Behavioral Inflexibility and Dorsal Striatal AMPA Receptors

项目摘要：行为不灵活与背侧纹状体AMPA受体(BIDSAR) 酒精使用问题可能源于行为不灵活，包括处理信息方面的困难 关于相互冲突的目标，比如寻求酒精的有益效果，同时避免其令人厌恶的效果，和/或 转向习惯性、刺激性饮酒。然而，未知的是行为的程度 如果长期自愿饮酒，缺乏灵活性会使个人倾向于高风险饮酒 调节行为灵活性的变化，或通过什么神经机制调节行为灵活性。在……里面 简而言之，在我们对潜在的遗传和神经机制的理解上仍然存在严重的差距 顽固的饮酒习惯。迫切需要了解这两种先天疾病背后的机制 倾向于行为僵化和酒精对行为僵化的影响，并有一个长期目标是发展 针对过度饮酒行为的新疗法。本申请的目标是(1)确定 僵硬行为的先天差异是否会导致其他强化剂(如糖精)的摄入 和其他认知领域(即注意定势转移)；(2)评估长期饮酒是否对 易感人群中的醉酒促进了僵化和强迫性的行为；以及(3)确定 无论是先天的还是后天的僵硬的行为都与AMPA受体表达的改变有关 背外侧纹状体与背内侧纹状体的药理学，与 谷氨酸紧张素。我们将通过使用遗传小鼠探索这些关系来实现这些目标 过度饮酒的典范。我们的中心假设是认知上的僵化(强迫性)既是 由前额叶皮质改变介导的慢性饮酒的内表型和后果 谷氨酸能传入背侧纹状体。

Project Summary: Behavioral Inflexibility and Dorsal Striatal AMPA Receptors (BIDSAR) Alcohol use problems may emerge from behavioral inflexibility, including difficulties processing information about conflicting goals such as seeking alcohol's rewarding effects while avoiding its aversive ones, and/or shifts towards habitual, stimulus-bound drinking. However, unknown is the extent to which behavioral inflexibility predisposes an individual toward risky alcohol drinking, if chronic voluntary alcohol drinking mediates shifts in behavioral flexibility, or by what neural mechanisms behavioral flexibility is mediated. In short, there remains a critical gap in our understanding of the genetic and neural mechanisms underlying inflexible alcohol drinking. There is a critical need to understand the mechanisms underlying both an innate proclivity towards, and the effects of alcohol on, behavioral inflexibility, with a long-term goal of developing novel treatments for excessive drinking behavior. The objectives of this application are to (1) to determine whether innate differences in inflexible behavior generalize to consumption of other reinforcers (e.g. saccharin) and to other cognitive domains (i.e., attentional set-shifting); (2) assess whether long-term alcohol drinking to intoxication in susceptible populations facilitates inflexible and compulsive-like behavior; and (3) determine whether either innate or acquired inflexible behavior is associated with altered AMPA receptor expression and pharmacology in the dorsolateral versus dorsomedial striatum, consistent with the idea of heightened glutamatergic tone. We will achieve the objectives by exploring these relationships using genetic mouse models of excessive alcohol drinking. Our central hypothesis is that cognitive inflexibility (compulsivity) is both an endophenotype and consequence of chronic alcohol consumption, mediated by altered prefrontal cortical glutamatergic input to the dorsal striatum.