Identifying gene networks driving neuronal states during alcohol withdrawal

描述（由申请人提供）：长期酒精暴露导致CNS分子功能的广泛变化，影响脑功能和行为，导致酒精依赖和病理学。由于酒精戒断的性质以及情绪和身体后果，杏仁核中央核（CeA）是一个重要的兴趣区域。最近发表的初步数据表明，这些分子过程适应长期酒精暴露。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的整个组织穿孔中基因表达的显着变化中。这些变化在酒精戒断过程中会持续很长一段时间。此外，初步的数据支持我们的假设，神经元的表型脑核是适应性的变化输入。这些不同的输入导致在细胞表型内形成不同的功能状态。在上下文中，我们注意到，CeA神经元整合了各种突触输入和信号来源，包括儿茶酚胺传入，脑桥内脏输入，下丘脑。因此，它是可能的，个别CeA神经元响应不同的和组合的输入，导致分化的功能状态。这些不同的功能状态，随后导致分化的神经元的贡献，在撤退过程中的CeA的发展状态。因此，了解这些不同的功能状态的分子框架将有助于揭示机制subtending响应的CeA。为此，我将在分子水平上描述在酒精依赖和戒断的各个阶段下，CeA内神经元的反应。我建议开发基因调控网络模型，这将有助于表征功能基因的关系，管理个别神经元的适应性反应。其结果将是精细的网络模型，将描述不同的输入驱动的神经元状态下的复杂的功能关系。随后，这些改进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，这些差异化状态对CeA相关神经元的进化反应有不同的贡献。 酒精依赖和戒断的不同阶段。

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.