Microglia and Adolescent Susceptibility to Developing an Alcohol Use Disorder

小胶质细胞和青少年对酒精使用障碍的易感性

• 批准号: 9403830
• 负责人: Kimberly Nixon
• 金额: $ 42.61万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403830
• 关键词: Adolescence; Adolescent; Adolescent Behavior; Adolescent Development; Adult; Age; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcohols; Attention; Behavior; Behavior Control; Behavioral; Biological Assay; Brain; Brain Injuries; Brain region; Cells; Coupled; Data; Development; Disease; Dose; Employee Strikes; Event; Exposure to; Flow Cytometry; Grant; Growth Factor; HMGB1 gene; Heavy Drinking; Histology; Hypersensitivity; Immune; Immune system; Impulsivity; Incidence; Intake; Intervention; Long-Term Effects; Microglia; Morphology; Motivation; Nerve Degeneration; Neuroglia; Neuroimmune; Outcome; Pathology; Phenotype; Predisposition; Process; Publishing; Rattus; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Signal Transduction; Surface Antigens; System; Testing; Therapeutic Intervention; Time; addiction; adolescent alcohol; adolescent alcohol exposure; alcohol effect; alcohol exposure; alcohol response; alcohol use disorder; behavioral impairment; brain behavior; cytokine; cytotoxic; cytotoxicity; discount; discounting; drug of abuse; early life exposure; immune activation; immune function; in vivo; inflammatory marker; interest; macrophage; neuroinflammation; neuropathology; neuroprotection; neurotoxic; new therapeutic target; preference; protein expression; response; underage drinking

Alcohol use and abuse often begins in adolescence where many factors collide to promote excessive intake. Most striking though is that those who drink during adolescence - specifically before age 15 - are four times more likely to develop an alcohol use disorder in adulthood. This suggests that alcohol impacts the adolescent brain in such a way to make it more susceptible to developing an alcohol use disorder. Indeed, the adolescent brain is more susceptible to brain damage due to alcohol, which has led several groups to examine subsequent neuroinflammatory signaling in alcohol use disorders. A hallmark of neuroinflammation is microglial activation. Microglia are one of the three types of non-neuronal, glia cells in the brain that act as the brain’s immune system, but their role in alcohol use disorders is poorly understood. Microglia display a full spectrum of phenotypes from beneficial to cytotoxic and the phenotype of these microglia after alcohol exposure has not been defined. Further, microglia may become “primed” by an event, then upon subsequent challenge they aggressively over-respond, a phenomenon intertwined with their phenotype. Microglia priming appears to be more evident in development, where early life exposure to immune insult has long-term consequences on a variety of adult outcomes. Thus, the priming or activation of microglia by alcohol during adolescent development may result in long term consequences. Therefore, the overarching hypothesis of this proposal is that young adolescents are more to susceptible to microglia priming by alcohol versus adults and that alcohol priming produces long term effects on alcohol-induced neuropathology and addiction-relevant behavior. We will test this hypothesis through three specific aims that (1) determine the adolescent’s susceptibility to alcohol-induced effects on microglia, (2) examine whether adolescents have a greater susceptibility to alcohol priming microglia and (3) elucidate the role of microglia priming in addiction-relevant behavior. By understanding the events that prime the adolescent brain to be susceptible to developing an alcohol use disorders, better interventions and treatments can be developed so that we can reduce the incidence of alcohol use disorders.

饮酒和滥用通常从青少年开始，许多因素相撞以促进 摄入过多。虽然最引人注目的是那些在青少年期间喝酒的人 - 特别是 在15岁之前 - 成年后发生饮酒障碍的可能性要高四倍。这 表明酒精会以这种方式影响青春期的大脑，以使其更容易受到影响 发展饮酒障碍。确实，青春期大脑更容易受到大脑的影响 由于酒精而造成的损害，这导致几组检查随后的神经炎症 酒精使用障碍中的信号。神经炎症的标志是小胶质细胞激活。 小胶质细胞是大脑中的三种非神经元细胞之一，充当大脑 免疫系统，但是它们在酒精使用障碍中的作用知之甚少。小胶质细胞显示 从有益到细胞毒性和这些小胶质细胞的表型的全光谱 酒精暴露尚未定义。此外，小胶质细胞可能会被事件“启动”， 然后，在随后的挑战下，他们积极地超越了，这一现象与 他们的表型。小胶质细胞启动似乎是开发中的更多证据，早期生活 暴露于免疫损伤对各种成人结果产生长期后果。那， 在青春期发育过程中，酒精对小胶质细胞的启动或激活可能会导致长期 术语后果。因此，该提议的总体假设是年轻 青少年更容易受到酒精与成人的小胶质细胞的影响，并且酒精 启动对酒精引起的神经病理学和与成瘾相关的长期影响 行为。我们将通过（1）确定的三个特定目的来检验这一假设 青少年对酒精引起的小胶质细胞影响的敏感性，（2）检查是否是否 青少年对酒精灌注小胶质细胞具有更大的敏感性，（3）阐明 与成瘾的行为中的小胶质细胞启动。通过了解启动的事件 青少年大脑容易患上酒精含量障碍，更好的干预措施 并且可以开发治疗，以便我们可以减少酒精使用障碍的事件。