Modeling age-specific computational strategies during reward seeking

项目总结 青春期模型中潜在的动机过程的神经回路尚未得到充分的研究，但在临床上 相关，因为抑郁症、精神分裂症和物质使用障碍等疾病被标记为 通过动机的改变，在青春期出现。额叶皮质和纹状体是关键目标。 因为它们是最后成熟的地区之一。我目前的工作研究了眼眶额叶皮质如何 (OFC)-背内侧(DMS)回路控制青春期和成年大鼠的反应抑制，以及 青少年在这些网络上接触酒精。我发现青少年饮酒与 OFC和DMS对条件刺激反应的变化以及成年后大鼠抑制反应的能力。在……里面 酒精天真的动物、青少年和成年人对奖赏和之前的行为的反应都不同 在OFC和DMS中都有奖励。在另一项研究中，我记录了多巴胺神经元，并观察到 在刺激驱动的任务中，青少年表现出对奖励的较大阶段反应，而成年人表现出较大的阶段反应 在目标驱动的任务中获得奖励时的反应。总体而言，这些数据表明青少年 酒精暴露促进OFC-DMS回路的持久变化，青少年和成年人使用 在寻求奖励时不同的计算策略，可能是由于皮质-纹状体的特定年龄活动所致 电路。拟议的项目结合了体内电生理记录、计算 用模型和化学遗传学来检验以下假设：(1)发育成熟的特征是 增强采用目标导向控制行为的能力和(2)青少年饮酒导致 目标导向控制所需的神经回路中的病理，从而导致与成瘾相关的风险 行为。我将在青少年的OFC和DMS中同时记录单个单位和局部场电位 和执行操作性条件反射任务的成年大鼠(目标1)。接下来，我将把实验和 模拟青少年和成人动机行为的神经策略的计算方法 (目标2)。在独立阶段，我将使用化学遗传学来测试模型预测，并确定 行为和生理之间的因果关系(目标3)，并确定不同计算的参与如何 战略受到青少年酒精暴露的影响，并与成瘾脆弱性有关(目标4)。 这些翻译结果将增强我们对青春期大脑的机械和计算方面的理解 功能，这是了解疾病的病因和病理生理学的基础 青春期起病，如成瘾。

PROJECT SUMMARY The neuronal circuitry underlying motivational processes in adolescent models is understudied but clinically relevant because disorders such as depression, schizophrenia, and substance use disorder, which are marked by alterations in motivation, emerge during adolescence. The frontal cortex and striatum are critical targets because they are amongst the last regions to mature. My current work investigated how orbitofrontal cortex (OFC)-dorsomedial (DMS) circuits control response inhibition in adolescent and adult rats, and the impact of adolescent alcohol exposure on these networks. I found that adolescent alcohol exposure is associated with changes in OFC and DMS response to conditioned stimuli and rats' ability to inhibit a response in adulthood. In alcohol-naive animals, adolescents and adults differed in response to both reward, and actions preceding rewards in both the OFC and DMS. In a separate study, I recorded from dopamine neurons and observed that adolescents exhibited a larger phasic response to reward in a stimulus-driven task, while adults exhibit a larger response when reward is acquired during a goal-driven task. Collectively, these data suggest adolescent alcohol exposure promotes lasting changes in OFC-DMS circuits, and that adolescents and adults employ different computational strategies during reward-seeking, likely due to age-specific activity in cortical-striatal circuits. The proposed projects use a combination of in vivo electrophysiology recordings, computational modeling and chemogenetics to test the hypotheses that (1) developmental maturation is characterized by an enhanced ability to employ goal-directed control of behavior and (2) adolescent alcohol exposure causes pathology in neural circuits required for goal-directed control, thereby leading to risk of addiction-related behaviors. I will simultaneously record single units and local field potentials in the OFC and DMS in adolescent and adult rats performing an operant conditioning task (Aim 1). Next, I will integrate experimental and computational approaches to model neural strategies underlying motivated behavior in adolescents and adults (Aim 2). During the independent phase, I will use chemogenetics to test the model predictions and determine causality between behavior and physiology (Aim 3), and determine how engagement of different computational strategies is impacted by adolescent alcohol exposure and associated with addiction vulnerability (Aim 4). These translational results will enhance our mechanistic and computational understanding of adolescent brain function which is fundamental for understanding the etiology and pathophysiology of disorders with an adolescent onset, such as addiction.