Microglia and Adolescent Susceptibility to Developing an Alcohol Use Disorder

酒精的使用和滥用通常始于青春期，在青春期，许多因素相互碰撞， 过量摄入。最引人注目的是，那些在青春期饮酒的人，特别是 在15岁之前，成年后患酒精使用障碍的可能性是成年后的四倍。这 表明酒精会影响青少年的大脑，使其更容易受到 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。 由于酒精的损害，这导致了几个小组检查随后的神经炎症 酒精使用障碍的信号。神经炎症的标志是小胶质细胞活化。 小胶质细胞是大脑中的三种非神经元胶质细胞之一，它们充当大脑的 免疫系统，但他们在酒精使用障碍的作用知之甚少。小胶质细胞显示a 从有益到细胞毒性的全谱表型和这些小胶质细胞的表型 酒精暴露没有定义。此外，小胶质细胞可以通过事件变得“启动”， 然后，在随后的挑战，他们积极过度反应，一个现象交织在一起， 它们的表型。小胶质细胞启动似乎在发育中更为明显， 暴露于免疫损伤对多种成人结果具有长期后果。因此，在本发明中， 在青少年发育期间，酒精引发或激活小胶质细胞可能导致长时间的 长期后果。因此，这项提议的首要假设是， 与成人相比，青少年更容易受到酒精引发的小胶质细胞的影响， 引发对酒精诱导的神经病理学和成瘾相关的神经病理学产生长期影响。 行为我们将通过以下三个具体目标来检验这一假设：（1）确定 青少年对酒精诱导的小胶质细胞影响的易感性，（2）检查是否 青少年对酒精引发的小胶质细胞有更大的易感性;（3）阐明 小胶质细胞引发成瘾相关行为。通过了解引发 青少年大脑容易发展为酒精使用障碍，更好的干预措施 并且可以开发治疗方法，这样我们就可以减少酒精使用障碍的发生率。

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.