本科生和医科学生，并独立领导一个研究小组，研究动机和情绪相关行为背后的神经回路，最终将这种见解用于转化研究。为了实现这一目标，我提出了一个项目，通过研究齿状回（DG）回路如何影响焦虑样行为，为我提供重要的训练。具体来说，我将研究DG颗粒细胞（GCs）的发育起源或区域位置是否决定了它们对情绪行为的贡献。为了测试这一点，我将使用

DESCRIPTION (provided by applicant): My career goal is to train graduate, undergraduate, and medical students, and independently lead a research group that investigates the neural circuitry underlying motivated and mood-related behavior to eventually use this insight for translational research. To achieve this goal, I am proposing a project that provides me with significant training by examining how the dentate gyrus (DG) circuit contributes to anxiety-like behavior. Specifically, I will examine whether the developmental origin or regional position of DG granule cells (GCs) dictates their contribution to emotional behavior. To test this, I will use optogenetic techniques to control the activity of mature and adult-born granule cells in the dorsal or ventral DG to determine their relative contribution to anxiety-like behavior. My primary expertise is in mouse behavior, molecular biology and mouse genetics. My career development plan will expand on this by providing me essential training in patch clamp electrophysiology, in vivo electrophysiology, and in vivo optogenetic neuromodulation during behavior. As my career goal is to lead a research group examining the circuits that underlie affective behavior, and how they go wrong in disease states, these skills are not only required, but also essential to my success in leading a well-rounded, independent research career. In addition, as my previous focus has been on basic research, I have proposed to expand my training in translational neuroscience, so that I may apply my research to successfully collaborate with clinicians. Research Project Identifying the circuit mechanisms that underlie anxiety and depression is of utmost importance for treating psychiatric illness. In this proposal, I will examine how the dentate gyrus (DG) contributes to anxiety-like behavior. While classically studied for its role in spatial learning, there is significant support for a role for the DG in emotional behavior, but the mechanism for this remains unknown. A potential mechanism derives from the observation that emotional state can influence the production of new granule cells (GCs) from stem cells located in the adult DG. In addition, recent studies suggest the hippocampus is functionally segregated along its dorsal-ventral axis, influencing anxiety-like behavior through its ventral pole. This would suggest that GCs represent a functionally heterogeneous pool of neurons determined locally by their developmental origin and regionally by their position along the dorsal-ventral axi of the hippocampus. To test these possibilities, we have selectively expressed the blue light activated cation channel channelrhodopsin-2 (ChR2) and the yellow light activated chloride pump halorhodopsin (eNpHR3.0) in populations of mature and adult-born GCs. Using local circuit mapping in vitro, we will test the hypothesis that adult-born GCs modulate DG output. In vivo, we will test the hypothesis that optical stimulation or inhibition of GCs in the ventral DG preferentially influences anxiety-like behavior, while the dorsal DG impacts spatial learning. Finally, we will dissect the preferential contribution of adult-born GCs to anxiety-like behavior.