Neuroimmune mechanisms of adult chronic ethanol consumption

成人慢性乙醇消耗的神经免疫机制

• 批准号: 10727281
• 负责人: Florence Prabha Varodayan
• 金额: $ 40.45万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727281
• 关键词: Abstinence; Adult; Aging; Alcohols; Autopsy; Binding; Brain; COVID-19 pandemic; Chronic; Clinical; Complex; Data; Decision Making; Development; Drug usage; Emotional; Ethanol; Female; Functional disorder; Glutamates; Goals; Heavy Drinking; Hippocampus; Impaired cognition; Impairment; Individual; Inflammatory; Infusion procedures; Injections; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Knowledge; Lead; Learning; MAP Kinase Gene; Medial; Mediating; Memory impairment; Messenger RNA; Mus; Neurobehavioral Manifestations; Neuroimmune; Neuroimmune system; Neuroimmunomodulation; Neurons; Neurotransmitters; Outcome; PIK3CG gene; Pathway interactions; Peripheral; Pharmacologic Substance; Prefrontal Cortex; Proteins; Regulation; Relapse; Role; Sex Differences; Signal Transduction; Synapses; Synaptic plasticity; System; Testing; Withdrawal; aged; alcohol exposure; alcohol use disorder; antagonist; chronic alcohol ingestion; cognitive function; cytokine; gamma-Aminobutyric Acid; genetic association; improved; interest; male; neuroinflammation; neuroprotection; novel; p38 Mitogen Activated Protein Kinase; pharmacologic; premature; prevent; receptor; receptor expression; recruit; reduce symptoms; response; sex; side effect; spatial memory; treatment adherence

ABSTRACT Excessive alcohol consumption has risen during the ongoing COVID 19 pandemic, and there is an urgent need to improve treatment options. Individuals with alcohol use disorder (AUD) struggle with inhibitory control, decision making and emotional processing, and these cognitive symptoms reduce treatment adherence, worsen clinical outcomes, and promote relapse. The neuroimmune system is a key player in the pathophysiology of AUD, and targeting this modulatory system is less likely to produce unwanted side effects compared to directly targeting neurotransmitter dysfunction. Of particular interest, the cytokine interleukin-1β (IL-1β) is implicated in the cognitive symptoms of AUD. There are strong genetic associations among the IL-1 system, AUD and cognitive decline, and individuals with AUD have elevated postmortem brain and peripheral levels of IL-1β. The IL-1 signaling complex typically contains AcP, which generates neuroinflammatory responses. However, neurons also express AcPb, a second accessory protein that is neuroprotective and curbs the canonical AcP neuroinflammatory response. Aging increases the ratio of AcP to AcPb, leading to a stronger neuroinflammatory response, impaired synaptic plasticity and spatial memory deficits. Since individuals with AUD show signs of premature cortical aging, we hypothesize that chronic ethanol exposure produces a similar proinflammatory bias in IL-1β/AcP signaling within the medial prefrontal cortex (mPFC), thereby contributing to deficits in cognitive function. Therefore, here we will examine IL-1β synaptic regulation in early withdrawal and protracted abstinence in male and female mice. We will also test the hypothesis that early withdrawal and protracted abstinence lead to AcP-mediated cognitive impairment. Thus, the overarching goal of this proposal is to determine the neuroimmune mechanisms by which chronic ethanol produces long-lasting changes in mPFC function. The proposed studies will (i) fill critical gaps in our knowledge regarding IL-1β/neuroimmune regulation of basal mPFC function, (ii) provide essential information about how the consequences of chronic ethanol on the IL-1/neuroimmune system manifest in males and females, and (iii) potentially identify AcP as a novel pharmaceutical target for treating the cognitive symptoms of AUD. These studies will have important implications for our understanding of how persistent neuroinflammation can lead to the pathophysiology of AUD, and will promote the development of a new class of pharmacotherapeutics.

抽象的 在正在进行的Covid 19大流行期间，过度饮酒量增加了，并且有一个 迫切需要改善治疗选择。患有饮酒障碍（AUD）的人与 抑制性控制，决策和情绪处理以及这些认知症状减少 治疗依从性，临床结果较差并促进缓解。神经免疫系统是 AUD病理生理学的关键参与者，针对此调节系统的主要参与者不太可能 与直接靶向神经递质功能障碍相比，产生了不良的副作用。的 在AUD的认知症状中暗示了细胞因子白介素1β（IL-1β）的特别关注。 IL-1系统，AUD和认知能力下降以及 具有AUD的个体具有升高后脑脑和IL-1β的外周水平。 IL-1 信号传导复合物通常包含ACP，该ACP产生神经炎症反应。然而， 神经元还表达ACPB，ACPB，一种神经保护性并遏制的第二辅助蛋白 规范的ACP神经炎症反应。衰老增加了ACP与ACPB的比率，导致A 更强的神经炎症反应，合成可塑性受损和空间记忆缺陷。自从 有aud的个体显示过早皮质衰老的迹象，我们假设慢性乙醇 暴露在介质前额叶内产生类似的IL-1β/ACP信号传导的促炎偏差 皮层（MPFC），从而有助于定义认知功能。因此，我们将在这里检查 IL-1β突触调节在雄性和雌性小鼠的早期戒断和持久性中。我们 还将检验以下假设，即早期戒断和旷日持久导致ACP介导 认知障碍。这是该提议的总体目标是确定神经免疫 慢性乙醇在MPFC功能中产生持久变化的机制。这 拟议的研究将（i）填补有关IL-1β/神经免疫性调节的关键空白 基本MPFC功能，（ii）提供有关慢性后果的基本信息 IL-1/神经免疫系统上的乙醇在男性和女性中都表现出来，（iii）可能识别 ACP是治疗AUD认知症状的新型药物靶标。这些研究会 对于我们对持续性神经炎症如何导致的理解具有重要意义 AUD的病理生理学，并将促进新的一类 药物治疗学。