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， 饮酒和复发的风险。慢性酒精诱导的酒精偏好选择行为 破坏奖励导向的决策和奖励评估，增加酒精的激励价值， 与其他非药物奖励相比。重要的是，酒精偏见的选择与酒精使用有关 疾病（AUD）的严重程度和治疗结果;因此，减少酒精偏见的选择在很大程度上代表了 潜在AUD治疗的未探索途径。虽然这种现象已经在患者中得到了很好的描述， 在动物模型中复制，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。眶额皮层是酒精研究领域中的一个研究不足的区域 并在奖励导向的决策和奖励评估中发挥重要作用。AUD患者表现出增加 OFC激活对酒精相关线索和酒精消费的反应。在经历了 慢性间歇性乙醇（CIE）蒸汽暴露模型的酒精依赖，外侧OFC神经元有 改变了对酒精和蔗糖寻求和消费的内在兴奋性和反应。特定奖励 眶额皮层中的神经元群体对可用或预期奖励的价值做出反应并进行编码， 被高价值奖励激活的神经元的比例。OFC神经元的激活比例和程度 表示奖励偏好。研究发现， OFC神经元编码药物奖励（可卡因，海洛因）和替代非药物奖励（蔗糖）。同样地， 我的初步数据表明，外侧OFC神经群体编码蔗糖和乙醇奖励。没有研究 到目前为止，已经研究了慢性酒精对酒精偏置过程中奖励特异性外侧OFC合奏的影响。 选择评估这项研究的目的是确定慢性酒精的机制， 暴露改变了奖励接近过程中奖励特异性外侧OFC神经群的活动， 消费来调节酒精偏见的选择。为了实现这一目标，我验证了一个慢性 使用CIE酒精依赖模型和两瓶选择的酒精诱导的酒精偏向选择 饮酒评估的酒精偏见的选择。本提案的目标1将侧重于表征CIE诱导的 酒精和蔗糖刺激下大鼠外侧眶额皮层神经元cFos表达和神经活动的变化 酒精偏见的选择评估目标2将利用FosTRAP方法学来特异性抑制酒精， 蔗糖激活的外侧OFC神经元，以确定这些神经系综如何调节酒精偏性 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， 调节酒精偏见的选择，一个标志性的AUD，通过改变奖励特定的神经合奏， 外侧眶额皮层