Neuroimmune Cell Networks in Opioid Dependence and Withdrawal

描述(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，几乎没有研究阿片类药物依赖和戒断期间细胞因子反应的进展，这是一个严重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，在戒断期间有显著的神经免疫反应。这些发现表明，突然停止阿片类药物摄入会导致杏仁中央核(CEA)的急性中枢神经系统(CNS)炎症反应，从神经解剖学角度看，CEA是一个与情感和心肺调节相关的脑区。现在，我们可以合理地假设，在包括血管、神经胶质细胞和神经细胞的网络中，构成这个组织的一连串促炎反应是合理的。我们现在建议将为这项先前工作开发的方法扩展到是否类似的多细胞类型组织炎症过程是阿片类药物戒断的基础这一具体问题。我们建议对CEA在体内戒断大鼠模型中的炎症反应进行高维度的系统研究，旨在了解神经炎性反应的细胞类型特异性和分子框架。这将为改善阿片类药物戒断及其相关病理的治疗提供潜力。研究人员组成了一个合作小组，具有这项实验设计和分析所需的专门知识，其中包括阿片剂暴露和戒断在大脑中的分子影响方面的专家，以及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家。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、单核细胞系细胞和神经元在组织反应中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性病理和神经效应，这些都有助于急性阿片类药物戒断的症状。

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.