Behavioral Inflexibility and Dorsal Striatal AMPA Receptors

项目摘要：行为不灵活和背侧纹状体AMPA受体（BIDSAR） 酒精使用问题可能源于行为的不稳定性，包括处理信息的困难 关于相互冲突的目标，如寻求酒精的有益效果，同时避免其令人厌恶的，和/或 转向习惯性的刺激性饮酒然而，不知道行为的影响程度 如果长期自愿饮酒，缺乏灵活性会使个人倾向于危险饮酒， 调节行为灵活性的变化，或者通过什么神经机制调节行为灵活性。在 简而言之，在我们对遗传和神经机制的理解方面仍然存在着一个关键的差距， 不灵活的饮酒。有一个关键的需要，以了解机制的基础上，既有先天的 倾向，以及酒精对行为能力的影响，长期目标是发展 治疗过度饮酒行为的新方法本申请的目的是（1）确定 不灵活行为的先天差异是否可以推广到其他甜味剂（如糖精）的消费 以及其他认知领域（即，注意定势转移）;（2）评估长期饮酒是否 易感人群中的中毒促进不灵活和强迫性行为;（3）确定 先天或后天的不灵活行为是否与AMPA受体表达的改变有关， 药理学在背外侧与背内侧纹状体，符合的想法，提高 听起来像是音乐。我们将通过使用遗传小鼠来探索这些关系来达到目的 过度饮酒的模型。我们的中心假设是，认知能力（强制性）是两者兼而有之 慢性饮酒的内在表型和后果，由改变的前额叶皮层介导 背侧纹状体的神经递质输入。

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.