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

项目总结 娱乐性饮酒发展到酒精使用障碍的特征是失去对 寻求，这涉及继续使用酒精，尽管有各种负面后果。然而，由于 关于酒精使用障碍的这一方面的翻译模型很少，对电路知之甚少 潜在的不适应酒精寻求，这阻碍了治疗靶点的发现。现在 研究提出了一种新的非适应性酒精自我给药任务(MAST)，该任务将被用来评估 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 证明从杏仁基底外侧核向核投射的化学发生抑制 伏隔核(BLA-NACC)或从海马腹下托至伏隔核 壳牌(vSub-NAcSh)能均匀减少饮酒欲望，对 消费。我们的实验室和其他实验室都另外表明，慢性间歇性乙醇(CIE)不仅 在BLA和vSub中产生高度的兴奋性，但也产生一种行为表型，其特征是 寻求和吸收的升级。尽管寻找酒精是衡量动物模型的一个常见而重要的指标， 很少有人努力将这一结构解析为动机行为的更具体方面。增加了 寻求可能产生于解除抑制，在这种情况下，适当和不适当的行为之间的区别 是已知的但被覆盖的，或歧视失败，在这种情况下，它是适当的还是 不宜饮酒变得不清楚。因此，拟议的研究将采用多学科 检验CIE暴露会导致酒精失控这一假设的实验策略 寻找和BLA-NACC的过度兴奋有助于行为去抑制表型， 而vSub-NAcSh的过激发导致分辨失败。AIM 1将聘请一名 在肥大期间选择性地激活BLA-NACC或vSub-NAcSh的化学发生技术。在AIM 2、我们将CIE作为酒精依赖的模型。行为变化将使用桅杆进行评估 靶向伏隔神经投射的Bla和vSub种群的神经活动的变化将是 用活体纤维光度法测量。这些研究可能确定一种新的行为机制，通过 这些回路对与饮酒有关的行为施加控制，有可能进一步提供 有证据表明，以这些环路为靶点可能在治疗一种关键的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.