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:
  • 金额:
    $ 16.72万
  • 依托单位:
  • 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

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):这项提案探索了杏仁核中气质(焦虑)和基因表达(NPY)模式的差异,作为可能有助于酒精消费的内表型的例子。酒精滥用和依赖是一种由基因-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与酒精依赖有关。这一建议扩展了我们早期的研究,并将利用在大鼠模型中看到的焦虑的内在表型变化来探索杏仁核(一种焦虑的行为表型)中NPY基因表达与酒精消费之间的因果关系。杏仁核在焦虑相关行为中起着关键作用,NPY的抗焦虑作用可能是通过杏仁核实现的。我们之前的研究表明,焦虑或非焦虑表型的大鼠,通过探索高架加迷宫来定义,在酒精偏好方面表现出差异。改变杏仁核中NPY的表达也会改变对酒精的偏好,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,本申请检验了杏仁核中NPY基因表达水平决定个体焦虑表型的假设,基于这种焦虑表型,低NPY水平可能使动物更容易摄入更多酒精。目的1研究杏仁核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过程中的酒精消耗。这一目标将开发慢病毒介导的基因转移方法,以更直接地测试杏仁核NPY表达降低是否会增强焦虑,从而促进酒精消费和/或杏仁核NPY基因表达增强是否具有抗焦虑作用,从而降低酒精偏好。这一目的还利用其他行为模型来表征焦虑的表型。目标2将使用有限获取模型检查焦虑和非焦虑表型的酒精消耗。这种有限的获取方法将允许更有效地筛选基因靶点,以制定与酒精依赖作斗争的治疗策略。目的3将研究杏仁核(和其他区域)神经元的激活模式是否与升高加上迷宫暴露在焦虑和非焦虑表型上的不同,以及NPY神经元是否在有限的访问期间被乙醇注射或酒精消费激活。与这项R21发展拨款中描述的病毒载体方法相结合,这些研究将导致更好地描述杏仁核中NPY基因表达调控的焦虑表型的特定方面,并更好地理解这些焦虑表型和NPY基因表达的差异如何预测酒精消费。 公共卫生相关性:尽管压力和焦虑导致酒精消费和滥用,但使某些人容易滥用酒精的大脑系统以及酒精如何缓解焦虑状态仍不清楚。目前的研究使用动物模型来阐明在情绪行为背后的大脑区域,即杏仁核中表达的基因是如何控制引发焦虑的情况下的个人反应的,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是如何导致压力和酗酒之间相互作用的,并可能导致新的目标,以应对青少年和成年人日益增长的酒精消费问题。

项目成果

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JIM R FADEL其他文献

JIM R FADEL的其他文献

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{{ truncateString('JIM R FADEL', 18)}}的其他基金

Hypocretin/orexin modulation of cognitive correlates of brain aging
下丘脑分泌素/食欲素对大脑衰老认知相关性的调节
  • 批准号:
    10445459
  • 财政年份:
    2015
  • 资助金额:
    $ 16.72万
  • 项目类别:
Hypocretin/orexin modulation of cognitive correlates of brain aging
下丘脑分泌素/食欲素对大脑衰老认知相关性的调节
  • 批准号:
    8937397
  • 财政年份:
    2015
  • 资助金额:
    $ 16.72万
  • 项目类别:
Hypocretin/orexin modulation of cognitive correlates of brain aging
下丘脑分泌素/食欲素对大脑衰老认知相关性的调节
  • 批准号:
    9120726
  • 财政年份:
    2015
  • 资助金额:
    $ 16.72万
  • 项目类别:
Aging, acetylcholine and the hypothalamus
衰老、乙酰胆碱和下丘脑
  • 批准号:
    7675265
  • 财政年份:
    2008
  • 资助金额:
    $ 16.72万
  • 项目类别:
Aging, acetylcholine and the hypothalamus
衰老、乙酰胆碱和下丘脑
  • 批准号:
    7533192
  • 财政年份:
    2008
  • 资助金额:
    $ 16.72万
  • 项目类别:
Aging, acetylcholine and the hypothalamus
衰老、乙酰胆碱和下丘脑
  • 批准号:
    8113318
  • 财政年份:
    2008
  • 资助金额:
    $ 16.72万
  • 项目类别:
Aging, acetylcholine and the hypothalamus
衰老、乙酰胆碱和下丘脑
  • 批准号:
    7900012
  • 财政年份:
    2008
  • 资助金额:
    $ 16.72万
  • 项目类别:
Amygdala NPY, anxiety phenotypes and alcohol consumption
杏仁核 NPY、焦虑表型和饮酒
  • 批准号:
    7414346
  • 财政年份:
    2007
  • 资助金额:
    $ 16.72万
  • 项目类别:
Amygdalar Neuropeptides and Anxiety
杏仁核神经肽和焦虑
  • 批准号:
    7523990
  • 财政年份:
    2002
  • 资助金额:
    $ 16.72万
  • 项目类别:
Amygdalar Neuropeptides and Anxiety
杏仁核神经肽和焦虑
  • 批准号:
    7686186
  • 财政年份:
    2002
  • 资助金额:
    $ 16.72万
  • 项目类别:

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