中枢生长激素促泌受体GHSR1a调控应激后焦虑相关行为的突触和神经环路机制研究

促进摄食和调节能量平衡的肽类激素 ghrelin 是生长激素促泌受体 GHSR1a 的天然配体，我们及其它实验室的前期研究均表明各种急慢性应激刺激明显升高内源性ghrelin水平，但中枢ghrelin/GHSR1a对焦虑相关行为的调控作用却是复杂双向的，具体机制尚不清楚。本课题拟在已有研究基础上，以内侧前额叶皮层、腹侧海马、基底外侧杏仁核这三个 GHSR1a 表达丰富且为焦虑环路重要节点的神经核团为研究对象，借助GHSR1a基因敲除、病毒介导的GHSR1a在特定脑区过表达，遗传操控GHSR1a神经元活动以及在体钙信号记录等手段，深入探讨GHSR1a 参与调控焦虑相关行为的突触和神经环路机制。同时结合单细胞测序技术对特定核团内GHSR1a 神经元所属亚群进行基因水平上的细化。研究可深化对 ghrelin/ GHS-R多重生理功能的了解，并为PTSD等应激障碍性神经精神疾病的治疗提供新思路。

Acute and chronic stress both elevate plasma ghrelin, the endogenous ligand for GH secretagogue receptor GHSR1a. Growing evidence suggest central ghrelin/GHSR1a system plays a dual role (anxiogenic or anxiolytic) in intergrating circuitry involved in anxiety, however the underlying mechanism are uncertain yet. Besides hypothalamus, GHSR1a was found to be relatively enriched in basolateral amygdala (BLA), ventral hippocampus (vHPC), medial prefrontal cortex (mPFC), three important nodes among a distributed array of interlinked neural circuits of anxiety. Therefore, we propose to combine cutting-edge in vivo and in vitro techniques, including genetic GHSR1a knock-out mice, virus-mediated GHSR1a overexpression in specific subtype of neurons, optogenetic/chemogenetic manipulation of activity of neurons expressing GHSR1a in specific brain regions, optical fiber recording and miniscope images to uncover the effects, and explore the synaptic and circuits mechanisms underlying GHS-R1a-dependent modulation of anxiety-related behaviors after restraint stress. Meanwhile, to explore diversity of GHSR1a neurons in specific brain regions, we plan to use Drop-Seq single cell sequence to subcluster GHSR1a neurons with identified cell markers. Our study will not only shed light on our understanding about multiple brain functions of ghrelin/GHS-R1a system, it may also contribute to the development of new treatment for certain affective disorders, such as PTSD and anxiety.