Identifying gene networks driving neuronal states during alcohol withdrawal

识别酒精戒断期间驱动神经元状态的基因网络

• 批准号: 8718678
• 负责人: James Park
• 金额: $ 4.27万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718678
• 关键词: Affect; Alcohol abuse; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Area; Automobile Driving; Behavior; Brain; Brain Injuries; Brain region; Calcitonin Gene-Related Peptide; Cell Nucleus; Cells; Chronic; Complex; Data; Development; Diet; Emotional; Emotions; Exposure to; Fuzzy Logic; Gene Expression; Gene Expression Profile; Genes; Goals; Homeostasis; Hypothalamic structure; Individual; Inflammatory; Knowledge; Liquid substance; Masks; Measures; Messenger RNA; Methods; Microfluidics; Modeling; Molecular; Molecular Profiling; Nature; Neurons; Output; Pathology; Pathway Analysis; Pathway interactions; Phenotype; Physiology; Pontine structure; Population; Process; Proteins; Publishing; Rattus; Regulator Genes; Sampling; Signal Transduction; Source; Staging; Synapses; Time; Tissues; Visceral; Withdrawal; Work; alcohol exposure; base; biological adaptation to stress; cell type; combinatorial; cytokine; in vivo; insight; interest; laser capture microdissection; network models; public health relevance; receptor; relating to nervous system; release factor; response

7. Project Summary Chronic alcohol exposure causes widespread changes in CNS molecular function impacting brain function and behavior, contributing to alcohol dependence and pathology. Due to the nature of the alcohol withdrawal and the emotional and physical consequences, the central nucleus of the amygdala (CeA) is an area of significant interest. Recently published and preliminary data suggest that these molecular processes accommodate to chronic alcohol exposure over time. However these same molecular processes respond quickly to abrupt changes in alcohol exposure as reflected in significant changes in gene expression in whole tissue punches of the CeA. These changes progress over a long period of time during alcohol withdrawal. Moreover, preliminary data supports our hypothesis that neurons of a phenotypic brain nucleus are adaptive in response to changed inputs. These varied inputs result in the formation of distinct functional states within a cell-phenotype. Taken in context, we note that the CeA neurons integrate a variety of synaptic inputs and signals from sources including catecholaminergic afferents, pontine-visceral inputs, and the hypothalamus. Therefore it is likely that individual CeA neurons respond to varied and combinatorial inputs resulting in differentiated functional states. These distinct functional states subsequently result in differentiated neuronal contributions to the evolving state of the CeA during withdrawal. Thus, understanding the molecular framework of these distinct functional states will help reveal mechanisms subtending the response of the CeA. To this end, I will characterize the responses of neurons within the CeA at the molecular level under various stages of alcohol dependence and withdrawal. I propose to develop gene regulatory network models that will help characterize the functional gene relationships governing the adaptive response of individual neurons. The result will be refined network models that will describe the complex functional relationships underlying distinct input-driven neuronal states. Subsequently these refined networks will yield insight into how synaptic inputs drive individual neurons into differentiated states that differentially contribute to the evolving response of the CeA associated with the various stages of alcohol dependence and withdrawal.

7.项目摘要 慢性酒精暴露引起CNS分子功能的广泛变化，影响脑功能， 行为，导致酒精依赖和病理学。由于酒精戒断的性质， 杏仁核中央核（CeA）是一个重要的区域， 兴趣最近发表的初步数据表明，这些分子过程适应于 长期酒精暴露然而，这些相同的分子过程对突然的 酒精暴露的变化反映在整个组织中基因表达的显着变化， 的CEA。这些变化在酒精戒断过程中会持续很长一段时间。此外，初步 数据支持我们的假设，即表型脑核的神经元对改变的 输入。这些不同的输入导致在细胞表型内形成不同的功能状态。采取 在上下文中，我们注意到CeA神经元整合了各种突触输入和来自以下来源的信号， 儿茶酚胺能传入、脑桥-内脏输入和下丘脑。因此，个人很可能 CeA神经元对不同的组合输入作出反应，从而产生分化的功能状态。这些 不同的功能状态随后导致分化的神经元对神经元的进化状态的贡献。 退出期间的CeA。因此，了解这些不同功能状态的分子框架将有助于 有助于揭示对抗CeA反应的机制。为此，我将描述以下国家的反应： 在不同阶段的酒精依赖和戒断下，在分子水平上观察CeA内的神经元。我 建议开发基因调控网络模型，这将有助于表征功能基因 控制个体神经元的适应性反应的关系。其结果将是完善的网络模型 这将描述不同的输入驱动神经元状态下的复杂功能关系。 随后，这些精细的网络将深入了解突触输入如何驱动单个神经元进入 差异化状态对与肿瘤相关的CeA的演变反应有不同的贡献 酒精依赖和戒断的不同阶段。