Regulation of VTA inhibitory synapses by acute and chronic stress

修改项目摘要/摘要部分 该项目是乔治华盛顿大学药理学和生理学系完成的K99/R 00奖的R 00阶段。在这个项目中，我将调查的作用，抑制性突触腹侧被盖区多巴胺神经元在动物模型的弹性和易感性，以应激诱导的快感缺失。腹侧被盖区（VTA）的多巴胺神经元是大脑奖赏加工系统的重要组成部分，应激对这些神经元的功能有很大影响。特别是，投射到丘脑核的多巴胺神经元的活动与动物对压力的行为反应有因果关系。多巴胺神经元上的抑制性突触有力地调节它们的活性，因此有望成为压力对腹侧被盖区影响的重要介质。在这个提议中，我将采取多学科的方法，利用电生理学，光遗传学，化学遗传学和行为技术来解决这一假设，即抑制性突触投射腹侧被盖区多巴胺神经元的核是一个人的行为反应的一个关键决定因素压力。我提出了两个目标，修改了我最初的K99/R 00申请。在第一，我将研究抑制性突触的生理和可塑性到神经核投射多巴胺神经元在小鼠表现出不同的反应，两种形式的重复压力：慢性社会失败和亚慢性变量压力。在第二，我将研究两个特定的输入（本地腹侧被盖区中间神经元和RMTg的预测）的强度的变化到神经核投射多巴胺神经元后，慢性社会失败和化学遗传操纵这些输入的能力，以促进弹性，这种压力。这些研究有可能对我们理解奖励系统如何被压力改变做出重大贡献，并可能为抑郁症和其他与压力相关的疾病的治疗方法的发展带来新的途径。

Modified Project Summary/Abstract Section This project is the R00 phase of a K99/R00 award to be completed in the Department of Pharmacology and Physiology at George Washington University. In this project, I will investigate the role of inhibitory synapses on VTA dopamine neurons in animal models of resilience and susceptibility to stress-induced anhedonia. Dopamine neurons of the ventral tegmental area (VTA) are a crucial part of the brain's reward processing system, and function of these neurons is greatly influenced by stress. In particular, activity of dopamine neurons projecting to the nucleus accumbens has been causally linked to an animal's behavioral response to stress. Inhibitory synapses onto dopamine neurons powerfully modulate their activity, and are thus poised to be a significant mediator of stress's effects on the VTA. In this proposal, I will take a multidisciplinary approach, utilizing electrophysiological, optogenetic, chemogenetic, and behavioral techniques to address the hypothesis that inhibitory synapses onto nucleus accumbens-projecting VTA dopamine neurons are a key determinant of an individual's behavioral responses to stress. I propose two aims, revised from my original K99/R00 application. In the first, I will examine inhibitory synaptic physiology and plasticity onto nucleus accumbens projecting dopamine neurons in mice exhibiting differential responses to two forms of repeated stress: chronic social defeat and subchronic variable stress. In the second, I will examine changes in the strength of two specific inputs (local VTA interneurons and RMTg projections) onto nucleus accumbens-projecting dopamine neurons following chronic social defeat and the ability of chemogenetic manipulation of these inputs to promote resilience to this stressor. These studies hold the potential to contribute significantly to our understanding of how the reward system is altered by stress and may lead to novel avenues for the development of therapeutic treatments for depression and other stress-linked disorders.