Amygdala NPY, anxiety phenotypes and alcohol consumption

杏仁核 NPY、焦虑表型和饮酒

• 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
• 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

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，这是可能有助于乙醇消耗的内酚的例子。酒精滥用和依赖性是由基因环境相互作用引起的复杂疾病，但是编码神经肽Y（NPY）或其受体似乎赋予临床和临床前研究中酒精依赖的风险。该提案扩大了我们的早期研究，并将探索NPY在杏仁核中的基因表达，一种焦虑的行为表型和使用大鼠模型中焦虑中固有的表型变化的焦虑行为表型和乙醇消耗之间的因果关系。杏仁核在与焦虑相关的行为中起着至关重要的作用，NPY的抗焦虑作用可以通过杏仁核介导。我们以前的研究表明，使用升高的迷宫的探索来定义具有焦虑或非氧化表型的大鼠，表现出乙醇偏好的差异。改变杏仁核中的NPY表达也会改变乙醇的偏好，但仅在焦虑的大鼠中。鉴于有证据表明杏仁核NPY水平调节与焦虑相关的反应，因此本应用研究了以下假设：杏仁核中的NPY基因表达水平确定个体的焦虑表型，而NPY水平低可能会使动物易于基于这种焦虑表型的乙醇消耗。 AIM 1检查杏仁核中的NPY表达是否改变会改变焦虑状态，随后在两瓶自我给药程序中修饰乙醇消耗。如果降低杏仁核中的NPY表达会增强焦虑，从而促进乙醇的消耗和/或如果增强的杏仁核NPY基因表达是抗焦虑症，从而减少乙醇偏好，则该目标将开发出慢病毒介导的基因转移方法，以更直接地测试杏仁核的NPY表达，从而促进乙醇的消耗和/或/或/或促进乙醇npy基因的表达并降低乙醇偏好。这个目的还使用其他行为模型来表征焦虑表型。 AIM 2将使用有限的访问模型检查焦虑和非焦虑表型中的乙醇消耗。这种有限的访问方法将允许对基因靶标进行更有效的筛查，以开发治疗策略以打击酒精依赖性。 AIM 3将检查杏仁核（和其他区域）中神经元激活的模式是否有所不同，而焦虑和非焦虑表型中的迷宫暴露却有所不同，以及在有限的进入期间，NPY神经元是否被乙醇注射或乙醇消耗激活。结合此发育R21授予的病毒矢量方法，这些研究将使杏仁核中NPY基因表达调节的焦虑表型的特定方面更好地表征，并更好地了解焦虑表型和NPY基因表达中这些差异如何预测乙醇的消耗。 公共卫生相关性：尽管压力和焦虑有助于饮酒和滥用，但使某些人容易滥用酒精以及酒精如何缓解焦虑状态的大脑系统仍然未知。本研究使用动物模型来阐明情绪行为的基因在大脑区域的表达方式，即杏仁核，控制发人深省的情况下的个体反应，以及这些相同的过程是否有助于酒精消耗。这些研究将更好地理解基因表达中的个体差异如何构成压力与酗酒之间的相互作用，并可能导致新的目标，以应对青少年和成人种群中日益增长的饮酒问题。