The comparative contributions of basolateral amygdala and ventral subiculum inputs to the nucleus accumbens in a novel rodent model of maladaptive alcohol self-administration

项目摘要 娱乐性饮酒发展为酒精使用障碍的特征是对酒精的控制丧失， 寻求，这涉及继续使用酒精，尽管有各种负面后果。但由于 由于缺乏酒精使用障碍这方面的翻译模型，因此对该电路知之甚少 潜在的适应不良的酒精寻求，这排除了治疗靶点的发现。本 一项研究提出了一种新的适应不良酒精自我管理任务（MAST），该任务将用于评估 两个不同的神经回路在抑制控制中可能发挥的作用。我们实验室的初步发现 表明化学发生抑制从基底外侧杏仁核到核的投射 从海马体腹侧下托到海马核 壳（vSub-NAcSh）产生对酒精的食欲寻求的均匀减少，对 消费我们的实验室和其他实验室还表明，慢性间歇性乙醇（CIE）不仅 在BLA和vSub中产生增强的兴奋性，但也是一种行为表型，其特征在于 寻求和摄入的升级。虽然酒精寻求是动物模型的一个常见和重要的指标， 很少有人努力将这种结构解析为动机行为的更具体的方面。增加 寻求可能是由去抑制引起的，在去抑制中，适当和不适当的行为之间的区别 是已知的，但被推翻，或歧视失败，其中区分时，它是适当的，或 不适合喝酒变得不清楚。因此，拟议的研究将采用多学科 一种实验策略，以测试假设，即CIE暴露产生对酒精的控制丧失 寻找和BLA-NAcC的过度兴奋有助于行为去抑制表型， 而vSub-NAcSh的过度兴奋导致辨别失败。目标1将采用 在MAST期间，使用化学遗传学技术选择性地激活BLA-NAcC或vSub-NAcSh。在Aim中 2、我们将CIE作为酒精依赖的模型。将使用MAST评估行为变化 并且在靶神经元投射的BLA和vSub群体中神经活动的改变将是 通过体内纤维光度法测量。这些研究可能会发现一种新的行为机制， 这些神经回路控制与饮酒有关的行为，并有可能提供进一步的功能。 有证据表明，靶向这些回路可能在治疗糖尿病的一个关键行为症状方面具有治疗价值。 酒精使用障碍

PROJECT SUMMARY The progression of recreational drinking to alcohol use disorder is characterized by loss of control over seeking, which involves continued use of alcohol despite a variety of negative consequences. However, due to a paucity of translational models for this aspect of alcohol use disorder, little is known about the circuitry underlying maladaptive alcohol seeking, which precludes the discovery of therapeutic targets. The present study proposes a novel maladaptive alcohol self-administration task (MAST), which will be used to assess the role that two distinct neural circuits might play in inhibitory control. Preliminary findings from our lab demonstrate that chemogenetic inhibition of projections from the basolateral amygdala to the nucleus accumbens core (BLA-NAcC) or from the ventral subiculum of the hippocampus to the nucleus accumbens shell (vSub-NAcSh) produces a uniform reduction in appetitive seeking for alcohol with minimal effects on consumption. Both our lab and others have additionally shown that chronic intermittent ethanol (CIE) not only produces heightened excitability in the BLA and vSub, but also a behavioral phenotype characterized by escalation of seeking and intake. Though alcohol seeking is a common and important metric of animal models, there have been few efforts to parse this construct into more specific facets of motivated behavior. Increased seeking might result from disinhibition, in which the distinction between appropriate and inappropriate behavior is known but overridden, or discrimination failure, in which the distinction between when it is appropriate or inappropriate to drink becomes unclear. Therefore, the proposed studies will employ a multidisciplinary experimental strategy to test the hypothesis that CIE exposure produces a loss of control over alcohol seeking and that hyperexcitation of the BLA-NAcC contributes to a behavioral disinhibition phenotype, while hyperexcitation of the vSub-NAcSh results in discrimination failure. Aim 1 will employ a chemogenetic technique to selectively activate either the BLA-NAcC or vSub-NAcSh during the MAST. In Aim 2, we will use CIE as a model of alcohol dependence. Behavioral changes will be assessed using the MAST and alterations in neural activity in the target accumbens-projecting BLA and vSub populations will be measured by in vivo fiber photometry. These studies may identify a novel behavioral mechanism through which these circuits exert control over alcohol drinking-related behaviors, with the potential to provide further evidence that targeting these circuits may have therapeutic value in treating a key behavioral symptom of alcohol use disorder.