Neurophysiological Basis of Susceptibility and Resilience to Social Defeat Stress

描述(由申请人提供)：由于目前可用的抗抑郁药物，只有不到50%的抑郁症患者完全缓解，许多患者没有反应，因此迫切需要更有效的药物来治疗严重抑郁障碍(MDD)。众所周知，长期的应激事件是MDD的一个重要原因。然而，个体对压力的反应有一个有趣的差异：大多数经历压力事件的人保持正常的心理功能(对压力的弹性)，而其他人则发展成抑郁(对压力的敏感性)。许多心理社会技能已经成功地应用于我们的日常生活中，以促进压力恢复能力。最近的研究已经开始揭示这些心理社会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边缘奖赏神经回路的功能有关。与这一观点一致，我们先前发现，腹侧被盖区(VTA)多巴胺(DA)神经元在同一奖励回路中的活动是决定对社会失败应激的敏感性和韧性的关键决定因素。在易感但没有弹性的小鼠中，这些神经元的放电率因慢性挫败而显着增加。此外，实验诱导的放电减少提高了复原力，而增加的放电则提高了敏感性。令人惊讶的是，在分子水平上，慢性挫败在弹性小鼠中比在敏感亚群中调节更多的基因，并仅在弹性小鼠中诱导了几个K+通道的显著上调，这可能会促使更高的激发恢复到正常水平。这些发现有力地支持了这样的观点，即弹性表型不是简单地被动地缺乏应激诱导的病理生理学，而是一种可促进的和积极的大脑功能，动物通过激活更多的基因来成功地应对应激条件。在目前的项目中，我们问：(1)VTA DA神经元生理上重要的放电模式是否编码了应激脆弱的信号，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)机制来寻找潜在的药物靶点。因此，我们建议使用先进的光遗传技术直接将特定的放电模式与自由活动动物的应激敏感性和弹性联系起来。我们还将深入探索失败导致VTA DA神经元放电特性变化的通道和受体基础，特别是研究主动弹性的离子机制。此外，这些新的离子和受体机制在调节标准的抗抑郁作用中的作用将被系统地研究。这些拟议的分子和细胞研究将提供非常有用和非常新颖的信息，既可以提高我们对抑郁症的认识，也可以识别新的药物靶点，以开发更有效的抑郁症治疗方法。这种治疗将基于模仿自然产生的复原力的积极应对机制，因此可能更有效，更不容易产生副作用。

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.