Of Mice and Primates: Gene Networks in Excessive Ethanol Consumption and Anxiety

描述(由申请人提供)：INIA-Stress联盟的一个基本前提是，进展为滥用乙醇消费至少部分伴随并可能由有机体对压力的反应变化引起，包括过量摄入/戒酒的压力。我们认为，大脑基因表达网络的变化是导致渐进性酒精消耗和对压力的异常反应的变态机制的重要组成部分。我们之前已经在BXD重组近交系小组的大脑区域中使用了遗传和基因组方法来定义受急性乙醇调控的强大基因网络，并将这些网络与乙醇行为联系起来，特别是关于对压力的反应。我们还发现小鼠对急性乙醇的表达反应显著重叠，并改变了由INIA-Stress联盟的PI Grant博士开发的灵长类过度乙醇摄入(SIP)模型中的基因表达模式。此外，最近对暴露于多个周期的慢性间歇性乙醇蒸气(CIE)过量乙醇消耗模型的BXD小鼠进行的试点阵列研究，已确认与急性乙醇暴露的结果和我们的食蟹猴数据具有显著的同源性。这些研究已经产生了基因网络，可以测试最初的主要“中枢”基因，以确定它们在改变CIE模型中乙醇消耗和对压力的反应方面可能发挥的作用。例如，我们最近利用AAV病毒载体的基因传递研究，发现Gsk3p是酒精消费和戒断诱导的焦虑的重要调节因子。基于这些发现，我们提出了以下组织假说：小鼠CIE和猴子SIP模型中酒精饮酒和应激/内分泌表型的改变是脑基因表达网络中适应性反应的结果，导致了一个新的同素平衡设定点。该项目的目标将通过在BXD小鼠小组和Grant博士的恒河猴样本(项目1)中对CIE治疗进行表达谱分析，与Williams博士的Project 10的RNA-Seq数据共同分析结果，以及使用病毒载体基因传递对包括Gsk3P在内的候选基因进行测试，从而定义CIE和猴子SIP模型中存在异构性变化的新的基因网络。

DESCRIPTION (provided by applicant): An underlying premise of the INIA-Stress consortium is that progression to abusive ethanol consumption is, at least in part, accompanied and perhaps caused by alterations in an organism's response to stress, including the stress of excessive ethanol intake/withdrawal. We propose that changes in brain gene expression networks are an important part of allostatic mechanisms leading to progressive ethanol consumption and aberrant responses to stress. We have previously used genetic and genomic approaches across brain regions of BXD recombinant inbred panel to define robust gene networks regulated by acute ethanol and relate these to ethanol behaviors, particularly regarding responses to stress. We have also identified significant overlap in expression responses to acute ethanol in mice and altered gene expression patterns seen in a primate model of excessive ethanol intake (SIP) developed by Dr. Grant, the PI of the INIA-Stress consortium. Furthermore, very recent pilot array studies in BXD mice exposed to multiple cycles of the chronic intermittent ethanol vapor (CIE) model of excessive ethanol consumption have identified remarkable homology with results from acute ethanol exposure and our data from cynomolgus macaque. Those studies have generated gene networks that allow testing initial major "hub" genes for their possible role in modifying ethanol consumption and response to stress in the CIE model. For example, we recently identified Gsk3p as an important regulator of ethanol consumption and withdrawal-induced anxiety, using AAV viral vector gene delivery studies. Based on these findings, we propose the following Organizing Hypothesis: Altered ethanol drinking and stress/endocrine phenotypes in the mouse CIE and monkey SIP models result from (and cause) adaptive responses in brain gene expression networks, resulting in a new allostatic set point. The aims of this project will define new gene networks underlying allostatic changes in the CIE and monkey SIP models by expression profiling of CIE treatment across the BXD mouse panel and Rhesus Macaque samples of Dr. Grant (Project 1), co-analysis of results with RNA-Seq data of Dr. Williams' Project 10, and testing of candidates, including Gsk3P, using viral vector gene delivery.