Modeling age-specific computational strategies during reward seeking

在奖励寻求过程中对特定年龄的计算策略进行建模

• 批准号: 10579064
• 负责人: Aqilah M McCane
• 金额: $ 19.98万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579064
• 关键词: Adolescence; Adolescent; Adult; Age; Alcohol consumption; Alcohol dependence; Alcohols; Animals; Behavior; Behavior Control; Behavioral; Brain; Computer Models; Corpus striatum structure; Data; Development; Disease; Dopamine; Electrophysiology (science); Employment; Etiology; Exhibits; Extinction (Psychology); Functional disorder; Glare; Goals; Home; Impairment; Lateral; Measures; Mental Depression; Mental Processes; Mental disorders; Methods; Modeling; Mood Disorders; Motivation; Neurons; Operant Conditioning; Pathology; Performance; Phase; Physiological; Physiology; Play; Population; Process; Property; Psychopathology; Rattus; Resistance; Rewards; Risk; Role; Schizophrenia; Stimulus; Substance Use Disorder; Sucrose; System; Testing; Time; Training; Work; addiction; adolescent alcohol exposure; age difference; age related; alcohol use disorder; alcohol use initiation; behavioral response; clinically relevant; developmental disease; dopaminergic neuron; drug of abuse; experimental study; frontal lobe; in vivo; mature animal; motivated behavior; motivational processes; neural circuit; neural model; neural network; neuronal circuitry; neurophysiology; novel; predictive modeling; relating to nervous system; response; tool; underage drinking

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.

项目摘要 青少年模型中的动机过程的神经元电路被研究研究，但在临床上是 相关是因为抑郁症，精神分裂症和药物使用障碍等疾病被标记 通过动机的改变，在青春期出现。额叶皮层和纹状体是关键目标 因为它们是最后一个成熟的地区之一。我目前的工作调查了轨道皮层如何 （OFC） - 反向反应（DMS）电路控制青少年和成年大鼠的抑制作用，以及 这些网络上的青少年酒精暴露。我发现青少年酒精暴露与 OFC和DMS对条件刺激和大鼠成年后反应的能力的反应变化。在 饮酒的动物，青少年和成年人在奖励和之前的行动方面有所不同 在OFC和DMS中奖励。在另一项研究中，我从多巴胺神经元记录下来，观察到 青少年在刺激驱动的任务中表现出更大的质量反应，而成年人表现出较大的奖励 在目标驱动任务中获得奖励时的响应。总的来说，这些数据表明青少年 酒精暴露会促进OFC-DMS电路的持久变化，而青少年和成年人则使用 寻求奖励期间的不同计算策略，可能是由于皮质纹状体中特定年龄的活动而引起的 电路。拟议的项目结合了体内电生理记录，计算 建模和化学遗传学来检验（1）发育成熟的假设的特征是 增强了采用目标指导控制行为和（2）青少年酒精暴露原因的能力 目标指导控制所需的神经回路中的病理学，从而导致与成瘾有关的风险 行为。我将同时在青少年的OFC和DMS中记录单个单元和本地现场电位 以及执行操作调节任务的成年大鼠（AIM 1）。接下来，我将整合实验和 计算方法来建模青少年和成人动机行为的神经策略 （目标2）。在独立阶段，我将使用化学遗传学测试模型预测并确定 行为与生理学之间的因果关系（AIM 3），并确定不同计算的参与度如何 策略受到青少年酒精暴露的影响，并与成瘾脆弱性有关（AIM 4）。 这些翻译结果将增强我们对青少年大脑的机械和计算理解 对于理解疾病的病因和病理生理的基础 青少年发作，例如成瘾。