Enabling Stress Resistance

描述(申请人提供)：虽然大多数人能够在面对压力时保持心理健康，但众所周知，压力经历会引发包括MDD和PTSD在内的严重神经精神疾病的发作和复发。社会压力在几乎所有哺乳动物物种中都是常见的，啮齿动物的慢性从属压力最常见的是表现出一种长期的行为综合征，包括社交回避、快感缺乏、对其他环境应激源的应对反应受损，以及类似焦虑的行为。在近交系小鼠C57BL/6J中，并不是所有处于慢性社会失败压力下的个体都会出现显著表达的应激诱导综合征，因此可以测量弹性。据推测，这些结果表明，老鼠之间的个体差异调节了对慢性应激有害影响的易感性或抵抗力。然而，这一假设缺乏明确的验证，因为 大多数旨在研究慢性应激易感性的研究都是基于在先前已暴露于慢性应激的小鼠身上进行的实验，或在应激暴露前接受分子操作(最终改变正常大脑功能)的小鼠身上进行的实验。本研究建议使用多回路活体记录与使用由设计药物(DREADD)专属激活的设计受体(DREADD)进行的电路选择性调制相结合，以表征C57BL/6J小鼠介导应激抵抗的基于电路的机制。这项拟议的研究的基本原理是，皮质-杏仁核回路功能的变化将与应激反应相关，而这一回路的直接调节将改变小鼠的应激抵抗力。这一策略将提供前所未有的电路层面的理解，了解应激暴露如何最终改变调节恐惧和奖励处理的神经回路的活动，并揭示情绪和焦虑症治疗干预的新回路靶点。

DESCRIPTION (provided by applicant): Though most individuals are capable of maintaining psychological integrity in the face of stress, stress-experiences are well known for instigating th onset and relapse of severe neuropsychiatric disorders including MDD and PTSD. Social stress is common to practically all mammalian species, and chronic subordination stress in rodents is most often followed by the expression of a long-lasting behavioral syndrome that includes social avoidance, anhedonia, impaired coping responses to other environmental stressors, and anxiety-like behaviors. Within the inbred strain of mouse C57BL/6J, the prominently expressed stress-induced syndrome does not occur in all individuals subjected to chronic social defeat stress, thereby allowing for measurements of resiliency. Presumably, these results suggest that individual differences across mice mediate the susceptibility or resistance to the deleterious effects of chronic stress. Nevertheless, unequivocal validation of this hypothesis is lacking since the majority of studies aimed at investigating susceptibility to chronic stress are based on experiments performed in mice that have been previously exposed to chronic stress, or mice that are subjected to molecular manipulations prior to stress exposure (ultimately altering normal brain function).Here were propose to use multi-circuit in vivo recording in conjunction with circuit selective modulation using designer receptors exclusively activated by designer drugs (DREADDs) to characterize the circuit based mechanisms that mediate resistance to stress in C57BL/6J mice. The rationale that underlies the proposed research is that variations in cortical-amygdala circuit function will be associated with stress responses, and that direct modulation of this circuit will alter stress resistance across mice. This strategy will provide an unprecedented circuit level of understanding of how stress exposure ultimately alters activity across neural circuits that regulate fear and reward processing and reveal new circuit based targets for therapeutic intervention for mood and anxiety disorders.