Regulation of VTA inhibitory synapses by acute and chronic stress

 描述(申请人提供)：在这个项目中，我将研究VTA多巴胺神经元上抑制性突触在应激和抑郁动物模型中的作用。腹侧被盖区的多巴胺神经元是大脑奖赏处理系统的重要组成部分，这些神经元的功能受到急性和慢性应激的很大影响。多巴胺神经元上的抑制性突触有力地调节着它们的活动，因此有望成为应激对VTA影响的重要中介。在这项提案中，我将采用多学科的方法来解决这一假设，即VTA中的抑制性突触是应激对大脑影响的关键部位，也是慢性社会应激动物模型中易感性的决定因素。在指导的K99阶段，我将首先确定在急性应激源后，导致长期应激诱导的抑制性突触可塑性缺陷的细胞信号成分。其次，我将利用光遗传学技术来测试特定抑制输入对多巴胺神经元的应激敏感性，包括来自VTA内GABA能中间神经元以及来自其他大脑区域的那些。在独立的R00阶段，我将利用应激诱导抑郁行为易感性的慢性社会失败模型来研究VTA多巴胺神经元抑制性突触在应激易感性中的作用。在这个阶段，我将研究两个不同的多巴胺神经元亚群上的抑制性突触，一个投射到伏隔核，另一个投射到前额叶皮质，在对社会失败表现出不同行为反应的动物中。这些研究有可能极大地帮助我们理解压力是如何改变奖赏系统的，并可能为抑郁症和其他应激相关障碍的治疗方法的发展开辟新的途径。我的长期职业目标是成为一家学术机构的独立研究员，在那里我将建立一个研究项目，研究突触和回路水平的精神疾病机制。这样的职位将使我有机会将我在研究、指导和教学方面的兴趣结合起来。我的研究生和博士后培训使我在精神疾病的神经科学方面有了一个强有力的概念框架，并为我提供了一套行为、生化和电生理技能。这份提案中概述的培训计划将使我能够继续拓宽我的技术和智力专长，同时获得专业技能，这将帮助我成功地获得教员职位并建立创新研究计划。在K99阶段，我将接受我的导师Julie Kauer博士以及我的共同导师Chris Moore博士、Kevin Bath博士和Scott Russo博士的培训。在他们的指导下，我将学会使用光遗传技术和慢性社会挫败应激行为范式。此外，我的培训将得到布朗大学神经科学研究社区的支持和合作以及许多职业发展机会的加强。我的指导团队的支持和布朗大学特殊的培训环境将有助于我过渡到一个独立的职位。

 DESCRIPTION (provided by applicant): In this project, I will investigate the role of inhibitory synapses on VTA dopamine neurons in animal models of stress and depression. Dopamine neurons of the ventral tegmental area are a crucial part of the brain's reward processing system, and function of these neurons is greatly influenced by both acute and chronic 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 multidisciplinry approach to address the hypothesis that inhibitory synapses in the VTA are a key locus for the effects of stress on the brain and a determinant of susceptibility in an animal model of chronic social stress. During the mentored K99 phase, I will first determine the cellular signaling components that contribute to long-lasting stress-induced deficits in inhibitory synaptic plasticit after an acute stressor. Second, I will utilize optogenetic techniques to test the stress-sensitiviy of specific inhibitory inputs on dopamine neurons, including those from GABAergic interneurons within the VTA as well as from other brain regions. During the independent R00 phase, I will utilize the chronic social defeat model of susceptibility to stress-induced depressive behavior to investigate the role of inhibitory synapses on VTA dopamine neurons in stress susceptibility. In this phase, I will study inhibitory synapses onto two distinct subsets of dopamine neurons, those projecting to the nucleus accumbens and those projecting to the prefrontal cortex, in animals that show differential behavioral responses to social defeat. 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. My long term career goal is to become an independent investigator at an academic institution where I will establish a research program investigating synaptic and circuit level mechanisms of mental illness. Such a position will give me the opportunity to combine my interests in research, mentoring, and teaching. My graduate and postdoctoral training has given me a strong conceptual framework in the neuroscience of mental illness and provided me with a set of behavioral, biochemical, and electrophysiological skills. The training plan outlined in this proposal will allow me to continue to broaden my technical and intellectual expertise while gaining professional skills that will help me successfully obtain a faculty position and establish an innovative research program. During the K99 phase, I will receive training from my mentor, Dr. Julie Kauer, and my co-mentors, Dr. Chris Moore, Dr. Kevin Bath, and Dr. Scott Russo. Under their guidance, I will learn to use optogenetic techniques and the chronic social defeat stress behavioral paradigm. In addition, my training will be enhanced by the supportive and collegial neuroscience research community and the many professional development opportunities at Brown University. The support of my mentoring team and the exceptional training environment at Brown University will facilitate my transition to an independent position.