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

项目摘要 长期接触酒精会导致适应不良的行为和功能神经适应，这会增加 饮酒和复发的风险。长期饮酒导致的酒精偏向选择行为 破坏奖励导向的决策和奖励估值，增加酒精的激励价值， 与其他非药物奖励相比。重要的是，有酒精偏见的选择与饮酒有关。 精神障碍(AUD)的严重性和治疗结果；因此，减少酒精偏向的选择在很大程度上代表了 潜在的AUD治疗的未知途径。虽然这种现象已经在患者身上得到了很好的描述 通过AUD并在动物模型中复制，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。摘要眼眶前额叶皮质(OFC)是酒精领域研究较少的区域。 并在奖励导向决策和奖励评估中发挥着重要作用。AUD患者表现为增加 对酒精相关提示和酒精消费作出反应的OFC激活。在小鼠中经历了 慢性间歇性乙醇(CIE)蒸气暴露酒精依赖模型，外侧OFC神经元 改变了内在的兴奋性和对酒精和蔗糖寻求和消费的反应。特定于奖励 OFC中的神经群体对可用或预期奖励的价值做出反应并进行编码，具有更大的 被较高价值奖励激活的神经元比例。激活的OFC神经元的比例和程度 奖赏相关激活代表奖赏偏好。研究已经确定了不同的种群 编码毒品奖赏(可卡因、海洛因)和其他非毒品奖赏(蔗糖)的OFC神经元。同样， 我的初步数据显示，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，我已经研究了长期酒精对酒精偏向期间奖赏特异性外侧OFC集合的影响 选择评估。这项研究提案的目的是确定慢性酒精如何 暴露改变奖赏途径和刺激过程中奖赏特异性外侧OFC神经群体的活动 通过消费来调节酒精偏向的选择。为了实现这个目标，我验证了一个慢性病模型 基于CIE酒精依赖模型和两瓶酒的酒精诱导偏向选择 饮酒评估偏重于酒精的选择。本提案的目标1将重点描述CIE引发的 酒精和蔗糖刺激的外侧OFC神经元CFos表达和神经活动的变化 酒精偏向选择评估。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丛如何调节酒精偏向 选择。这些结果将产生重要的科学影响，通过确定慢性酒精暴露 通过改变特定于奖赏的神经系综来调节酒精偏向的选择，这是AUD的一个标志 横向OFC。

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.