Amygdala NPY, anxiety phenotypes and alcohol consumption

杏仁核 NPY、焦虑表型和饮酒

基本信息

批准号：
7504054
负责人：
JIM R FADEL
金额：
$ 16.72万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7504054
关键词：
Adolescent Adult Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Amygdaloid structure Animal Model Animals Anti-Anxiety Agents Anxiety Attenuated Behavior Behavioral Behavioral Model Behavioral Paradigm Brain Brain region Breeding Cell Nucleus Cells Clinical Complex Dependence Development Disease Emotional Ethanol Exploratory/Developmental Grant FOS gene Fright Future Gene Expression Gene Targeting Gene Transfer Genes Grant Individual Individual Differences Injection of therapeutic agent Lead Lentivirus Vector Localized Mediating Mental Depression Methodology Methods Modeling Mood Disorders Nature Neurons Organism Pattern Personality Phenotype Play Population Procedures Process Public Health Rat Strains Rattus Risk Role Screening procedure Self Administration Somatostatin Stress Subfamily lentivirinae System Temperament Testing Therapeutic Ultrasonics Variant Viral Vector Virus addiction alcohol exposure base conditioned fear endophenotype gene environment interaction molecular modeling neuropeptide Y novel preclinical study preference receptor response stressor trait vocalization

项目摘要

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.

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。酒精滥用和酒精依赖是一种由基因与环境相互作用引起的复杂疾病，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会带来酒精依赖的风险。该提案扩展了我们早期的研究，并将利用大鼠模型中焦虑的固有表型变异来探索杏仁核中 NPY 基因表达（一种焦虑行为表型）与乙醇消耗之间的因果关系。杏仁核在焦虑相关行为中起着至关重要的作用，NPY 的抗焦虑作用可能是通过杏仁核介导的。我们之前的研究表明，通过探索高架十字迷宫来定义具有焦虑或非焦虑表型的大鼠，表现出对乙醇的偏好差异。改变杏仁核中的 NPY 表达也会改变乙醇偏好，但仅限于焦虑的大鼠。鉴于杏仁核NPY水平调节焦虑相关反应的证据，本申请检验了这样的假设：杏仁核中的NPY基因表达水平决定个体的焦虑表型，并且基于这种焦虑，低NPY水平可能使动物倾向于消耗更多的乙醇表型。目标 1 检查杏仁核中 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，以更直接地测试降低杏仁核中的 NPY 表达是否会增强焦虑，从而促进乙醇消耗和/或增强的杏仁核 NPY 基因表达是否具有抗焦虑作用，从而减少乙醇偏好。该目标还使用其他行为模型来表征焦虑表型。目标 2 将使用有限访问模型检查焦虑和非焦虑表型的乙醇消耗情况。这种有限的获取方法将允许更有效地筛选基因靶标，以制定对抗酒精依赖的治疗策略。目标 3 将检查杏仁核（和其他区域）的神经元激活模式是否因焦虑和非焦虑表型中高架十字迷宫暴露而不同，以及 NPY 神经元是否在有限的访问期内通过乙醇注射或乙醇消耗而被激活。结合本次发育 R21 资助中表征的病毒载体方法，这些研究将更好地表征杏仁核中 NPY 基因表达调节的焦虑表型的特定方面，并更好地理解焦虑表型和 NPY 基因表达的这些差异如何预测乙醇消耗。公共健康相关性：尽管压力和焦虑会导致饮酒和滥用酒精，但导致某些人酗酒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情绪行为背后的大脑区域（即杏仁核）表达的基因如何控制个体在引发焦虑的情况下的反应，以及这些相同的过程是否会导致饮酒。这些研究将更好地理解基因表达的个体差异如何构成压力和酗酒之间相互作用的基础，并可能产生新的目标来解决青少年和成年人日益严重的饮酒问题。