Regulation of VTA inhibitory synapses by acute and chronic stress

急性和慢性应激对 VTA 抑制性突触的调节

• 批准号: 9041686
• 负责人: Abigail Marie Polter
• 金额: $ 9.36万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041686
• 关键词: Acute; Address; Affect; Animal Model; Animals; Award; Bathing; Behavior; Behavioral; Behavioral Model; Behavioral Paradigm; Biochemical; Brain; Brain region; Chronic; Chronic stress; Communities; Development; Disease; Educational process of instructing; Electrophysiology (science); Environment; Event; Exhibits; Faculty; Goals; Health; Individual; Individual Differences; Inhibitory Synapse; Institution; Interneurons; Knockout Mice; Lead; Learning; Link; MAPK14 gene; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Mentors; Modeling; Mus; Neurons; Neurosciences; Neurosciences Research; Nucleus Accumbens; Opioid Receptor; Phase; Physiology; Play; Positioning Attribute; Predisposition; Prefrontal Cortex; Regulation; Research; Research Personnel; Rewards; Role; Signal Transduction; Signaling Molecule; Stress; Stress Tests; Synapses; Synaptic plasticity; System; Techniques; Testing; Training; Universities; Ventral Tegmental Area; Viral; Work; acute stress; behavioral response; career; depressive behavior; dopaminergic neuron; innovation; interest; neural circuit; novel; optogenetics; post-doctoral training; programs; research study; response; reward processing; skills; social; social stress; stressor; therapeutic development; tool

 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.

 描述（申请人提供）：在这个项目中，我将研究在压力和抑郁的动物模型中抑制性突触对腹侧被盖区多巴胺神经元的作用。腹侧被盖区的多巴胺神经元是大脑奖赏加工系统的重要组成部分，其功能受到急性和慢性应激的影响。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。在这个建议中，我将采取多学科的方法来解决这一假设，即抑制性突触在腹侧被盖区的压力对大脑的影响和易感性的决定因素在慢性社会压力的动物模型的关键位点。在辅导K99阶段，我将首先确定细胞信号成分，有助于长期的压力诱导的缺陷，在抑制性突触可塑性急性应激后。其次，我将利用光遗传学技术来测试多巴胺神经元上特定抑制性输入的应激敏感性，包括来自VTA内的GABA能中间神经元以及来自其他大脑区域的多巴胺神经元。在独立R00阶段，我将利用对压力诱导的抑郁行为易感性的慢性社会失败模型来研究腹侧被盖区多巴胺神经元的抑制性突触在压力易感性中的作用。在这一阶段，我将研究多巴胺神经元的两个不同子集上的抑制性突触，这些突触投射到丘脑核和投射到前额叶皮层，在动物中表现出对社会失败的不同行为反应。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。 我的长期职业目标是成为一个学术机构的独立调查员，在那里我将建立一个研究项目，调查精神疾病的突触和回路水平机制。这样的职位将使我有机会联合收割机结合我在研究、指导和教学方面的兴趣。我的研究生和博士后培训给了我一个强大的概念框架，在精神疾病的神经科学，并为我提供了一套行为，生化和电生理技能。本建议书中概述的培训计划将使我能够继续扩大我的技术和知识专长，同时获得专业技能，这将有助于我成功获得教师职位并建立创新的研究计划。在K99阶段，我将接受我的导师Julie Kauer博士和我的共同导师Chris摩尔博士、Kevin Bath博士和Scott Russo博士的培训。在他们的指导下，我将学习使用光遗传学技术和慢性社会失败压力行为范式。此外，我的培训将通过支持和大学神经科学研究社区以及布朗大学的许多专业发展机会得到加强。我的导师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位置。