PROJECT 2: Imaging sex differences in stress-related neurochemical mechanisms of alcohol use disorders

越来越明显的是，女性比男性更容易受到慢性疾病的一些负面影响 饮酒，包括免疫系统功能障碍和神经退化。这很重要，因为 女性的问题饮酒率正在迅速上升，目前可用的治疗方法只有 有一定的效果。越来越多的证据表明，男性和女性饮酒的原因不同。女人 喝酒往往是为了调节压力和消极情绪，而男性则报告说喝酒是为了与酒精相关的积极作用 增援。这为探索性适宜的治疗提供了一个重要的机会。特别是，我们 需要了解这些行为性行为的基础和作用的神经化学机制 以期为药物开发提供新的治疗靶点。在这项提议中的耶鲁大学- Score，项目2将专注于识别酒精诱导的神经变性生物标记物的性别差异 这会导致神经适应，从而驱动成瘾循环。使用最先进的正电子发射 断层扫描(PET)技术，我们将检查性别差异的小胶质细胞水平和突触密度在 有酒精使用障碍(AUD)的活人。小胶质细胞是大脑的常驻免疫细胞，参与了一种 各种生理和病理过程，最主要的是调查大脑环境中的危险 并执行必要的修复功能。酒精最初会激活小胶质细胞，但长期饮酒会 已被证明同时抑制外周和神经免疫系统。我们有初步数据显示 与男性相比，患有AUD的女性受到更严重的神经免疫抑制，这可能是研究结果的基础 患有AUD的女性表现出比男性更糟糕的情绪和神经认知功能障碍。小胶质细胞也是 支持突触结构和功能，反之，小胶质细胞功能障碍导致突触缺陷 数量，并导致情绪和认知障碍。然而，小胶质细胞、 AUD患者的突触密度、压力、情绪和神经认知功能尚不清楚。在 目前的研究，我们将检查长期饮酒是否与小胶质细胞减少有关 (目标1)和突触密度(目标2)，如果损害因性别而异。我们假设患有这种疾病的女性 AUD证据表明，小胶质细胞和突触密度存在更大的缺陷，这是应激中性别差异的基础 AUD的反应性、负性情绪和神经认知功能障碍(目标3)。因此，拟议的项目具有 首次测量神经退行性变的神经化学标志物的性别差异 AUD患者的活脑及其与关键临床结局的关系。这些发现将会取得进展 通过发现新的、适合性行为的治疗目标，在酒精领域取得进展。

It is increasingly clear that women are more vulnerable than men to some of the negative effects of chronic alcohol consumption, including immune system dysfunction and neurodegeneration. This is important since the rates of problem drinking in women are rapidly increasing, and the currently available treatments are only moderately effective. There is mounting evidence that men and women drink for different reasons. Women tend to drink to regulate stress and negative affect, whereas men report drinking for alcohol-related positive reinforcement. This provides an important opportunity to explore sex-appropriate treatments. In particular, we need to understand the neurochemical mechanisms that underlie and contribute to these behavioral sex differences in order to provide new treatment targets for medication development. In this proposed Yale- SCORE, Project 2 will focus on identifying sex differences in biomarkers of alcohol-induced neurodegeneration that lead to neural adaptations that drive the addiction cycle. Using state-of-the-art positron emission tomography (PET) technology, we will examine sex differences in levels of microglia and synaptic density in living individuals with alcohol use disorder (AUD). Microglia, the brains’ resident immune cells, are involved in a variety of physiologic and pathologic processes, most notably surveying the brains’ environment for danger and carrying out necessary repair functions. Alcohol initially activates microglia but chronic consumption has been shown to suppress both peripheral and neuroimmune systems. We have preliminary data suggesting more severe neuroimmune suppression in women vs. men with AUD, which may underlie the findings that women with AUD exhibit worse mood and neurocognitive dysfunction than men. Microglia are also critical for supporting synaptic structure and function and conversely, microglial dysfunction leads to deficits in synapse number and contributes to mood and cognitive impairment. However, the relationships between microglia, synaptic density, stress, mood, and neurocognitive function in living humans with AUD are not known. In the current study, we will examine whether chronic alcohol consumption is associated with reductions in microglia (Aim 1) and synaptic density (Aim 2) and if the impairment varies by sex. We hypothesize that women with AUD evidence greater deficits in microglia and synaptic density, which underlie sex differences in stress reactivity, negative affect, and neurocognitive dysfunction in AUD (Aim 3). Thus, the proposed project has the potential to measure, for the first time, sex differences in neurochemical markers of neurodegeneration in the living brain of patients with AUD and their relationship to critical clinical outcomes. These findings will advance the alcohol field by uncovering novel, sex-appropriate treatment targets.