Cell-type and whole-brain dynamics underlying operant social stress resiliency

项目摘要 长期的高水平的压力与许多神经精神疾病共病，如重大 抑郁症（MDD），并可能对个人，他们的照顾者和医疗保健产生破坏性影响 专业人士MDD通常被划分为表现出悲伤的情绪，严重的动力丧失， 可以用社会赤字来定义。越来越多的文献表明，重度抑郁症的影响， 包括压力和奖赏回路在内的边缘脑区失调。尽管临床上 意识，情感障碍回路和相关神经元的直接临床前表征 目前还不存在将性别作为生物变量的机制，特别是不包括社会因素， 决策和动机作为行为指标。因此，我的建议旨在 必要的计算，行为和解剖训练，以识别，询问和操纵神经 调节这些复杂社会行为的群体。 本项目将集中在确定核神经元（NAc）电路和细胞类型的具体机制 调节对操作性社会压力（OSS）的弹性，然后进一步询问传入投射 驱动这些人口。OSS将社会决策和社会奖励作为社会决策的指标。 强调弹性。这个大脑区域的选择是基于融合的初步数据，这意味着 NAc多巴胺受体（Drd）1和Drd 2中棘神经元（MSN）在调节多巴胺受体（DRd）1和DRd 2的表达方面具有相反的作用。 应对社会压力的弹性。NAc回路和细胞类型特异性激活将使用以下组合来识别： 全脑清除、Fos（神经元活性的标志物）免疫组织化学和逆行病毒追踪。 由于Fos在这些行为期间的有限时间分辨率，唤醒行为光纤光度学 记录将用于观察NAc MSN如何编码不同水平的易感性和弹性， OSS实时监控接下来，NAc及其传入投射的因果意义将通过使用 区域、电路和细胞类型特异性光遗传学操纵。了解驱动大脑的神经机制 以性别依赖的方式运作的社会压力将允许发展更具体和有效的 治疗情感性情绪障碍，如重度抑郁症（MDD）。

Project Summary Prolonged elevated levels of stress are comorbid with many neuropsychiatric illnesses such as major depressive disorder (MDD), and can have devastating effects on individuals, their caretakers, and healthcare professionals. MDD is typically demarcated as exhibiting emotions of sadness, significant loss of motivation, and can be defined by social deficits. A growing literature indicates that major depressive disorder is influenced by dysregulation in limbic brain regions including stress and reward circuitry. Despite a significant clinical awareness, direct preclinical characterization of affective disorder circuitry and associated neuronal mechanisms inclusive of sex as a biological variable are currently absent, and notably do not include social decision making and motivation as behavioral metrics. Therefore, the aim of my proposal is to obtain the necessary computational, behavioral and anatomical training to identify, interrogate, and manipulate neural populations that modulate these complex social behaviors. This project will focus on identifying nucleus accumbens (NAc) circuit and cell type specific mechanisms that regulate resiliency to operant social stress (OSS), and then further interrogate the afferent projections driving these populations. OSS incorporates social decision making and social reward as metrics for social stress resiliency. The choice of this brain region is based on converging preliminary data, implicating that the NAc dopamine receptor (Drd) 1 and Drd2 medium spiny neurons (MSNs) confer opposing roles in regulating resiliency to social stress. NAc circuit and cell-type specific activation will be identified using a combination of whole brain clearing, Fos (a marker of neuronal activity) immunohistochemistry, and retrograde viral tracing. Because of the limited temporal resolution of Fos during these behaviors, awake-behaving fiber photometry recordings will be used to observe how NAc MSNs encode varying levels of susceptibility and resiliency to OSS in real-time. Next, the causal significance of the NAc and its afferent projections will be examined using region, circuit, and cell type specific optogenetic manipulations. Understanding the neural mechanisms driving operant social stress in a sex-dependent manner will allow for the development of more specific and effective treatments for affective mood disorders such as major depressive disorder (MDD).