Enabling Stress Resistance

描述（由申请人提供）：虽然大多数人能够在面对压力时保持心理完整性，但众所周知，压力经历会引发严重神经精神疾病（包括MDD和PTSD）的发作和复发。社会压力是常见的几乎所有的哺乳动物物种，和慢性从属压力在啮齿动物中最常见的是由一个长期的行为综合征，包括社会回避，快感缺乏，受损的应对其他环境压力的反应，和焦虑样行为的表达。在小鼠C57 BL/6 J的近交系中，显著表达的应激诱导综合征并不发生在所有遭受慢性社会失败应激的个体中，从而允许测量弹性。据推测，这些结果表明，小鼠之间的个体差异介导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 大多数旨在调查对慢性应激的易感性的研究是基于在先前已经暴露于慢性应激的小鼠中进行的实验，或者在应激暴露之前进行分子操作的小鼠这里提出使用多回路体内记录结合回路选择性调制，所述回路选择性调制使用仅由设计药物激活的设计受体（DREADDs）来表征介导C57 BL/6 J小鼠对应激的抗性的基于电路的机制。这项研究的基本原理是，皮质-杏仁核回路功能的变化与应激反应有关，而对该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水平的理解压力暴露如何最终改变跨神经回路的活动，调节恐惧和奖励处理，并揭示新的基于回路的情绪和焦虑症治疗干预目标。

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.