Amygdala NPY, anxiety phenotypes and alcohol consumption

描述（由申请人提供）：该提案探讨了杏仁核中气质（焦虑）和基因表达（NPY）模式的差异，作为可能导致乙醇消耗的内表型的例子。酒精滥用和依赖是一种基因-环境相互作用的复杂疾病，但在临床和临床前研究中，编码神经肽Y（NPY）或其受体的基因似乎赋予酒精依赖的风险。这一建议扩展了我们早期的研究，并将探讨杏仁核，焦虑的行为表型，和乙醇消耗量的固有表型变化，在大鼠模型中看到的焦虑的基因表达之间的因果关系。杏仁核在焦虑相关行为中起关键作用，NPY的抗焦虑作用可能通过杏仁核介导。我们以前的研究表明，大鼠与焦虑或nonanxious表型，定义使用探索高架十字迷宫，显示不同的乙醇偏好。杏仁核中NPY表达的改变也改变了乙醇偏好，但仅限于焦虑大鼠。鉴于杏仁核NPY水平调节焦虑相关反应的证据，本申请检验了杏仁核中的NPY基因表达水平决定个体的焦虑表型的假设，并且低NPY水平可能使动物基于这种焦虑表型倾向于更大的乙醇消耗。目的1研究杏仁核中NPY表达的改变是否会改变焦虑状态，并随后改变两瓶自我给药程序中的乙醇消耗量。这一目标将开发慢病毒介导的基因转移方法，以更直接地测试是否降低杏仁核中的NPY表达会增强焦虑，从而促进乙醇消耗和/或增强杏仁核中的NPY基因表达是否具有抗焦虑作用，从而降低乙醇偏好。该目标还使用其他行为模型表征焦虑表型。目标2将研究乙醇消费在焦虑和非焦虑表型使用有限的访问模型。这种有限的获取方法将允许更有效地筛选基因靶点，以开发治疗策略来对抗酒精依赖。目的3将检查杏仁核（和其他区域）中的神经元激活模式是否与焦虑和非焦虑表型中的升高的迷宫暴露不同，以及在有限的访问期间是否通过乙醇注射或乙醇消耗激活NPY神经元。结合病毒载体的方法，其特点是在这个发展R21授予这些研究将导致更好地表征的具体方面的焦虑表型调节杏仁核中的NPY基因表达，以及更好地了解这些差异在焦虑表型和NPY基因表达预测乙醇消费。 公共卫生相关性：虽然压力和焦虑会导致酒精消费和滥用，但使某些人易于滥用酒精的大脑系统以及酒精如何缓解焦虑状态仍然未知。目前的研究使用动物模型来阐明大脑区域中表达的基因是如何影响情绪行为的，即杏仁核，在焦虑的情况下控制个体的反应，以及这些相同的过程是否有助于饮酒。这些研究将更好地了解基因表达的个体差异如何构成压力和酒精滥用之间相互作用的基础，并可能导致新的目标，以应对青少年和成年人日益严重的饮酒问题。

DESCRIPTION (provided by applicant): This proposal explores differences in temperament (anxiety) and gene expression (NPY) patterns in the amygdala as examples of endophenotypes that may contribute to ethanol consumption. Alcohol abuse and dependence is a complex disorder resulting from gene-environment interactions, but the genes encoding neuropeptide Y (NPY) or its receptor appear to confer risk for alcohol dependence in clinical and preclinical studies. This proposal expands our earlier studies and will explore the causative relationship between gene expression of NPY in the amygdala, an anxious behavioral phenotype, and ethanol consumption using the inherent phenotypic variation in anxiety seen in a rat model. The amygdala plays a critical role in anxiety-related behaviors and the anxiolytic effects of NPY may be mediated through the amygdala. Our previous studies have shown that rats with an anxious or nonanxious phenotype, defined using exploration of the elevated plus maze, display differences in ethanol preference. Changing NPY expression in amygdala also shifts ethanol preference, but only in anxious rats. Given the evidence that amygdala NPY levels regulate anxiety-related responses, the present application examines the hypothesis that NPY gene expression levels in the amygdala determine the anxiety phenotype of an individual, and low NPY levels may predispose animals for greater ethanol consumption based on this anxious phenotype. Aim 1 examines if altered NPY expression in amygdala changes anxiety state and subsequently modifies ethanol consumption in a two bottle self-administration procedure. This aim will develop lentivirus-mediated gene transfer methodologies to more directly test if lowering NPY expression in the amygdala enhances anxiety and thereby promotes ethanol consumption and/or if enhanced amygdala NPY gene expression is anxiolytic and thereby reduces ethanol preference. This Aim also characterizes anxiety phenotypes using additional behavioral models. Aim 2 will examine ethanol consumption in anxious and non-anxious phenotypes using a limited access model. This limited access method will allow more efficient screening of gene targets for development of therapeutic strategies to combat alcohol dependence. Aim 3 will examine if the pattern of neuronal activation in the amygdala (and other regions) differs with elevated plus maze exposure in the anxious and non-anxious phenotypes, and if NPY neurons are activated by ethanol injection or ethanol consumption during a limited access period. Combined with viral vector methods characterized in this developmental R21 grant these studies will lead to better characterization of specific aspects of the anxiety phenotypes regulated by NPY gene expression in the amygdala, and a better understanding of how these differences in anxiety phenotype and NPY gene expression predict ethanol consumption. Public Health Relevance: Although stress and anxiety contribute to alcohol consumption and abuse, the brain systems that predispose certain individuals to abuse alcohol and how alcohol relieves anxiety states remains unknown. The present studies use animal models to elucidate how the genes expressed in the brain region underlying emotional behaviors, namely the amygdala, control individual responses in an anxiety-provoking situation and if these same processes contribute to the alcohol consumption. The studies will provide a better understanding of how individual differences in gene expression underlie the interaction between stress and alcohol abuse, and may lead to novel targets to combat the growing problem of alcohol consumption in adolescents and adult populations.