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征是对饮酒失去控制，个人持续 不顾负面后果使用。目前批准的酒精中毒治疗方法(如双硫兰)旨在 通过减少饮酒来减少饮酒。但是，这种方法存在问题，因为 酒精的享乐性特征可能不再会在疾病的晚期激发饮酒行为。 相反，当饮酒已经发展到抵抗令人厌恶的后果的阶段时，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 调停强迫症和习惯。影响饮酒过渡到这一阶段的两个突出因素 有饮酒史和酗酒遗传风险(如家族病史)。印第安纳州的初步数据 酒精研究中心(IARC)的研究人员证明，某些啮齿动物模型存在遗传风险 过度饮酒也容易很快形成习惯和强迫行为。因此，存在着一种迫切需要 了解酒精暴露和遗传因素如何影响大脑的计算特性 动机行为的认知控制所必需的区域。这个项目的长期目标是 了解神经计算中的可遗传变化，这些变化有助于向失去控制的过渡 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特性 即使与令人厌恶的后果联系在一起。一种常用的评估抗厌恶能力的方法 在啮齿动物中饮酒(ARD)是衡量它们是否愿意饮用掺有难闻味道的酒精-- 奎宁贬值程序。这一建议的中心假设是，遗传易感性 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以促进 ARD。电生理记录将从内侧前额叶皮质和腹侧纹状体获得 清醒行为偏爱酒精(P)和Wistars大鼠进行巴甫洛夫提示通路饮酒 程序。这种方法将允许在个体上测量酒精配对线索的表征 神经元和集合水平，以确定它们在ARD期间是如何不同地处理的。严谨的统计 程序将被用来量化酒精配对的线索在皮质纹状体回路中的表现，以及如何 他们受到饮酒史和遗传风险的影响。目标1将检查表示的变化 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 皮层纹状体回路中酒精配对线索的编码。目标2将确定饮酒史和基因 风险削弱了皮质纹状体回路重新映射酒精配对线索表征的能力。最后，目标3 将确定饮酒史和遗传风险是否会增强对酒精配对线索的皮质纹状体表征 在抗厌恶的饮酒中。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.