Long term consequences of adolescent alcohol use on behavioral inhibition

项目摘要 青春期是一个“脆弱”的时期，因为这一时期的某些经历会导致有害的持久性。 方面的影响.一个重要的例子是青少年饮酒，这可能使他们终身受到不良影响 包括冲动和反应抑制受损。在这个探索性的R21应用中，我们建议 利用啮齿类动物的行为模型，开始了解长期后果的神经基础， 青少年自愿饮酒对反应抑制的影响使用一种新的行为任务，我们发现， 在青春期自愿摄入酒精会导致男性和女性反应抑制的显著降低， 成年雌性大鼠。在基础和临床文献的指导下，眶额皮质（OFC）和 背侧纹状体（DS）是关键的行动引导学习和冲动，我们提出了两个探索性的目标， 开始理解这两个区域在调解或调节中的计算和基于回路的参与， 调节有青少年饮酒史的成年人的反应抑制受损。在目标1中，我们 同时在外侧OFC和内侧DS中记录多个单位和局部场电位（LFP）， 任务表现，以确定相关任务事件和OFC-DS协调活动的神经编码是否 与行为变化相关。在目标2中，我们将使用化学遗传学方法来操纵 OFC-DS连接，以确定该途径对持续影响的潜在因果作用。 青少年饮酒对成年人冲动的影响无论结果如何，完成这项探索性工作将 提供技术和机制知识，以支持未来更全面的研究神经元 青少年饮酒的持久影响的基础。

PROJECT SUMMARY Adolescence is a “vulnerable” period because certain experiences in this period lead to detrimental lasting effects. A critical example is teenage drinking which may predispose them to life-long adverse consequences including impulsivity and impaired response inhibition. In this exploratory R21 application, we propose to exploit a rodent behavioral model to begin to understand the neuronal basis of the long-term consequences of voluntary adolescent drinking on response inhibition. Using a novel behavioral task, we find that moderate voluntary intake of alcohol during adolescence causes a robust reduction in response inhibition in both male and female adult rats. Guided by basic and clinical literature suggesting that orbitofrontal cortex (OFC) and dorsal striatum (DS) are critical for action-guided learning and impulsivity, we propose two exploratory aims to begin to understand the computational and circuit-based involvement of these two regions in mediating or modulating impaired response inhibition in adults with a history of adolescent alcohol drinking. In Aim 1, we will record from multiple units and local field potentials (LFPs) simultaneously in lateral OFC and medial DS during task performance to determine if neural encoding of relevant task events and OFC-DS coordinated activity is affected in correlation with behavioral changes. In Aim 2, we will use a chemogenetic approach to manipulate OFC-DS connections to determine the potential causative role of this pathway on the sustained impact of adolescent alcohol use on adult impulsivity. Regardless of the outcome, completion of this exploratory work will provide technical and mechanistic knowledge to support future more comprehensive studies on the neuronal basis of the lasting impact of adolescent alcohol use.