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 在持续的 COVID 19 大流行期间，过度饮酒有所增加，并且存在 迫切需要改善酒精使用障碍 (AUD) 患者的治疗选择。 抑制控制、决策和情绪处理，这些认知症状会减少 治疗依从性、临床结果恶化并促进复发。 AUD 病理生理学的关键参与者，并且针对该调节系统不太可能 与直接针对神经递质功能障碍相比，会产生不必要的副作用。 特别有趣的是，细胞因子白细胞介素-1β (IL-1β) 与 AUD 的认知症状有关。 IL-1 系统、AUD 和认知能力下降之间存在很强的遗传关联， 患有 AUD 的个体死后大脑和外周的 IL-1β 水平升高。 信号复合物通常含有 AcP，它会产生神经炎症反应。 神经元还表达 AcPb，这是第二种辅助蛋白，具有神经保护作用并抑制 典型的 AcP 神经炎症反应会增加 AcP 与 AcPb 的比率，从而导致 更强的神经炎症反应、突触可塑性受损和空间记忆缺陷。 患有 AUD 的个体表现出皮质过早老化的迹象，我们追求长期乙醇 暴露在内侧前额叶内的 IL-1β/AcP 信号传导中产生类似的促炎偏向 皮层（mPFC），导致认知功能缺陷，因此，我们将在此进行检查。 IL-1β突触对雄性和雌性小鼠早期戒断和长期戒断的调节。 还将检验以下假设：早期戒断和长期戒断会导致 AcP 介导的 因此，该提案的首要目标是确定神经免疫障碍。 长期乙醇对 mPFC 功能产生持久变化的机制。 拟议的研究将 (i) 填补我们关于 IL-1β/神经免疫调节的知识的关键空白 mPFC 功能，(ii) 提供有关慢性疾病的基本后果如何产生的重要信息 乙醇对 IL-1/神经免疫系统的影响在男性和女性中都有体现，并且 (iii) 可能识别 AcP 作为治疗 AUD 认知症状的新药物靶点。 对于我们理解持续性神经炎症如何导致 AUD 的病理生理学，并将促进一类新疾病的发展 药物治疗学。