Reward-specific neural ensembles in the lateral orbitofrontal cortex modulate alcohol-biased choice behavior

外侧眶额皮质中的奖励特异性神经元调节酒精偏向的选择行为

• 批准号: 10679456
• 负责人: Kaitlin Charlotte Reeves
• 金额: $ 2.34万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-04 至 2023-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10679456
• 关键词: Affect; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Animals; Behavior; Behavioral; Choice Behavior; Chronic; Cocaine; Complex; Consumption; Cues; Data; Decision Making; Disease model; Ethanol; Ethanol dependence; Goals; Growth; Heroin; Human; Implant; Knowledge; Lateral; Measures; Mentors; Methodology; Microelectrodes; Modeling; Motivation; Mus; Neurons; Neurophysiology - biologic function; Neurosciences; Outcome; Patients; Population; Process; Recovery; Research Personnel; Research Proposals; Rewards; Role; Severities; Study models; Sucrose; Techniques; Testing; Training; Treatment outcome; Viral Vector; Water; Work; alcohol cue; alcohol effect; alcohol exposure; alcohol involvement; alcohol response; alcohol reward; alcohol use disorder; chronic alcohol ingestion; craving; drinking; drug reward; human imaging; imaging study; innovation; neural; neuroadaptation; non-drug; novel; optogenetics; preference; relapse risk; response; skills; translational impact; treatment strategy; vapor

Project Summary Chronic alcohol exposure causes maladaptive behavioral and functional neural adaptations, which increase alcohol consumption and the risk of relapse. Alcohol-biased choice behaviors result from chronic alcohol-induced disruptions in reward-guided decision making and reward valuation, increasing the motivational value of alcohol, compared to alternative non-drug rewards. Importantly, alcohol-biased choice is associated with alcohol use disorder (AUD) severity and treatment outcomes; therefore, reducing alcohol-biased choice represents a largely unexplored avenue for potential AUD treatment. While this phenomenon has been well-described in patients with AUD and replicated in animal models, the mechanism of how chronic alcohol exposure modulates alcohol- biased choice is largely unknown. The orbitofrontal cortex (OFC) is an understudied region in the alcohol field and has a heavy role in reward-guided decision making and reward valuation. Patients with AUD show increased OFC activation in response to alcohol-related cues and alcohol consumption. In mice that have undergone the chronic intermittent ethanol (CIE) vapor exposure model of alcohol dependence, lateral OFC neurons have altered intrinsic excitability and responses to alcohol and sucrose seeking and consumption. Reward-specific neural populations in the OFC respond to and encode the value of available or expected rewards, with a larger proportion of neurons activated by higher value rewards. The proportion of activated OFC neurons and degree of reward-associated activation represents reward preference. Studies have identified distinct populations of OFC neurons that encode drug rewards (cocaine, heroin) and alternative non-drug rewards (sucrose). Similarly, my preliminary data demonstrates lateral OFC neural populations encode sucrose and EtOH rewards. No studies to date have investigated chronic alcohol effects on reward-specific lateral OFC ensembles during alcohol-biased choice assessment. The objective of this research proposal is to determine mechanisms of how chronic alcohol exposure alters the activity of reward-specific lateral OFC neural populations during reward approach and consumption to modulate alcohol-biased choice. To accomplish this goal, I have validated a model of chronic alcohol-induced alcohol biased choice using the CIE model of alcohol dependence and a two-bottle choice drinking assessment of alcohol-biased choice. Aim 1 of this proposal will focus on characterizing CIE-induced changes in cFos expression and neural activity in alcohol and sucrose-activated lateral OFC neurons during alcohol-biased choice assessment. Aim 2 will utilize FosTRAP methodology to specifically inhibit alcohol- and sucrose-activated lateral OFC neurons to determine how these neural ensembles modulate alcohol-biased choice. These results will have important scientific impact by determining how chronic alcohol exposure modulates alcohol-biased choice, a hallmark of AUD, through changes in reward-specific neural ensembles in the lateral OFC.

项目摘要 慢性酒精暴露会导致适应不良的行为和功能性神经适应，从而增加 饮酒和复发风险。酒精偏见的选择行为是由慢性酒精引起的 奖励指导决策和奖励估值的破坏，增加酒精的动机价值， 与替代性非药品奖励相比。重要的是，酒精偏见与酒精使用有关 障碍（AUD）严重性和治疗结果；因此，减少酒精偏见的选择代表 未开发的大道用于潜在的AUD治疗。虽然这种现象在患者中被很好地描述了 随着AUD并在动物模型中进行了复制，慢性酒精暴露如何调节酒精的机制 有偏见的选择在很大程度上是未知的。眶额皮层（OFC）是酒精场的研究区域 并且在奖励指导决策和奖励估值中起着重大作用。 aud的患者显示增加 OFC激活与酒精有关的提示和饮酒。在经历过的老鼠中 慢性间歇性乙醇（CIE）酒精依赖性蒸气暴露模型，外侧OFC神经元具有 改变了内在的兴奋性以及对酒精和蔗糖寻求和消费的反应。特定于奖励 OFC中的神经种群响应并编码可用或预期奖励的价值，较大 由较高的价值奖励激活的神经元的比例。激活的OFC神经元和程度的比例 奖励相关的激活代表奖励偏好。研究已经确定了不同的人群 编码药物奖励的OFC神经元（可卡因，海洛因）和替代性非药物奖励（蔗糖）。相似地， 我的初步数据表明，OFC神经种群编码蔗糖和ETOH奖励。没有研究 迄今为止，已经调查了在酒精偏见期间对奖励特异性外侧OFC合奏的慢性酒精影响 选择评估。该研究建议的目的是确定慢性酒精的机制 暴露在奖励方法和 消费以调节酒精偏见的选择。为了实现这一目标，我验证了一种慢性模型 酒精诱导的酒精偏向选择，使用酒精依赖的CIE模型和两瓶选择 酒精偏见的选择评估。该提案的目标1将重点介绍CIE引起的 在酒精和蔗糖激活的CFOS表达和神经活性的变化中 酒精偏见的选择评估。 AIM 2将利用Fostrap方法专门抑制酒精和 蔗糖激活的外侧OFC神经元，以确定这些神经合奏如何调节酒精偏见 选择。这些结果将通过确定慢性酒精暴露如何产生重要的科学影响 通过奖励特定的神经合奏的变化，调节酒精偏见的选择（AUD的标志） 横向OFC。