Neural Circuit Basis of Behavioral Susceptibility and Resilience to Social Defeat

描述(申请人提供)：严重抑郁障碍(MDD)困扰着美国18岁以上人口的9.5%。目前迫切需要一种新的、更有效的治疗策略来治疗MDD，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单胺类传统抗抑郁药物没有反应。虽然人们已经努力了50多年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彻底改变。最近的研究表明，脑深部刺激(DBS)在治疗MDD患者方面效果显著，因此研究重点是发现这种疗法的潜在机制。通过这种方式，出现了一种新的范式，MDD被视为一种神经回路障碍。因此，了解MDD背后的神经回路是至关重要的，更重要的是，了解与这种疾病有关的特定投射通路。近年来，越来越多的证据表明，社交回避和快感缺乏等抑郁行为与腹侧被盖(VTA)多巴胺(DA)神经元的活动改变有关，这些神经元投射到与情绪相关的三个脑区：伏隔核(NAC)、内侧前额叶皮质(MPFC)和杏仁核。在一个慢性社交失败型抑郁症小鼠模型中，韩博士和他的同事此前发现，大脑奖励回路中的VTA DA神经元的活动是决定对社交失败型压力的敏感性和韧性的关键因素。这些神经元的放电率和爆裂事件在易感小鼠中因慢性挫败而显著增加，但在弹性亚群中则没有。弹性亚群是经历了慢性社会失败但没有表现出抑郁样行为的小鼠的一个亚群。此外，实验上(病毒或光遗传)诱导的混合投射的VTA DA神经元的放电频率和爆发放电的增加促进了一种敏感的表型，而放电频率的降低则促进了复原力。有趣的是，BDNF在VTA靶区NAC中的水平仅在易感小鼠中上调。在前人研究的基础上，本研究假设在易感小鼠中，慢性社会挫败导致VTA DA放电频率和放电机制的增加，特别是在投射到NAC的VTA DA神经元。此外，假设易感性和恢复力的行为表型是由通路特异性的多巴胺神经元和特异性的放电模式决定的。本研究试图通过病毒介导的基因转移、电生理和光遗传学技术，深入研究VTA DA神经元向NAC、mPFC和杏仁核的投射特征。这些拟议的分子、细胞和行为研究将提供非常有用和非常新颖的信息，既可以改善我们对抑郁症回路的了解，也可以识别新的治疗回路靶点，以开发更有效的抑郁症治疗方法。 公共卫生相关性：慢性压力可能在抑郁症的发展中发挥关键作用；一个重要的问题是，为什么有些人对压力有弹性，而另一些人则没有弹性。我提出的项目旨在通过研究控制这些异常行为的神经回路，来研究压力诱导的社交回避的系统水平分析。除了光遗传学，我还将使用电生理技术来测试逆转异常回路的放电模式是否可以逆转社交回避。

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.