Neuroimmune Cell Networks in Opioid Dependence and Withdrawal

描述（由申请人提供）：慢性阿片类药物使用改变大脑状态，包括神经免疫活动，影响大脑功能和行为，并导致持续的药物依赖和病理。然而，很少有研究在阿片类药物依赖和戒断期间细胞因子反应的进展，这是一个深刻的自主和情绪不安的时期。我们最近发表的和初步的数据表明，在戒断期间有显著的神经免疫反应。这些发现表明，突然停止摄入阿片类药物会导致杏仁核中央核（CeA）的急性中枢神经系统（CNS）炎症反应，杏仁核是神经解剖学上与情感和心肺调节相关的大脑区域。现在可以合理地假设，在一个包括血管细胞、神经胶质细胞和神经元细胞的网络中存在一系列促炎反应。我们现在建议将为这项先前工作开发的方法扩展到类似的多细胞型组织炎症过程是否是阿片类药物戒断的基础的具体问题。我们建议在体内大鼠戒断模型中对CeA炎症反应进行高维系统研究，旨在了解神经炎症反应的细胞类型特异性和分子框架。这将为改进阿片戒断及其相关病理的治疗提供潜力。研究人员组成了一个具有实验设计和分析所需专业知识的合作团队，包括阿片类药物暴露和戒断在大脑中的分子效应方面的专家，以及用于收集高维数据集及其分析和解释的计算生物学和基因组学专业知识。我们将收集CeA中分子和细胞网络反应的转录和蛋白质数据，以表征血管内皮细胞、胶质细胞、单核细胞谱系细胞和神经元对组织反应的细胞类型特异性贡献。这些数据将揭示细胞类型内改变的分子网络，它们对整个组织的影响，以及由此产生的神经炎症病理和神经元效应，这些都有助于急性阿片类药物戒断症状学。

DESCRIPTION (provided by applicant): Chronic opioid use changes the brain's state, including neuroimmune activity, impacting brain function and behavior and contributing to continued drug dependence and pathology. However, there is little work examining the progression of the cytokine response during opioid dependence and withdrawal, a period of profound autonomic and emotional upset. Our recent published and preliminary data demonstrate a significant neuroimmune response during withdrawal. These findings suggest that an abrupt cessation of opioid intake leads to an acute central nervous system (CNS) inflammatory response in the central nucleus of the amygdala (CeA), a brain region neuroanatomically associated with affective and cardiorespiratory regulation. It is now reasonable to postulate a chain of proinflammatory responses in a network involving vascular, glial and neuronal cells that comprise this tissue. We propose to now extend the approach developed for this prior work to the specific question of whether similar multi-cell type tissue inflammatory processes underlie opiate withdrawal. We propose a high-dimensional systematic investigation of the CeA inflammatory response in an in vivo rat model of withdrawal aiming to understanding the cell-type specific and molecular framework for neuroinflammatory responses. This will provide potential for improved treatment of opiate withdrawal and its associated pathology. The investigators comprise a collaborative team with the expertise required for this experimental design and analysis, including experts in the molecular effects of opiate exposure and withdrawal in the brain and computational biology and genomics expertise for collection of high dimensional datasets and their analysis and interpretation. We will collect transcriptional and protein data on the molecular and cellular network response in the CeA in order to characterize the cell-type specific contributions of vascular endothelial cells, glia, monocyte lineage cells and neurons to the tissue response. These data will reveal the molecular networks altered within the cell types, their impact on the tissue as a whole, and the resultant neuroinflammatory pathology and neuronal effects that contribute to acute opioid withdrawal's symptomatology.