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，这是多种因素相互作用的结果 摄入过多。然而，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普通人的四倍。这 表明酒精以这种方式影响青少年的大脑，使其更容易受到 出现酒精使用障碍。的确，青春期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递。神经炎症的一个特征是小胶质细胞的激活。 小胶质细胞是大脑中充当大脑的三种非神经元胶质细胞之一 免疫系统，但它们在酒精使用障碍中的作用鲜为人知。小胶质细胞显示为 从有益到细胞毒性的全谱表型以及这些小胶质细胞 酒精暴露还没有定义。此外，小胶质细胞可能会因某一事件而“启动”， 然后在随后的挑战中，他们咄咄逼人地过度反应，这一现象与 他们的表型。小胶质细胞的启动似乎在发育中更加明显，早期生命 暴露在免疫侮辱中会对成人的各种后果产生长期影响。因此， 在青少年发育期间，酒精对小胶质细胞的启动或激活可能会导致长时间的 长期后果。因此，这一提议的首要假设是 青少年比成年人更容易受到酒精引发的小胶质细胞的影响 激发对酒精诱导的神经病理和成瘾相关的长期影响 行为。我们将通过三个具体目标来检验这一假设：(1)确定 青少年对酒精诱导的小胶质细胞影响的敏感性，(2)检查 青少年对酒精刺激的小胶质细胞有更大的敏感性，(3)阐明了 小胶质细胞在成瘾相关行为中的启动。通过了解启动 青春期大脑易患酒精使用障碍，更好的干预 而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.