Corticolimbic Neuroimmune Determinants of Social Stress-Associated Alcohol Drinking

社交压力相关饮酒的皮质边缘神经免疫决定因素

• 批准号: 10602436
• 负责人: Reesha Patel
• 金额: $ 17.26万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-05 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602436
• 关键词: Alcohol consumption; Alcohols; Amygdaloid structure; Anxiety; Automobile Driving; Behavior; Behavioral; Brain; Brain region; Calcium; Cells; Data; Development; Development Plans; Diet; Dissection; Electrophysiology (science); Emotions; Faculty; Fluorescence-Activated Cell Sorting; Genes; Health; Human; Image; Individual; Link; Macrophage; Measures; Medial; Mediating; Microglia; Motivation; Mus; Neuroimmune; Neurons; Nucleus Accumbens; Outcome; Pathologic; Pattern; Peripheral; Pharmaceutical Preparations; Positioning Attribute; Predisposition; Prefrontal Cortex; Regulation; Research; Risk Factors; Rodent; Role; Shapes; Signal Transduction; Social Hierarchy; Social isolation; Social status; Socioeconomic Status; Stress; Technology; Testing; Therapeutic Intervention; Training; Water; alcohol free; alcohol intervention; alcohol use disorder; brain shape; cell type; drinking; experience; experimental study; genetic manipulation; health disparity; in vivo; mortality; neural; neuroadaptation; neurobiological mechanism; neuroinflammation; neuropsychiatric disorder; nonhuman primate; optogenetics; prevent; programs; recruit; response; social; social determinants; social stress; stressor; targeted treatment; tenure track; transcriptome sequencing; transcriptomics; virtual

PROJECT SUMMARY Social stress is a prevailing factor in the lives of all social species and can motivate the misuse of reinforcing drugs such as alcohol. Individuals that use alcohol to alleviate the negative emotions created by social stress are more likely to develop pathological drinking patterns, which can lead to an alcohol use disorder (AUD). Indeed, an individual’s standing in a social hierarchy (i.e. social rank) is inversely related to alcohol consumption in rodents and non-human primates as well as problematic drinking in humans, highlighting the conserved impact of subordination stress on motivation for alcohol. Social rank also influences how individuals respond to challenges, and social isolation is a particularly profound stressor with increasing human relevance. Our preliminary data identify a previously unknown relationship between mouse social rank and isolation- associated escalated alcohol drinking, where subordinates display a greater magnitude increase in drinking following social isolation compared to dominants. These data suggest that low social rank may be a potent risk factor for developing pathological alcohol drinking patterns. Understanding the neurobiological mechanisms by which social stress experiences engender aberrant alcohol drinking could have important translational implications for AUD. It is becoming increasingly evident that social stress induces microglia-mediated neuroimmune responses in select stress-responsive brain regions, including the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC), which contribute to stress-induced behavioral adaptations. Notably, social isolation-induced escalation of alcohol strongly parallels increases in microglia previously seen following social stress, supporting a potential role for microglia in isolation-induced adaptations in alcohol drinking. Despite the substantial evidence linking social stress and alcohol drinking as well as the impact of social stress on neuroimmune signaling, virtually nothing is known regarding the neuroimmune regulation of circuits underlying social stress-induced behavioral adaptions in alcohol drinking. To fill this gap, this proposal will test the central hypothesis that social stress activates microglia-mediated neuroimmune signaling, which re-shapes amygdalar-cortical circuits underlying escalated alcohol drinking. Preliminary data show that social isolation increases BLA excitability, and the BLA-mPFC circuit regulates alcohol drinking. Dr. Patel will use her new training in advanced circuit imaging and dissection technologies and previous training in cell type specific transcriptomic analysis and ex vivo electrophysiology to 1) dissect the BLA-mPFC contribution to social rank- and isolation-induced alcohol drinking, 2) delineate the impact of BLA substrates on mPFC encoding of alcohol consumption, and 3) identify social stress-induced neuroimmune determinants driving circuit adaptations underlying aberrant alcohol drinking. In executing the proposed experiments and professional development plan, Dr. Patel will be well-positioned to transition to a tenured-track faculty position and establish an independent research program centered around neuroimmune and social stress regulation of circuits in AUD.

项目摘要 社会压力是所有社会物种生活中普遍存在的因素，可以激发滥用强化。 药物，如酒精。使用酒精来缓解社会压力产生的负面情绪的人 更有可能发展出病态的饮酒模式，这可能导致酒精使用障碍（AUD）。 事实上，一个人在社会等级中的地位（即社会等级）与酒精呈负相关 啮齿动物和非人类灵长类动物的消费以及人类的饮酒问题，突出了 服从压力对饮酒动机的保守影响。社会等级也影响着个人 社会孤立是一个特别深刻的压力源，与人的关系越来越大。 我们的初步数据确定了老鼠社会等级和孤立之间的一种以前未知的关系- 相关的饮酒量增加，下属的饮酒量增加幅度更大 与统治者相比，社会孤立。这些数据表明，低社会地位可能是一个潜在的风险 形成病理性饮酒模式的因素。了解神经生物学机制， 哪些社会压力经历会导致异常饮酒， 对AUD的影响越来越明显的是，社会压力诱导小胶质细胞介导的 选择应激反应脑区的神经免疫反应，包括基底外侧杏仁核（BLA） 和内侧前额叶皮层（mPFC），这有助于压力诱导的行为适应。值得注意的是， 社交孤立引起的酒精升级与先前观察到的小胶质细胞的增加密切相关， 社会压力，支持小胶质细胞在饮酒中的隔离诱导的适应中的潜在作用。 尽管有大量证据表明社会压力和饮酒以及社会压力的影响有关， 关于神经免疫信号，实际上对神经免疫调节回路一无所知。 饮酒中潜在的社会压力诱导的行为适应。为了填补这一空白，该提案将测试 核心假设是社会压力激活了小胶质细胞介导的神经免疫信号， 杏仁核-皮层回路导致饮酒量增加初步数据显示，社交孤立 增加BLA兴奋性，BLA-mPFC回路调节饮酒。帕特尔医生会用她新的 高级电路成像和解剖技术培训，以及细胞类型特异性 转录组学分析和离体电生理学，以1）剖析BLA-mPFC对社会等级的贡献- 2）描述BLA底物对mPFC编码酒精的影响 消费，以及3）确定社会压力诱导的神经免疫决定因素驱动电路适应 潜在的异常饮酒在执行拟议的实验和专业发展 帕特尔将处于有利地位，过渡到终身教职，并建立一个 独立的研究项目围绕AUD中神经免疫和社会应激回路的调节。