Adolescent binge drinking and effects on adult brain and behavior: the importance of sex differences

 描述(由申请人提供)：早起饮酒与成年后认知缺陷和酒精使用障碍的易感性增加有关。个人在这个时候可能很容易受到酒精的影响，因为在整个青春期，额叶都在经历着大量的髓鞘形成，以增强工作记忆，并在成年后加强对行为和情绪的控制。髓鞘形成是一个过程，在这个过程中，少突胶质细胞将白色脂肪鞘包裹在成熟神经元的轴突周围，达到最佳厚度，以确保电信号沿轴突的高速传播，并增强神经连接。成像研究表明，大量饮酒可能会扰乱青少年发育过程中的髓鞘形成，从而增加成瘾风险和成年后心理健康的脆弱性。或者，这些关系可能是由于共同的遗传倾向，而不是酒精暴露的结果。我们使用了一个自愿狂饮的临床前动物模型，开始解剖酒精和额叶有髓纤维轨迹之间这些关系的因果性质。我们的发现表明，青少年酗酒会导致前额叶髓鞘丢失，并增加成年后饮酒的风险。目前的建议结合了强大的生化、神经解剖学和行为学方法，以深入了解酒精如何对男性和女性的前额叶骨髓结构产生不同的影响，并从经验上测试青春期激素在青春期对酒精的易感性增加中的作用。这些研究应该会导致对髓鞘形成的更好的理解，并有可能揭示对抗酒精使用障碍的新的治疗目标。

 DESCRIPTION (provided by applicant): Early onset of alcohol use is associated with cognitive deficits and enhanced vulnerability to alcohol use disorder in adulthood. Individuals may be vulnerable to alcohol at this time because the frontal lobes are undergoing significant myelination throughout adolescence to enhance working memory and increase control of behaviors and emotions in adulthood. Myelination is a process in which oligodendrocytes wrap white fatty sheaths around axons of mature neurons to an optimal thickness that ensures high-speed propagation of electrical signals along an axon and enhances neural connectivity. Imaging studies suggest that heavy drinking may increase addiction risk and mental health vulnerability in adulthood by disrupting myelination during adolescent development. Alternatively, these relationships could be due to shared genetic predispositions rather than result from alcohol exposure. We have used a preclinical animal model of voluntary binge drinking to begin dissecting the causal nature of these relationships between alcohol and myelinated fiber tracks in the frontal lobes. Our findings indicate adolescent binge drinking induces prefrontal myelin loss and enhances drinking risk in adulthood. The current proposal combines powerful biochemical, neuroanatomical, and behavioral approaches to gain insight into how alcohol differentially affects prefrontal myeloarchitecture in males and females and empirically test the role of pubertal hormones in heightened vulnerability to alcohol during adolescent development. These studies should lead to a greater understanding of myelination and potentially reveal new therapeutic targets to combat alcohol use disorder.