Neuroimmune Cell Networks in Opioid Dependence and Withdrawal

描述（由申请人提供）：长期使用阿片类药物会改变大脑的状态，包括神经免疫活性，影响大脑功能和行为，并导致持续的药物依赖和病理学。然而，很少有研究阿片类药物依赖和戒断过程中细胞因子反应的进展，这是一段深刻的自主神经和情绪不安的时期。我们最近发表的和初步的数据表明，在撤退显着的神经免疫反应。这些研究结果表明，阿片类药物摄入的突然停止导致急性中枢神经系统（CNS）杏仁核（CeA），与情感和心肺调节神经解剖学相关的脑区的炎症反应。现在有理由假设在包括血管、神经胶质和神经元细胞的网络中存在一系列促炎反应。我们建议现在扩展的方法，为这个先前的工作，以具体的问题，是否类似的多细胞型组织炎症过程的基础阿片类药物戒断。我们提出了一个高维度的系统调查的CeA炎症反应在体内大鼠模型的撤退，旨在了解细胞类型的具体和分子框架的神经炎症反应。这将为改善阿片类药物戒断及其相关病理学的治疗提供潜力。研究人员组成了一个具有该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以及计算生物学和基因组学专业知识的专家，用于收集高维数据集及其分析和解释。我们将收集转录和蛋白质数据的分子和细胞网络反应的CeA，以表征细胞类型的具体贡献的血管内皮细胞，神经胶质细胞，单核细胞谱系细胞和神经元的组织反应。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，以及导致急性阿片类药物戒断的神经炎症病理学和神经元效应。

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.