Cell Subtype Mechanisms Underlying Stress Susceptibility and Resilence

项目概要： 压力改变了大脑奖赏回路的结构和功能，导致奖赏中断， 动机压力可能是一个主要的风险因素或触发精神疾病的发作，其中包括 动机行为改变;包括重度抑郁症、双相情感障碍、精神分裂症和后抑郁症。 创伤应激障碍目前的研究强调，需要从一个综合的角度来看待精神疾病。 电路和分子的角度来连接候选分子功能失调的细胞亚型。我们以前的工作 提供了初步的基础，了解神经核，一个主要的大脑奖励区，中等多刺 神经元（MSN）亚型对压力的反应。然而，迫切需要一个全面的 理解包括这些MSN亚型适应的内在分子调节因子和 外源性调节因子（如小胶质细胞）有助于在易受 压力，以及对压力表现出弹性反应的人。在本提案中，我们将完全描述 D1-MSN亚群，小胶质细胞的结构适应以及两者在应激中的相互作用 使用慢性社会失败压力（CSDS）和慢性目击者， 失败压力（CWDS）范式。我们将操纵小胶质细胞和D1-MSN亚群，以确定如何 这些改变影响其他类型的细胞，D1-MSN回路的活动，并最终压力脆弱或弹性 行为包括奖励价值行为。最后，使用细胞亚型RNA-seq，我们将确定小胶质细胞是如何在细胞内表达的。 D1-MSN亚型人群中冲击应激介导的分子适应以及D1-MSN如何影响应激 介导的小胶质细胞适应。总的来说，我们的研究可以提高对NAc细胞亚型的了解 在易感和弹性主体中的机制。我们的研究可以揭示未来的治疗途径， 在精神病学中模仿压力弹性机制或对抗压力敏感机制， 动机症状

Project Summary: Stress alters the structure and function of brain reward circuitry leading to disruption of reward and motivation. Stress can be a major risk factor or trigger episodes of psychiatric disorders, which encompass altered motivational behavior; including major depressive disorder, bipolar disorder, schizophrenia, and post traumatic stress disorder. Current studies emphasize a need to approach psychiatric diseases from a combined circuit and molecular perspective to link candidate molecules to dysfunctional cell subtypes. Our previous work provided an initial foundation for understanding nucleus accumbens, a major brain reward region, medium spiny neuron (MSN) subtypes in response to stress. However, there is a critical need for a comprehensive understanding that encompasses intrinsic molecular regulators of these MSN subtype adaptations and the extrinsic regulators (such as microglia) that help to shape these structural adaptations in mice susceptible to stress, as well as those displaying resilient response to stress. In this proposal we will completely characterize structural adaptations in D1-MSN subpopulations, microglia, and the interaction between the two in stress susceptible and resilient conditions of both sexes using chronic social defeat stress (CSDS) and chronic witness defeat stress (CWDS) paradigms. We will manipulate microglia and D1-MSN subpopulations to determine how these alterations affect the other cell type, D1-MSN circuit activity, and ultimately stress vulnerable or resilient behavior including reward value behaviors. Finally, using cell subtype RNA-seq we will determine how microglia impact stress mediated molecular adaptations in D1-MSN subtype populations and how D1-MSNs impact stress mediated microglia adaptations. Collectively our studies can provide improved understanding of NAc cell subtype mechanisms in susceptible and resilient subjects. Our studies could uncover future therapeutic avenues aimed at mimicking stress resilient mechanisms or combating stress susceptible mechanisms in psychiatric motivational symptoms