The neuroimmune model of excessive alcohol consumption: Transition to Alcohol Use Disorder.

项目摘要/摘要 天然免疫系统的激活会导致促炎细胞因子的释放，这可能会导致 神经免疫信号的变化和行为异常，如高酒精(乙醇) 饮酒，这最终可能导致酒精使用障碍(AUD)。我们缺少 了解神经免疫信号的变化是如何整合到神经网络中的 调解从正常(社交)饮酒向过度饮酒的转变。在这里，我们建议 过度饮酒的神经免疫模型，其中反复注射免疫激活剂 Poly(I：C)在饮酒几周后会逐渐增加酒精摄入量。我们假设 这种免疫激活诱导特定细胞类型的基因表达变化，这些变化被整合到一起影响 神经功能和驱使过度饮酒。我们将使用分子、细胞、行为的组合 以及检验这一假设的计算方法。基因表达将在神经元中进行测量， 星形胶质细胞和小胶质细胞研究免疫激活的细胞类型特异性分子机制。我们 然后将使用来自不同细胞类型的分子签名和计算驱动的药物再利用 鉴定和测试可能降低高酒精含量的药理化合物的方法 喝酒。我们将通过以下方式研究特定神经网络在免疫诱导饮酒升级中的作用 测量神经功能和操纵关键投射神经元的兴奋性。时间侧写 跨越三个关键时间点将确定细胞类型特定转录本和 神经功能。拟议中的实验结果将增进我们对 神经免疫信号在向AUD的转变中的作用，并将广泛应用于有PRO-2的脑部疾病 炎症表型。

Project Summary/Abstract Activation of the innate immune system results in the release of pro-inflammatory cytokines, which may lead to changes in neuroimmune signaling and behavioral abnormalities, such as high alcohol (ethanol) consumption, which may ultimately lead to the development of alcohol use disorder (AUD). We lack understanding of how changes in neuroimmune signaling are integrated into neuronal networks that mediate the transition from normal (social) drinking to excessive alcohol consumption. Here, we propose the neuroimmune model of excessive alcohol consumption, where repeated injections of the immune activator Poly(I:C) produce progressive escalation of alcohol intake over several weeks of drinking. We hypothesize that immune activation induces cell type-specific changes in gene expression, which are integrated to affect neuronal functions and drive excessive drinking. We will use a combination of molecular, cellular, behavioral and computational approaches to test this hypothesis. Gene expression will be measured in neurons, astrocytes and microglia to investigate cell type-specific molecular mechanisms of immune activation. We will then use molecular signatures from different cell types and computationally-driven drug-repurposing approaches to identify and test pharmacological compounds with the potential to reduce high alcohol drinking. We will investigate roles of specific neural networks in immune-induced escalation of drinking by measuring neuronal functions and manipulating excitability of critical projection neurons. Temporal profiling across three critical time points will identify dynamic changes in cell type-specific transcriptomes and neuronal functions. Results of the proposed experiments will advance our understanding of the role of neuroimmune signaling in the transition to AUD and will be widely applicable to brain disorders with pro- inflammatory phenotypes.