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

项目 2：酒精使用障碍的压力相关神经化学机制的性别差异成像

• 批准号: 10357883
• 负责人: Kelly P Cosgrove
• 金额: $ 42.93万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357883
• 关键词: Abstinence; Affinity; Alcohol abuse; Alcohol consumption; Alcohols; Behavioral; Binding; Biological Markers; Brain; Brain imaging; Cardiovascular system; Cells; Cerebellum; Chronic; Clinical; Clinical Trials; Consumption; Country; Data; Development; Ensure; Environment; Ethanol Metabolism; Exhibits; Functional disorder; Glycoproteins; Gonadal Steroid Hormones; Guanfacine; Health; Hippocampus (Brain); Human; Image; Imaging Device; Imaging Techniques; Immune; Immune System Diseases; Impaired cognition; Impairment; Individual; Interruption; Laboratories; Lead; Light; Link; Measures; Microglia; Moods; Negative Reinforcements; Nerve Degeneration; Neurocognitive; Neuroimmune; Neuroimmune system; Outcome; Outer Mitochondrial Membrane; Outpatients; Participant; Pathologic Processes; Patients; Peripheral; Pharmaceutical Preparations; Phase; Physiological Processes; Placebos; Positive Reinforcements; Positron-Emission Tomography; Property; Proteins; Public Health; Reporting; Research; Rewards; Scanning; Sex Differences; Side; Signal Transduction; Stress; Structure; Surveys; Synapses; Synaptic Vesicles; System; Technology; Therapeutic; Time; Treatment outcome; United States; Vesicle; Well in self; Woman; addiction; alcohol abuse therapy; alcohol effect; alcohol use disorder; base; cerebral atrophy; chronic alcohol ingestion; craving; density; drinking; drinking behavior; gray matter; hypothalamic-pituitary-adrenal axis; imaging biomarker; men; men' s group; molecular marker; negative affect; neuroadaptation; neurochemistry; neuroimaging; novel; preclinical study; presynaptic; radiotracer; repair function; sex; stress reactivity; synergism; theories; tool

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.

越来越明显的是，女性比男性更容易受到慢性病的一些负面影响。 饮酒，包括免疫系统功能障碍和神经退行性变。这很重要，因为 女性饮酒问题的比例正在迅速增加，目前可用的治疗方法只有 效果中等。越来越多的证据表明，男性和女性饮酒的原因不同。女性 倾向于饮酒来调节压力和负面情绪，而男性则报告饮酒是为了与酒精相关的积极情绪 加强。这为探索适合性别的治疗提供了重要机会。特别是，我们 需要了解这些行为背后和促成这些性行为的神经化学机制 差异，以便为药物开发提供新的治疗靶点。在耶鲁大学的这个提议中—— SCORE，项目 2 将侧重于识别酒精引起的神经变性生物标志物的性别差异 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，我们将检查小胶质细胞水平和突触密度的性别差异 患有酒精使用障碍 (AUD) 的在世个体。小胶质细胞是大脑的常驻免疫细胞，参与 各种生理和病理过程，最显着的是检查大脑环境是否存在危险 并执行必要的修复功能。酒精最初会激活小胶质细胞，但长期饮酒会激活小胶质细胞 已被证明可以抑制外周和神经免疫系统。我们有初步数据表明 女性 AUD 患者的神经免疫抑制比男性更严重，这可能是以下发现的基础： 患有 AUD 的女性比男性表现出更差的情绪和神经认知功能障碍。小胶质细胞对于 支持突触结构和功能，相反，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，小胶质细胞之间的关系， 患有 AUD 的活人的突触密度、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）以及损伤是否因性别而异。我们假设女性 AUD 证明小胶质细胞和突触密度存在更大的缺陷，这是压力性别差异的基础 AUD 的反应性、负面影响和神经认知功能障碍（目标 3）。因此，拟议的项目具有 首次有可能测量神经退行性变的神经化学标记物的性别差异 AUD 患者的活体大脑及其与关键临床结果的关系。这些发现将推进 通过发现新颖的、适合性别的治疗目标来进入酒精领域。