Amygdala NPY, anxiety phenotypes and alcohol consumption

杏仁核 NPY、焦虑表型和饮酒

• 批准号: 7414346
• 负责人: JIM R FADEL
• 金额: $ 20.27万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414346
• 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

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）：本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由基因与环境相互作用导致的复杂疾病，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与酒精依赖的风险有关。这一建议扩展了我们早期的研究，并将利用在大鼠模型中观察到的焦虑固有表型变异，探索杏仁核中NPY基因表达、焦虑行为表型和乙醇消耗之间的因果关系。杏仁核在焦虑相关行为中起关键作用，NPY的抗焦虑作用可能是通过杏仁核介导的。我们之前的研究表明，焦虑型和非焦虑型的大鼠在乙醇偏好上表现出差异。杏仁核中NPY表达的改变也改变了乙醇偏好，但仅在焦虑大鼠中发生。鉴于杏仁核NPY水平调节焦虑相关反应的证据，本研究检验了杏仁核NPY基因表达水平决定个体焦虑表型的假设，并且基于这种焦虑表型，低NPY水平可能使动物倾向于更多的乙醇消耗。目的1研究在两瓶自我给药过程中，杏仁核中NPY表达的改变是否会改变焦虑状态并随后改变乙醇消耗。这一目标将发展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NPY表达是否会增强焦虑，从而促进乙醇消耗和/或增强杏仁核中NPY基因表达是否具有抗焦虑作用，从而降低乙醇偏好。本研究还使用额外的行为模型来表征焦虑表型。目的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。这种有限的访问方法将允许更有效地筛选基因靶点，以制定对抗酒精依赖的治疗策略。目的3将检查在焦虑和非焦虑表型中，杏仁核（和其他区域）的神经元激活模式是否随着增加的迷宫暴露而不同，以及NPY神经元是否在有限的访问期内被乙醇注射或乙醇消耗激活。结合本研究中描述的病毒载体方法，这些研究将更好地表征杏仁核中NPY基因表达调控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。