Corticostriatal processing of alcohol-paired cues in aversion-resistant drinking

项目摘要：抗厌恶饮酒中酒精配对线索的皮质纹状体处理 （CAPD） 难治性酒精中毒的特点是对饮酒失去控制， 尽管有负面后果。目前批准的酒精中毒治疗（如双硫仑）旨在 通过使人厌恶饮酒来减少饮酒。然而，这种方法是有问题的， 酒精的享乐特性在疾病的晚期可能不再激发饮酒行为。 相反，当饮酒已经发展到一个阶段，是抵制令人厌恶的后果，控制 行为被认为是从调节高级认知功能的神经回路过渡到 调解强迫和习惯。影响饮酒过渡到这一阶段的两个突出因素 酒精使用史和酒精滥用的遗传风险（例如家族史）。来自印第安纳州的初步数据 酒精研究中心（IARC）的研究人员证明，某些啮齿动物模型的遗传风险， 过量饮酒也容易迅速形成习惯和强迫行为。因此，迫切需要 了解酒精暴露和遗传因素如何影响大脑的计算特性， 对动机性行为进行认知控制所必需的区域。该项目的长期目标是 理解神经计算中的遗传变化，这些变化促进了对大脑失去控制的过渡。 喝酒在这种转变之后，与酒精相关的线索保留了极端的激励动机属性 即使与令人厌恶的后果有关。一种通常用于评估厌恶抵抗力的方法 在啮齿类动物中，饮酒（ARD）是衡量它们是否愿意饮用掺杂了不良味道的酒精-- 奎宁贬值程序。这一建议的核心假设是， 以刺激依赖的方式分配认知资源与慢性酒精使用相互作用， ARD。将从受试者的内侧前额叶皮层和腹侧纹状体获得电生理记录。 清醒行为的酒精偏好（P）和Wistars大鼠执行巴甫洛夫线索访问饮酒 procedure.这种方法将允许酒精配对线索的代表性在个人进行测量 神经元和整体水平，以确定它们在ARD期间如何被不同地处理。严格的统计 程序将用于量化皮质纹状体回路中酒精配对线索的代表性，以及如何 他们受到酒精史和遗传风险的影响。目标1将审查以下方面的变化： 酒精暴露后的酒精配对线索，以确定饮酒史和遗传风险是否会增加 皮质纹状体回路中酒精配对线索的编码。目标2将确定是否饮酒史和遗传 风险损害了皮质纹状体回路重新映射酒精配对线索的能力。第三，目标 将确定饮酒史和遗传风险是否会增强皮质纹状体对酒精配对线索的表达 抗厌恶饮酒这些数据将阐明皮质纹状体功能的变化， ARD，因此符合IARC的总体目标。

Project Summary: Corticostriatal processing of alcohol-paired cues in aversion-resistant drinking (CAPD) Treatment resistant alcoholism is characterized by a loss of control over drinking where individuals persistently use in spite of negative consequences. Currently approved treatments for alcoholism (e.g. disulfiram) aim to reduce drinking by making alcohol consumption aversive. However, this approach is problematic as the hedonic properties of alcohol may no longer motivate drinking behavior in advanced stages of the disease. Rather, when drinking has advanced to a stage that is resistant to aversive consequences, the control of behavior is thought to transition from neural circuits that mediate higher cognitive functions to those that mediate compulsions and habits. Two prominent factors that influence the transition to this stage of drinking are history of alcohol use and genetic risk for alcohol abuse (e.g. family history). Preliminary data from Indiana Alcohol Research Center (IARC) investigators demonstrate that certain rodent models of genetic risk for excessive drinking also tend to quickly form habits and compulsive behaviors. Therefore, a critical need exists to understand how alcohol exposure and genetic factors influence the computational properties of brain regions necessary for the cognitive control of motivated behavior. The long-term goal of this project is to understand the heritable changes in neural computation that facilitate the transition to a loss of control over drinking. Following this transition, alcohol associated cues retain extreme incentive motivational properties even when associated with aversive consequences. A method commonly used to assess aversion resistant drinking (ARD) in rodents is measuring their willingness to consume alcohol adulterated with a bad taste - the quinine devaluation procedure. The central hypothesis of this proposal is that the genetic predisposition to allocate cognitive resources in a stimulus-dependent manner interacts with chronic alcohol use to facilitate ARD. Electrophysiological recordings will be obtained from the medial prefrontal cortex and ventral striatum of awake behaving alcohol preferring (P) and Wistars rats performing a Pavlovian cued access drinking procedure. This approach will allow the representation of alcohol-paired cues to be measured at the individual neuron and ensemble levels to determine how they are processed differently during ARD. Rigorous statistical procedures will be use to quantify the representation of alcohol-paired cues in corticostriatal circuits, and how they are influenced by alcohol history and genetic risk. Aim 1 will examine changes in the representation of alcohol-paired cues following alcohol exposure to determine if drinking history and genetic risk enhances the encoding of alcohol-paired cues in corticostriatal circuits. Aim 2 will determine if drinking history and genetic risk impair the ability of corticostriatal circuits to remap representations of alcohol-paired cues. Finally, Aim 3 will determine if drinking history and genetic risk enhance corticostriatal representations of alcohol-paired cues in Aversion-Resistant Drinking. These data will shed light on the changes in corticostriatal function that underlie ARD, and are therefore consistent with the overarching goals of the IARC.