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.

摘要 在正在进行的COVID19大流行期间，过度饮酒有所上升，而且有 迫切需要改进治疗方案。酒精使用障碍(AUD)患者与 抑制性控制、决策和情绪处理，这些认知症状会减少 坚持治疗，恶化临床结果，促进复发。神经免疫系统是一个 在AUD的病理生理学中起关键作用，而针对这种调节系统的可能性较小 与直接靶向神经递质功能障碍相比，会产生不想要的副作用。的 尤其令人感兴趣的是，细胞因子白介素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强烈的遗传关联，以及 AUD患者死后大脑和外周IL-1β水平升高。白介素1 信号复合体通常含有ACP，它能产生神经炎性反应。然而， 神经元也表达AcPb，这是一种第二种辅助蛋白，具有神经保护作用，可以抑制 典型的ACP神经炎性反应。老化会增加ACP与AcPb的比例，导致 神经炎性反应增强，突触可塑性受损，空间记忆障碍。自.以来 AUD患者表现出皮质过早老化的迹象，我们假设慢性酒精 暴露在内侧前额叶的IL-1β/ACP信号中产生类似的促炎倾向 大脑皮质(MPFC)，从而导致认知功能障碍。因此，在这里我们将考察 IL-1β对雄性和雌性小鼠早期戒断和稽延性戒断的突触调节我们 也将检验早期戒断和长期戒断导致ACP介导的假说 认知障碍。因此，这项建议的首要目标是确定神经免疫 慢性酒精引起mPFC功能长期变化的机制。这个 拟议的研究将(I)填补我们关于IL-1β/神经免疫调节的关键知识空白 基本的mPFC功能，(Ii)提供有关慢性疾病后果的基本信息 酒精对IL-1/神经免疫系统的影响在男性和女性中都表现出来，以及(Iii)潜在地识别 ACP作为治疗AUD认知症状的新药物靶点。这些研究将 对于我们理解持续性神经炎是如何导致 AUD的病理生理学，并将促进发展的一类新的 药物治疗学。