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: 8898513
• 负责人: James Park
• 金额: $ 4.31万
• 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/8898513
• 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; Health; 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; receptor; relating to nervous system; release factor; response

DESCRIPTION (provided by applicant): 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 state 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.

描述（由申请人提供）：长期接触酒精会导致中枢神经系统分子功能发生广泛变化，影响大脑功能和行为，导致酒精依赖和病理。由于酒精戒断的性质以及对情绪和身体的影响，杏仁核中央核 (CeA) 是一个令人感兴趣的区域。最近发表的初步数据表明，随着时间的推移，这些分子过程会适应长期的酒精暴露。然而，这些相同的分子过程对酒精暴露的突然变化迅速做出反应，这反映在 CeA 整个组织冲孔中基因表达的显着变化。这些变化是在戒酒过程中经过很长一段时间才会发生的。此外，初步数据支持我们的假设，即表型脑核的神经元能够适应变化的输入。这些不同的输入导致细胞表型内形成不同的功能状态。从上下文来看，我们注意到 CeA 神经元整合了多种突触输入和来自儿茶酚胺能传入神经、脑桥内脏输入和下丘脑等来源的信号。因此，单个 CeA 神经元可能会对不同的组合输入做出反应，从而导致不同的功能状态。这些不同的功能状态随后导致神经元在戒断期间对 CeA 的进化状态做出不同的贡献。因此，了解这些不同功能状态的分子框架将有助于揭示 CeA 响应的机制。为此，我将在分子水平上描述 CeA 内神经元在酒精依赖和戒断各个阶段的反应。我建议开发基因调控网络模型，这将有助于表征控制单个神经元适应性反应的功能基因关系。结果将是完善的网络模型，该模型将描述不同输入驱动的神经元状态背后的复杂功能关系。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不同的状态，这些状态对相关 CeA 的进化反应有不同的贡献 酒精依赖和戒断的各个阶段。