Neuroimmune mechanisms of adult chronic ethanol consumption

摘要 在持续的COVID 19大流行期间，过度饮酒有所增加， 迫切需要改善治疗方案。酒精使用障碍（AUD）患者 抑制控制，决策和情绪处理，这些认知症状减少 治疗依从性，恶化临床结果，并促进复发。神经免疫系统是 是AUD病理生理学的关键参与者，靶向这种调节系统不太可能 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。的 特别令人感兴趣的是，细胞因子白细胞介素-1 β（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的个体具有升高的死后脑和外周IL-1β水平。的IL-1 信号复合物通常含有AcP，其产生神经炎症反应。然而，在这方面， 神经元还表达AcPb，这是第二种辅助蛋白，具有神经保护作用， 典型的AcP神经炎症反应。老化增加了AcP与AcPb的比率，导致 更强的神经炎症反应、受损的突触可塑性和空间记忆缺陷。以来 患有AUD的个体显示出过早的皮质老化迹象，我们假设慢性乙醇 暴露在内侧前额叶内的IL-1β/AcP信号中产生类似的促炎倾向 皮质（mPFC），从而导致认知功能的缺陷。因此，在这里我们将研究 IL-1β突触调节在雄性和雌性小鼠早期戒断和长期戒断中的作用我们 还将测试假设，即早期戒断和长期禁欲导致ACP介导的 认知障碍因此，这项提议的首要目标是确定神经免疫 慢性乙醇导致mPFC功能长期变化的机制。的 拟议的研究将（i）填补我们关于IL-1β/神经免疫调节知识的关键空白， 基础mPFC功能，（ii）提供有关慢性 乙醇对IL-1/神经免疫系统的影响在男性和女性中表现出来，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 对于我们理解持续的神经炎症如何导致 的病理生理学，并将促进一类新的 药物治疗学

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.