Neurophysiological Basis of Susceptibility and Resilience to Social Defeat Stress

对社会失败压力的敏感性和恢复力的神经生理学基础

• 批准号: 8645750
• 负责人: Ming-Hu Han
• 金额: $ 42.29万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645750
• 关键词: Adverse effects; Animal Model; Animals; Antidepressive Agents; Back; Behavior; Behavioral; Brain; Chronic; Chronic stress; Data; Depressed mood; Development; Disease remission; Drug Targeting; Exposure to; Functional disorder; Genes; Goals; In Vitro; Individual; Ion Channel; Knowledge; Life; Light; Link; Major Depressive Disorder; Mediating; Mediator of activation protein; Mental Depression; Mission; Modeling; Molecular; Mus; National Institute of Mental Health; Neurobiology; Neurons; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Play; Potassium Channel; Predisposition; Property; Regulation; Research Personnel; Rewards; Role; Signal Transduction; Social Interaction; Stress; Stressful Event; Subgroup; Sucrose; Techniques; Testing; United States National Institutes of Health; Up-Regulation; Ventral Tegmental Area; Work; base; coping; coping mechanism; dopamine system; dopaminergic neuron; effective therapy; experience; hyperpolarization-activated cation channel; improved; in vivo; inhibitor/antagonist; neural circuit; neurophysiology; novel; optogenetics; positive emotional state; preference; psychologic; psychosocial; receptor; resilience; response; skills; social

DESCRIPTION (provided by applicant): There is an urgent need for more effective medications for major depressive disorder (MDD) treatment, as less than 50% of depressed patients achieve full remission and many are not responsive, with currently available antidepressants. It is known that prolonged stressful events are an important cause of MDD. However, there is an intriguing difference in individual responses to stress: most people experiencing stressful events maintain normal psychological functioning (resilience to stress), whereas others develop depression (susceptibility to stress). Many psychosocial skills have been successfully used in our daily life to promote stress resiliency. Recent studies have begun to reveal the neurobiological basis for these psychosocial resilient factors, and show that positive emotions and mutual cooperation are linked to the function of the mesolimbic reward neural circuit. Consistent with this idea, we previously found that the activity of ventral tegmental area (VTA) dopamine (DA) neurons in the same reward circuit is a key determinant of susceptibility vs. resilience to social defeat stress. The firing rate of these neurons was significantly increased by chronic defeat in susceptible but not resilient mice. Furthermore, experimentally induced decreased firing promoted resilience, while increased firing promoted susceptibility. Surprisingly, at the molecular level, chronic defeat regulated more genes in resilient mice than in the susceptible subgroup, and induced dramatic upregulation of several K+ channels only in resilient mice, which may drive the higher firing back to normal levels. These findings strongly support the notion that a resilience phenotype is not simply a passive absence of stress-induced pathophysiology, but a promotable and active brain function by which animals successfully cope with stressful conditions via activation of more genes. In the current project, we ask: (1) whether the physiologically important firing patterns of VTA DA neurons encode the signal of stress vulnerability and play a role in active coping or deleterious behaviors; (2) whether we can find potential drug targets by understanding the molecular (ion channel and receptor) mechanisms of susceptibility and active resilience. Accordingly, we propose to use advanced optogenetic techniques to directly link specific firing patterns to stress susceptibility and resilience in freely-moving animals. We will also intensively explore the channel and receptor basis of defeat-induced changes in the firing properties of VTA DA neurons and particularly investigate the ionic mechanisms of active resiliency. Moreover, the roles of these new ionic and receptor mechanisms in mediating standard antidepressant action will be systematically investigated. These proposed molecular and cellular studies will provide very useful and highly novel information, both for improving our knowledge of depression and for identifying new drug targets to develop more effective treatments for depression. Such treatments would be based on imitating active coping mechanisms of naturally occurring resilience and therefore might be likely to be more effective and less prone to side effects.

描述（由申请人提供）：迫切需要对重度抑郁症（MDD）治疗的更有效的药物，因为不到50％的抑郁症患者可以完全缓解，许多人没有反应迅速，目前可用的抗抑郁药。众所周知，长时间的压力事件是MDD的重要原因。但是，个人对压力的反应有很有趣的差异：大多数经历压力事件的人保持正常的心理功能（对压力的韧性），而其他人则会发展抑郁症（对压力的敏感性）。在我们的日常生活中，许多心理社会技能已成功地用于促进压力弹性。最近的研究开始揭示了这些社会心理弹性因素的神经生物学基础，并表明积极的情绪和相互合作与中脑脱脂奖励神经回路的功能有关。与这个想法一致，我们先前发现，在同一奖励电路中腹侧对接区域（VTA）多巴胺（DA）神经元的活动是易感性与对社交失败压力的弹性的关键决定因素。这些神经元的发射率因易感但没有弹性的小鼠而慢性失败显着提高。此外，通过实验诱导的减小降低促进了弹性，同时发射的增加促进了敏感性。令人惊讶的是，在分子水平上，慢性失败调节了弹性小鼠中比易感亚组更多的基因，并且仅在弹性小鼠中诱导了几个K+通道的急剧上调，这可能会将较高的射击恢复到正常水平。这些发现强烈支持这样的观念，即弹性表型不仅是被动缺乏应激诱导的病理生理学，而且是可促进和活跃的大脑功能，通过激活更多基因，动物成功地应对压力状况。在当前项目中，我们问：（1）VTA DA神经元的生理上重要的射击模式是否编码了压力脆弱性的信号并在主动应对或有害行为中发挥作用； （2）我们是否可以通过了解易感性和主动弹性的分子（离子通道和受体）机制来找到潜在的药物靶标。因此，我们建议使用先进的光遗传技术将特定的射击模式与压力敏感性和自由移动动物的韧性联系起来。我们还将深入探讨VTA DA神经元的发射特性变化的通道和受体基础，并特别研究主动弹性的离子机制。此外，将系统地研究这些新离子和受体机制在介导标准抗抑郁作用中的作用。这些提出的分子和细胞研究将提供非常有用的和高度新颖的信息，既可以改善我们对抑郁症的了解，又用于识别新药物靶标，以开发更有效的抑郁症治疗方法。这种处理将基于模仿天然发生的弹性的主动应对机制，因此可能更有效，也不太容易发生副作用。