Identifying gene networks driving neuronal states during alcohol withdrawal

描述(申请人提供)：慢性酒精暴露会导致中枢神经系统分子功能的广泛变化，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，杏仁中央核(CEA)是一个令人感兴趣的区域。最近公布的初步数据表明，随着时间的推移，这些分子过程适应了长期的酒精暴露。然而，这些相同的分子过程对酒精暴露的突然变化反应迅速，这反映在CEA整个组织冲孔中基因表达的显着变化。在戒酒期间，这些变化会在很长一段时间内发生。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做出反应是适应性的。这些不同的输入导致在一个细胞表型内形成不同的功能状态。综上所述，我们注意到CEA神经元整合了各种突触输入和信号来源，包括儿茶酚胺能传入、桥-内脏输入和下丘脑。因此，单个CEA神经元很可能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不同的神经元对戒断过程中CEA的进化状态做出贡献。因此，了解这些不同功能状态的分子框架将有助于揭示抑制CEA反应的机制。为此，我将从分子水平描述酒精依赖和戒断不同阶段下CEA内神经元的反应。我建议开发基因调控网络模型，该模型将有助于描述控制单个神经元适应性反应的功能基因关系。其结果将是精细化的网络模型，它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，这些精细化的网络将深入了解突触输入如何将单个神经元驱动到分化状态，从而对CEA相关的进化反应做出不同的贡献 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.