Orbitofrontal coding of alcohol preference and compulsive drinking

项目摘要/摘要 眼眶前额叶皮质(OFC)与奖赏评估和寻求密切相关，而且 OFC功能障碍与滥用药物成瘾之间有很强的相关性。越来越多的证据表明 OFC可能是酒精使用障碍中强迫性酒精寻求发展的一个关键节点。 然而，尽管OFC功能与饮酒有明显的相关性，但很少有关于这方面的直接研究 酒精戒断与OFC神经元功能的关系及研究。我们将调查OFC的功能 在酒精预期、寻找、服用和消费过程中，以及OFC如何在强迫症中被扰乱 长期使用酒精后的动机。根据之前的结果，我们预计OFC活性是乙醇的基础 偏好和动机，并在强迫性酒精使用的增强动机过程中被上调。 我们将记录不同组大鼠的OFC神经元群的活动，无论是短的(~1 )或长时间(约4个月)获得乙醇。将对雄性和雌性大鼠进行研究，以了解 不同的OFC功能是如何支持前面描述的乙醇使用的性别差异的。简而言之-接入 我们和其他人观察到动物对乙醇的偏好存在显著的个体差异。我们假设 OFC活性与饮酒动机呈正相关，与饮酒呈负相关 这群人。在长期饮酒的动物中，饮酒变得强迫--其特征是 对掺入奎宁的动机和抵抗力，这通常是令人厌恶的。我们假设，在 抵抗惩罚的强迫性酒精寻求者，OFC神经元将表现出病理增强的激活 在酒精提示期间，寻求和减少在消费期间的抑制。在这两项研究中，我们还将 操纵OFC活动以评估OFC和乙醇使用之间的因果关系。我们假设 抑制OFC会降低对乙醇的偏好和动机。 这些研究将提供有关由以下因素驱动的特定酒精相关行为的新信息 OFC激活以及过度饮酒和问题酒精易感性的潜在机制 使用。通过将OFC功能和向强迫性酒精寻求的转变直接联系起来， 这些研究有很大的潜力确定治疗酒精使用障碍的重要新靶点。 本项目要调查的两个具体目标是： 1.识别与酒精使用行为成分的个体差异有关的OFC信号 短距离接触大鼠酒精期望和寻求的巴甫洛夫和可操作性测试。我们将调查 关注个体和性别行为差异的酒精动机与OFC功能的关系。 2.在长距离接触中使用相同的测试来识别与酒精强迫动机有关的OFC信号 表现出高涨的、抵抗惩罚的酒精寻求的大鼠。我们将调查OFC活动如何与 在长期使用乙醇后，对乙醇的寻求和消费被增强或抑制。

PROJECT SUMMARY/ABSTRACT The orbitofrontal cortex (OFC) has been heavily implicated in reward valuation and seeking, and there is a strong association between OFC dysfunction and addiction to drugs of abuse. Accumulating evidence suggests that OFC may be a critical node in the development of compulsive alcohol seeking in alcohol use disorders. Despite the clear relevance of OFC function to alcohol use, however, there have been few direct studies of this relationship and no studies of OFC neuron function during alcohol seeking. We will investigate OFC function during ethanol expectation, seeking, taking, and consumption, as well as how OFC is disrupted in compulsive ethanol motivation following chronic use. Based on previous results, we expect OFC activity to underlie ethanol preference and motivation and to be upregulated during enhanced motivation in compulsive ethanol use. We will record the activity of OFC neuron ensembles in different groups of rats given either short (~1 month) or long (~4 months) access to ethanol. Both male and female rats will be studied in order to understand how differential OFC function underlies previously described sex differences in ethanol use. In short-access animals, we and others have observed striking individual differences in preference for ethanol. We hypothesize that OFC activity will positively correlate with ethanol motivation and negatively correlate with consumption in this group. In long-access animals, ethanol drinking becomes compulsive – characterized by increased motivation and resistance to adulteration with quinine, which is normally aversive. We hypothesize that, in punishment-resistant compulsive ethanol seekers, OFC neurons will exhibit pathologically enhanced activation during ethanol cues and seeking and diminished inhibition during consumption. In both studies, we will also manipulate OFC activity to assess a causal relationship between OFC and ethanol use. We hypothesize that OFC inhibition will decrease preference and motivation for ethanol. These studies will provide new information regarding the specific ethanol-related behaviors driven by OFC activation as well as mechanisms underlying susceptibility for excessive drinking and problematic alcohol use. By drawing direct connections between OFC function and the transition to compulsive alcohol seeking, these studies have a strong potential to identify an important new target for treatment of alcohol use disorders. The two Specific Aims to be investigated in this project are: 1. Identify OFC signals related to individual differences in behavioral components of ethanol use using Pavlovian and operant tests of ethanol expectation and seeking in short-access rats. We will probe the relationship between OFC function and ethanol motivation focusing on individual and sex differences in behavior. 2. Identify OFC signals related to compulsive motivation for alcohol using the same tests in long-access rats who demonstrate elevated, punishment-resistant ethanol seeking. We will probe how OFC activity related to ethanol seeking and consumption is enhanced or suppressed after chronic ethanol use.