Cell Subtype Mechanisms Underlying Stress Susceptibility and Resilience

压力敏感性和弹性的细胞亚型机制

• 批准号: 10597331
• 负责人: Mary Kay Lobo
• 金额: $ 4.53万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597331
• 关键词: Anhedonia; Animals; Atrophic; Autopsy; Biology; Bipolar Disorder; Brain; Cell Nucleus; Cells; Chronic; Data; Doctor of Philosophy; Dopamine Receptor; Fostering; Gene Expression; Growth; Individual; Major Depressive Disorder; Mental Depression; Mental disorders; Microglia; Modeling; Molecular; Morphology; Motivation; Mus; Neurons; Neurosciences; Outcome; Phagocytes; Play; Post-Traumatic Stress Disorders; Predisposition; Rewards; Risk Factors; Rodent; Role; Schizophrenia; Shapes; Social Interaction; Stress; Structure; Time; Training; base; career development; density; motivated behavior; parent grant; resilience; reward circuitry; sex; social defeat; social stress

Summary/Abstract Repeated stress alters the structure and function of brain reward circuitry leading to disruption of the motivated pursuit of rewards. Stress can be a major risk factor or trigger episodes of psychiatric disorders, which are hallmarked by altered motivational processing observed in major depressive disorder, bipolar disorder, schizophrenia, and post-traumatic stress disorder. The nucleus is a critical brain hub for altered cellular and molecular actions underlying motivated behaviors in rodents and many of these adaptations are observed in postmortem NAc of individuals with mental illness, such as depression. Previously we uncovered dendritic atrophy, which correlated with disrupted activity and excitatory function, in NAc dopamine receptor 1 expressing medium spiny neurons (D1-MSNs), of mice displaying reduced social interaction and anhedonia after chronic social defeat stress (CSDS). While our group has delineated intrinsic mechanism that drive these morphological adaptations, the extrinsic factors are unknown. Mounting evidence implicates microglia, which play a role in shaping neuron dendritic adaptations, in social defeat stress outcomes. Thus, the parent grant investigates microglia mechanisms that may regulate D1-MSN dendritic atrophy in social stress models in both sexes. However, the proposed studies in the parent grant do not address the temporal dynamics that microglia initiate mechanisms to drive the D1-MSN atrophy during stress. Data we are generating from the parent grant suggest that microglia around D1-MSNs, in stressed animals, are phagocytic. However, these data also implicate reduced D1-MSN-microglia contact and reduced microglia density surrounding D1-MSNs suggesting that microglia have already impacted D1-MSNs at this time point where atrophy is observed. Based on this data, we hypothesize that microglia display a temporal increase in contact with NAc D1-MSNs and activation of phagocytic markers throughout social stress exposure, which will be assessed in this diversity supplement. In this proposal a set of experimental Aims and a training plan are devised to provide technical training in neuron-microglia morphological analysis and gene expression of microglia across a temporal profile of stress exposure. The technical training is accompanied by conceptual training in microglia biology, reward circuit biology, and molecular neuroscience. Additional, training and career development are outlined in the proposal to foster the candidate’s growth toward applying for a F99/K00 and completing the milestones of the PhD thesis.

摘要/摘要 重复应力改变了大脑奖励电路的结构和功能，导致破坏 积极追求奖励。压力可能是主要危险因素或触发精神疾病的发作，这是 在重度抑郁症，躁郁症中观察到的动机加工改变的标志 精神分裂症和创伤后应激障碍。核是改变细胞和改变的关键脑枢纽 在 患有精神疾病的个体（例如抑郁症的人）的NAC。以前我们发现了树突状 NAC多巴胺受体1表达萎缩，与活动和兴奋功能的破坏相关 中等棘神经元（D1-MSN），表现出降低的社交互动和慢性后的抗痛的小鼠 社交失败压力（CSD）。虽然我们的小组已经描述了驱动这些形态学的内在机制 适应，外部因素尚不清楚。越来越多的证据暗示了小胶质细胞，这在 在社会失败的压力结果中塑造神经元的树突状适应。那，父母赠款调查了 在男女中，社会压力模型中可能调节D1-MSN树突状萎缩的小胶质细胞机制。 但是，父母赠款中提出的研究并未解决小胶质细胞的临时动态 启动在应力期间驱动D1-MSN萎缩的机制。我们从父母赠款中生成的数据 表明在压力动物中D1-MSN周围的小胶质细胞是吞噬细胞。但是，这些数据也隐含 D1-MSN-Microglia接触降低，D1-MSN周围的小胶质细胞密度降低，这表明 在此时间点，小胶质细胞已经影响了D1-MSN，观察到萎缩。基于此数据，我们 假设小胶质细胞显示与NAC D1-MSN的接触暂时增加和吞噬细胞的激活 整个社会压力暴露的标志物将在这种多样性补充中进行评估。在此提案中 制定了一套实验目标和培训计划，以提供神经元 - 丝状训练的技术培训 小胶质细胞的形态分析和基因表达在压力暴露的临时特征中。 技术培训是通过小胶质细胞生物学，奖励电路生物学和 分子神经科学。培训和职业发展的其他提案概述了 候选人的成长旨在申请F99/K00并完成博士学位论文的里程碑。