Effect of Gabra2 Knockdown on Alcohol Preference

人类遗传学研究已将GABRA2(编码GABA-A a2亚基)基因的多态联系起来 酗酒(Edenberg等人，2004年；Soyka等人，2008年)。然而，准确的行为和 这种联系的神经化学机制(S)尚不清楚。例如，现有证据表明 GABRA2风险等位基因降低了a2亚基的表达(Heh等人，2008年)，并可能调节nsk 对于酒精中毒来说，行为的改变与冲动(Dick等人，2006)和特质焦虑相关 (Enoch等人)2006)。然而，由于研究人类的复杂性，包括无法控制 条件或获得大脑，发展良好的动物模型将是必要的，以更有效 阐明GABRA2NSK影响的行为和神经化学机制 当前提案的目标是研究GABRA2影响酒精的机制 两种不同高饮酒/酒精偏好人群的摄入/偏好、冲动选择和焦虑样行为 小鼠群体，C57BL/6J(B6)近交系和高酒偏爱(HAP2)选育小鼠 菌株/品系。将使用慢病毒载体介导的递送方法来降低(击倒)GABA-A a2- 几种被认为在酒精调节中起重要作用的小鼠脑结构中亚单位的表达 摄取/偏爱(后腹侧被盖区或pVTA；伏隔核壳或NACsh)，冲动 选择(眶前皮质或OFC)和焦虑样行为(杏仁核或艾米)。假设是这样的 敲除这些结构中的a2将减少B6和HAP2小鼠的酒精摄入量/偏好。 然而，假设是a2基因敲除对假定的冲动和焦虑的影响 行为关联将是特定地点的，只有OFC击倒会减少冲动，只有艾米 击倒减少焦虑类行为。这样的结果将进一步暗示a2的表达发生了变化 神经化学机制，和行为相关的冲动和焦虑作为行为 GABRA2基因影响酒精中毒风险的机制。

Human genetic studies have linked polymorphisms in the GABRA2 (encoding the GABA-A a2-subunit) gene to alcoholism (Edenberg et al., 2004; Soyka et al., 2008). However, the precise behavioral and neurochemical mechanism(s) for this linkage remain unclear. For example, the available evidence suggests that the GABRA2 risk allele reduces a2-subunit expression (Haughey et al., 2008), and may modulate nsk for alcoholism through alterations in the behavioral correlates impulsivity (Dick et al., 2006) and trait anxiety (Enoch et al. 2006). However, due to the complexities of studying humans, including the inability to control conditions or access the brain, the development of good animal models will be necessary to more effectively elucidate the behavioral and neurochemical mechanisms underlying the effects of the GABRA2 nsk allele.The goal of the current proposal is to investigate the mechanisms by which Gabra2 affects alcohol intake/preference, impulsive choice, and anxiety-like behavior in two different high drinking/alcohol preferring mouse populations, the C57BL/6J (B6) inbred and the high alcohol preferring (HAP2) selectively bred mouse strains/lines. A lentiviral vector-mediated delivery approach will be used to reduce (knockdown) GABA-A a2- subunit expression in several mouse brain structures believed important in the modulation of alcohol intake/preference (posterior ventral tegmental area or pVTA; nucleus accumbens shell or NACsh), impulsive choice (orbitofrontal cortex or OFC), and anxiety-like behavior (amygdala or AMY). The hypothesis is that knockdown of a2 in each of these structures will reduce alcohol intake/preference in B6 and HAP2 mice. However, the hypothesis is that the effects of a2 knockdown on the presumed impulsivity and anxiety behavioral correlates will be site-specific, with only OFC knockdown reducing impulsivity, and only AMY knockdown reducing anxiety-like behavior. Such results would further implicate altered expression of a2 as the neurochemical mechanism, and the behavioral correlates impulsivity and anxiety as the behavioral mechanisms, by which the GABRA2 genotype influences alcoholism risk.