Alcohol, Exercise & the Female Brain

项目摘要 酒精使用障碍(AUD)在美国是一个重要的公共健康问题。狂欢模式 消费是AUD最常见的形式，会损害大脑皮质边缘区域，这些区域对认知和 行为控制，包括海马体。与男性相比，女性经历了不成比例的 与酒精有关的健康问题，包括器官损伤，以及越来越多的研究表明，他们 也比男性更容易遭受酒精引起的脑损伤。女性明显的脆弱 从大脑到酒精需要更彻底地了解潜在的机制，以告知 制定有效的治疗策略。我们从老鼠模型中获得的初步数据显示，性别依赖 酗酒对海马区及海马区依赖认知的影响，女性显著 更负面的影响，我们提议的实验将发展这一模型。传统的嫌犯在 研究性别差异是性腺激素，要么是由于它们的永久性、组织性影响，要么是由于它们 它们的瞬时、激活(循环)效应。因为循环中的卵巢激素具有保护作用 其他形式的脑损伤，如中风，女性大脑对酒精损伤的脆弱性表现为 难解之谜。为了解决这个问题，我们提议的实验将测试新的假设，即早期组织(但 性激素效应导致女性大脑对暴饮暴食的选择性易损性 酒精暴露。最后，尽管女性海马体可能选择性地容易受到酗酒的影响，但我们 也发现它可以通过锻炼来修复。我们将利用这种运动驱动的修复模式来探索 并解决了一个新的问题，即修复的海马体功能是否像 从未受损的海马体。使用与临床相关的啮齿动物模型，我们的三个具体目标将1) 建立女性大脑对酗酒的选择性易感性；2)确定 组织和/或循环性激素效应以及3)精确定位运动的机制和效果- 驱动式修复。我们的发现将阐明女性大脑对酒精易感性的机制 损害并为开发新的干预措施提供信息，以加强大脑修复。

Project Summary Alcohol use disorder (AUD) is a significant public health problem in the United States. Binge pattern consumption, the most common form of AUD, damages corticolimbic brain regions essential for cognition and behavioral control, including the hippocampus. Compared to men, women disproportionately experience alcohol-related health problems, including organ damage, and a growing body of research indicates that they are also more likely than men to suffer alcohol-induced brain damage. The apparent vulnerability of the female brain to alcohol necessitates a more thorough understanding of underlying mechanisms, to inform the development of effective treatment strategies. Our preliminary data from a rat model show sex-dependent effects of binge alcohol on the hippocampus and hippocampal-dependent cognition, with females significantly more negatively affected, and our proposed experiments will develop this model. The traditional suspects when investigating sex differences are gonadal hormones, either due to their permanent, organizational effects or their transient, activational (circulating) effects. Because circulating ovarian hormones are protective against other forms of brain injury, such as stroke, the vulnerability of the female brain to alcohol damage presents a conundrum. To resolve it, our proposed experiments will test the novel hypothesis that early organizational (but not circulating) sex hormone effects are responsible for the selective vulnerability of the female brain to binge alcohol exposure. Finally, although the female hippocampus may be selectively vulnerable to binge alcohol, we have also found that it can be repaired by exercise. We will use this model of exercise-driven repair to probe underlying mechanisms and address the novel question of whether the repaired hippocampus functions like the never-damaged hippocampus. Using a clinically-relevant rodent model, our three specific aims will 1) establish the selective vulnerability of the female brain to binge alcohol; 2) determine the contribution of organizational and/or circulating sex hormone effects and 3) pinpoint mechanisms and efficacy of exercise- driven restoration. Our findings will elucidate the mechanisms underlying female brain susceptibility to alcohol damage and inform the development of novel interventions to enhance brain repair.