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的负面影响 饮酒，包括免疫系统功能障碍和神经退行性。这很重要，因为 女性饮酒率正在迅速增加，目前可用的治疗仅是 中度有效。有越来越多的证据表明，男人和女人的饮酒是出于不同的原因。女性 倾向于喝酒以调节压力和负面影响，而男性报告喝酒的阳性 加强。这为探索适合性的治疗提供了重要的机会。特别是我们 需要了解基于这些行为性别的基础的神经化学机制 差异是为了为药物开发提供新的治疗目标。在拟议的耶鲁 - 得分，项目2将集中于确定酒精引起的神经退行性生物标志物的性别差异 这会导致神经适应，从而驱动加法周期。使用最先进的极性排放 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 有饮酒障碍的活人（AUD）。小胶质细胞，大脑的居民免疫核管，参与了 各种生理和病理过程，最著名的是调查大脑环境的危险 并执行必要的维修功能。酒精最初激活小胶质细胞，但长期消费有 我们有提示的初步数据 女性与有声男性的更严重的神经免疫性抑制，这可能是发现的基础 aud的女性的情绪和神经认知功能障碍比男性更糟糕。小胶质细胞也至关重要 支持合成结构和功能，相反，小胶质细胞功能障碍导致定义突触 数量并有助于情绪和认知障碍。但是，小胶质细胞之间的关系， 在具有AUD的活人中，突触密度，压力，情绪和神经认知功能尚不清楚。在 当前的研究，我们将检查长期饮酒是否与小胶质细胞的减少有关 （AIM 1）和突触密度（AIM 2），以及损害的性别范围。我们假设妇女与 AUD证据在小胶质细胞和突触密度中更大的防御能力，这是压力差异的基础 AUD中的反应性，负面影响和神经认知功能障碍（AIM 3）。那就是拟议的项目 在首次测量神经化学标志物中的性别差异的潜力 AUD患者的生活大脑及其与关键临床结果的关系。这些发现将进步 通过发现新颖的性别治疗靶标的酒精场。