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.

越来越清楚的是，妇女比男子更容易受到慢性疾病的某些负面影响， 饮酒，包括免疫系统功能障碍和神经退行性变。这一点很重要，因为 女性饮酒问题的发生率正在迅速上升，目前可用的治疗方法只有 适度有效。越来越多的证据表明，男人和女人喝酒的原因不同。妇女 倾向于喝酒来调节压力和负面影响，而男性则表示喝酒是为了与酒精相关的积极影响 加固.这为探索适合性别的治疗方法提供了一个重要机会。我们尤其 我们需要了解这些性行为背后的神经化学机制 差异，以便为药物开发提供新的治疗靶点。在这个被称为耶鲁的地方- SCORE，项目2将专注于确定酒精诱导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。利用最先进的正电子发射技术 通过断层扫描（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， 酒精使用障碍（AUD）患者。小胶质细胞，大脑的常驻免疫细胞，参与了一个 各种生理和病理过程，最显著的是测量大脑的危险环境 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 被证明可以抑制外周和神经免疫系统。我们有初步数据显示 AUD患者中女性比男性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。小胶质细胞也是至关重要的 支持突触结构和功能，相反，小胶质细胞功能障碍导致突触 数量和有助于情绪和认知障碍。然而，小胶质细胞， 尚不清楚患有AUD的活体人类的突触密度、压力、情绪和神经认知功能。在 在目前的研究中，我们将研究长期饮酒是否与小胶质细胞减少有关。 (Aim 1）和突触密度（目标2），如果损害因性别而异。我们假设， AUD证明小胶质细胞和突触密度的更大缺陷，这是压力性别差异的基础 反应性、负面情绪和神经认知功能障碍（目标3）。因此，拟议项目具有 首次测量神经变性神经化学标志物的性别差异的潜力， AUD患者的活体大脑及其与关键临床结局的关系。这些发现将推动 酒精领域通过发现新的，性别适当的治疗目标。