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

项目总结/摘要 先天免疫系统的激活导致促炎细胞因子的释放，这可能导致 神经免疫信号和行为异常的变化，如高酒精（乙醇） 饮酒，这可能最终导致酒精使用障碍（AUD）的发展。我们缺乏 了解神经免疫信号的变化如何整合到神经网络中， 调解从正常（社交）饮酒到过度饮酒的过渡。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）在几周的饮酒中产生酒精摄入量的逐步增加。我们假设 免疫激活诱导基因表达的细胞类型特异性变化，这些变化被整合以影响 神经功能和驱动过度饮酒。我们将结合分子，细胞，行为 和计算方法来检验这一假设。将在神经元中测量基因表达， 星形胶质细胞和小胶质细胞，以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特征和计算驱动的药物再利用 鉴定和测试具有减少高酒精潜力的药理学化合物的方法 喝酒我们将研究特定神经网络在免疫诱导的饮酒升级中的作用， 测量神经元功能和操纵关键投射神经元的兴奋性。时间剖面 将确定细胞类型特异性转录组的动态变化， 神经元功能实验的结果将促进我们对 神经免疫信号在过渡到AUD，并将广泛适用于脑疾病与亲， 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.