Neural Circuit Basis of Behavioral Susceptibility and Resilience to Social Defeat

行为易感性和对社会失败的抵抗力的神经回路基础

• 批准号: 8316570
• 负责人: Jessica Jillian Walsh
• 金额: $ 3.3万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316570
• 关键词: Age; Amygdaloid structure; Anhedonia; Animals; Antidepressive Agents; Area; Behavior; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; Chronic; Chronic stress; Deep Brain Stimulation; Depressed mood; Development; Disease; Disease remission; Dopamine; Dyes; Emotions; Event; Frequencies; Functional disorder; Gene Transfer; Goals; Hyperactive behavior; Individual; Innovative Therapy; Investigation; Knowledge; Major Depressive Disorder; Measures; Medial; Mediating; Mental Depression; Modeling; Molecular; Mus; Neurons; Nucleus Accumbens; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Play; Population; Predisposition; Prefrontal Cortex; Research; Rewards; Role; Social Interaction; Specificity; Stress; Subgroup; Sucrose; System; Techniques; Testing; Therapeutic; Treatment Efficacy; Variant; Ventral Tegmental Area; Viral; Virus; Work; base; dopaminergic neuron; effective therapy; improved; interest; mesolimbic system; monoamine; mouse model; neural circuit; neuromechanism; novel; novel therapeutics; optogenetics; preference; resilience; social; theories

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.

描述（由申请人提供）：重度抑郁症（MDD）困扰着约9.5%的美国18岁以上人口。迫切需要一种新的，更有效的治疗策略来治疗MDD，因为不到50%的抑郁症患者达到完全缓解，许多人对目前可用的基于单胺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，目前的治疗方法还没有从单胺假设急剧变化。最近的研究表明，脑深部电刺激（DBS）在治疗MDD患者方面非常有效，因此研究重点是发现这种疗法的潜在机制。这样，一个新的范式已经出现，MDD被视为一种神经回路障碍。因此，了解MDD潜在的神经回路至关重要，更重要的是，这种疾病涉及的特定投射通路。近年来，越来越多的证据表明，抑郁样行为如社交回避和快感缺乏与腹侧被盖（VTA）多巴胺（DA）神经元活动的改变有关，这些多巴胺神经元投射到与情绪相关的三个脑区：丘脑核（NAc）、内侧前额叶皮层（mPFC）和杏仁核。在慢性社会失败抑郁症小鼠模型中，Han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会失败压力的敏感性与弹性的关键决定因素。这些神经元的放电率和爆发事件在易感小鼠中的慢性失败中显着增加，但在弹性亚组中则没有，弹性亚组是经历慢性社会失败的小鼠亚群，但没有表现出抑郁样行为。 此外，实验（病毒或光遗传学）诱导的发射率和突发发射的投射混合腹侧被盖区DA神经元的增加促进易感表型，而发射率的降低促进弹性。有趣的是，BDNF的水平仅在易感小鼠的VTA靶区NAc中上调。在这些和其他以前的研究的基础上，本建议假设，慢性社会失败诱导增加腹侧被盖区DA放电率和爆裂机制，特别是在腹侧被盖区DA神经元投射到NAc，在易感小鼠。此外，据推测，易感性和弹性的行为表型是由特定的多巴胺神经元和特定的放电模式的途径。该提案旨在通过使用病毒介导的基因转移、电生理学和光遗传学技术来集中表征投射特异性VTA DA神经元到NAc、mPFC和杏仁核。这些提出的分子，细胞和行为研究将提供非常有用的和高度新颖的信息，既为提高我们的知识抑郁症的电路和确定新的治疗电路的目标，以开发更有效的治疗抑郁症。 公共卫生关系：慢性压力在抑郁症的发展中起着关键作用;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调查控制这些异常行为的神经回路来研究压力引起的社会回避的系统水平分析。除了光遗传学，我还将使用电生理学技术来测试是否逆转异常回路的放电模式可以逆转社交回避。