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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

基本信息

批准号：
10227964
负责人：
Kimberly Nixon
金额：
$ 42.11万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227964
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 Dose Enzyme-Linked Immunosorbent Assay 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 exposure alcohol effect alcohol exposure alcohol response alcohol use disorder behavioral impairment brain behavior cytokine cytotoxic cytotoxicity 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

项目摘要

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.

酒精的使用和滥用通常始于青春期，此时许多因素相互碰撞，促进酒精的使用和滥用。摄入过多。但最引人注目的是那些在青春期饮酒的人——特别是 15 岁之前 - 成年后患酒精使用障碍的可能性是其他人的四倍。这表明酒精会影响青少年的大脑，使其更容易受到影响出现酒精使用障碍。事实上，青少年的大脑更容易受到大脑的影响。酒精造成的损害，这导致几个小组检查随后的神经炎症酒精使用障碍中的信号传导。神经炎症的一个标志是小胶质细胞激活。小胶质细胞是大脑中三种非神经元胶质细胞之一，充当大脑的免疫系统，但人们对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的全谱表型以及这些小胶质细胞的表型酒精暴露尚未定义。此外，小胶质细胞可能会因某个事件而“启动”，然后，在随后的挑战中，他们会做出积极的过度反应，这种现象与他们的表型。小胶质细胞启动似乎在发育过程中更为明显，其中早期生命暴露于免疫损伤会对多种成人结局产生长期影响。因此，在青少年发育过程中，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，该提案的总体假设是年轻人与成年人相比，青少年更容易受到酒精引发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成瘾相关产生长期影响行为。我们将通过三个具体目标来检验这一假设：(1) 确定青少年对酒精引起的小胶质细胞影响的易感性，（2）检查是否青少年对酒精启动小胶质细胞更敏感，并且（3）阐明了小胶质细胞启动成瘾相关行为。通过了解引发事件的事件青少年大脑容易出现酒精使用障碍，需要更好的干预措施我们可以开发治疗方法来减少酒精使用障碍的发生率。