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.

总结/摘要 反复的压力改变了大脑奖赏回路的结构和功能，导致大脑皮层的破坏。 积极追求奖励。压力可能是一个主要的风险因素或引发精神疾病， 其特征是在重度抑郁症、双相情感障碍、 精神分裂症和创伤后应激障碍细胞核是改变细胞和 啮齿类动物动机行为背后的分子作用和许多这些适应性被观察到， 有精神疾病的人的死后NAc，如抑郁症。之前我们发现了树突状细胞 在NAc多巴胺受体1表达中， 中棘神经元（D1-MSNs）的小鼠显示减少的社会互动和快感缺乏，慢性 社交失败压力（CSDS）。虽然我们的团队已经描绘了驱动这些形态学的内在机制， 适应，外在因素是未知的。越来越多的证据表明，小胶质细胞在 塑造神经元树突的适应，在社会失败的压力结果。因此，父母补助金调查 小胶质细胞机制，可能会调节D1-MSN树突萎缩的社会压力模型在两种性别。 然而，在父母补助金的拟议研究没有解决的时间动态，小胶质细胞 启动机制，在压力期间驱动D1-MSN萎缩。我们从父母补助金中生成的数据 提示在应激动物中D1-MSNs周围的小胶质细胞是吞噬细胞。然而，这些数据也表明， D1-MSN-小胶质细胞接触减少和D1-MSN周围小胶质细胞密度降低，表明 在观察到萎缩的时间点，小胶质细胞已经影响D1-MSN。根据这些数据，我们 假设小胶质细胞与NAc D1-MSNs接触和吞噬细胞活化显示暂时增加， 在整个社会压力暴露的标记，这将在这个多样性补充评估。本提案中 设计了一套实验目标和培训计划，以提供神经元小胶质细胞的技术培训 形态学分析和基因表达的小胶质细胞在整个应激暴露的时间概况。的 技术培训伴随着小胶质细胞生物学，奖励电路生物学， 分子神经科学此外，建议中还概述了培训和职业发展，以促进 申请F99/K 00和完成博士论文的里程碑候选人的成长。