Neural Circuit Basis of Behavioral Susceptibility and Resilience to Social Defeat

描述（由申请人提供）：重性抑郁症（MDD）折磨着大约9.5%的18岁以上的美国人口。迫切需要一种新的、更有效的治疗策略来治疗重度抑郁症，因为只有不到50%的抑郁症患者完全缓解，而且许多人对目前可用的以单胺为基础的传统抗抑郁药没有反应。虽然已经有超过50年的努力来了解这种疾病的神经机制，但目前的治疗方法并没有从单胺假说中得到很大的改变。最近的研究表明深部脑刺激（DBS）治疗重度抑郁症患者非常有效，因此研究的重点是发现这种治疗的潜在机制。通过这种方式，一种新的范式出现了，重度抑郁症被视为一种神经回路障碍。因此，了解MDD背后的神经回路至关重要，更重要的是，了解与该疾病相关的特定投射通路。近年来，越来越多的证据表明，类似抑郁的行为，如社交回避和快感缺乏，与腹侧被皮层（VTA）多巴胺（DA）神经元的活动改变有关，这些神经元投射到大脑的三个与情绪相关的区域：伏隔核（NAc）、内侧前额叶皮层（mPFC）和杏仁核。在慢性社交失败抑郁症小鼠模型中，韩博士及其同事先前发现，大脑奖励回路中VTA DA神经元的活动是对社交失败压力的易感性与弹性的关键决定因素。在易感小鼠中，这些神经元的放电率和破裂事件在慢性失败中显著增加，但在弹性亚组中没有。弹性亚组是一种经历了慢性社会失败，但没有表现出抑郁样行为的小鼠亚群。此外，实验（病毒或光遗传学）诱导的投射混合VTA DA神经元的放电速率和爆发放电的增加促进了易感表型，而放电速率的降低促进了恢复。有趣的是，仅在易感小鼠中，BDNF水平在VTA靶区NAc上调。在这些和其他先前的研究的基础上，本建议假设慢性社会失败导致易感小鼠VTA DA放电率和破裂机制的增加，特别是在VTA DA神经元投射到NAc。此外，假设易感性和恢复力的行为表型是由通路特异性多巴胺神经元和特定放电模式决定的。本研究旨在通过使用病毒介导的基因转移、电生理和光遗传学技术，深入表征VTA DA神经元对NAc、mPFC和杏仁核的投射特异性。这些提出的分子、细胞和行为研究将提供非常有用和高度新颖的信息，既可以提高我们对抑郁症回路的认识，也可以确定新的治疗回路靶点，从而开发出更有效的抑郁症治疗方法。

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) afflicts about 9.5% of the U.S. population over the age 18. There is an urgent need for a novel, more effective therapeutic strategy for MDD treatment, as less than 50% of depressed patients achieve full remission and many individuals are not responsive to currently available monoamine-based traditional antidepressants. While there has been over 50 years of effort made to understand the neural mechanism underlying this disease, current therapeutics have not drastically changed from the monoamine hypothesis. Recent studies have shown Deep Brain Stimulation (DBS) to be robustly efficacious in treating MDD patients and thus research has focused on discovering the underlying mechanisms of this therapy. In this way, a new paradigm has emerged with MDD being viewed as a neural circuit disorder. Therefore, it is crucial to understand the neural circuits underlying MDD, and more importantly, the specific projection pathways implicated in this disease. In recent years, an increasing body of evidence shows that depression-like behaviors such as social avoidance and anhedonia are associated with altered activity of ventral tegmental (VTA) dopamine (DA) neurons that project to three emotion-related brain regions: the nucleus accumbens (NAc), medial prefrontal cortex (mPFC) and amygdala. In a chronic social defeat mouse model of depression, Dr. Han and colleagues previously found that the activity of VTA DA neurons in the brain reward circuit is a key determinant of susceptibility vs. resilience to social defeat stress. The firing rate and bursting events of these neurons was significantly increased by chronic defeat in susceptible mice, but not in resilient subgroup, a subpopulation of mice that went through chronic social defeat, but do not show depression-like behaviors. Furthermore, an experimentally (virally or optogenetically) induced increase in the firing rate and burst firing of projection-mixed VTA DA neurons promoted a susceptible phenotype, while a decrease in the firing rate promoted resilience. Interestingly, the level of BDNF is upregulated in the VTA target area NAc only in susceptible mice. On the basis of these and other previous studies, this proposal hypothesizes that chronic social defeat induces an increase in VTA DA firing rate and bursting mechanisms specifically in VTA DA neurons projecting to the NAc, in susceptible mice. Furthermore, it is hypothesized that the behavioral phenotypes of susceptibility and resilience are determined by pathway specific dopamine neurons and specific firing patterns. This proposal seeks to intensively characterize the projection specific VTA DA neurons to the NAc, mPFC, and amygdala through the use of viral-mediated gene transfer, electrophysiological and optogenetic techniques. These proposed molecular, cellular and behavioral studies will provide very useful and highly novel information both for improving our knowledge of the circuitry of depression and for identifying new therapeutic circuitry targets to develop more effective treatments for depression. PUBLIC HEALTH RELEVANCE: Chronic stress can play a key role in the development of depression; an important question is why some people are resilient to stress, while others are not resilient. My proposed project seeks to investigate systems level analysis of stress induced social avoidance through investigations of the neural circuits governing these abnormal behaviors. I will use electrophysiological techniques, in addition to optogenetics, to test if reversing the firing patterns of abnormal circuits can reverse social avoidance.