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: 10703513
• 负责人: Aqilah M McCane
• 金额: $ 19.94万
• 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 2023-10-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10703513
• 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; Functional disorder; Genetic; 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; neural circuit; neural model; neural network; neuronal circuitry; neurophysiology; novel; predictive modeling; 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 青少年模型中动机过程的神经元回路研究不足，但临床上 相关，因为抑郁症、精神分裂症和物质使用障碍等疾病， 通过动机的改变，在青春期出现。额叶皮层和纹状体是关键的目标 因为它们是最后成熟的区域之一。我目前的工作是研究眶额皮层 （OFC）-背内侧（DMS）回路控制青少年和成年大鼠的反应抑制，以及 青少年酒精暴露在这些网络上。我发现青少年酒精暴露与 OFC和DMS对条件刺激反应的变化以及大鼠在成年期抑制反应的能力。在 未接触酒精的动物、青少年和成年人对奖励和之前的行为的反应不同 OFC和DMS的奖励。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，青少年对奖励表现出更大的相位反应，而成年人则表现出更大的相位反应。 在目标驱动的任务中获得奖励时的反应。总的来说，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 不同的计算策略，在奖励寻求，可能是由于年龄特异性的活动，在皮层-纹状体 电路.拟议的项目使用体内电生理记录，计算 模型和化学遗传学来测试假设，即（1）发育成熟的特点是 增强的能力，采用目标导向的行为控制和（2）青少年酒精暴露的原因 目标导向控制所需的神经回路中的病理学，从而导致成瘾相关的风险 行为。我将同时记录青少年OFC和DMS的单个单位和局部场电位 和成年大鼠执行操作性条件反射任务（目标1）。接下来，我将整合实验和 模拟青少年和成人动机行为背后的神经策略的计算方法 (Aim 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），并确定如何参与不同的计算 策略受到青少年酒精暴露的影响，并与成瘾脆弱性相关（目标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 功能，这是理解疾病的病因学和病理生理学的基础， 青少年发病，如成瘾。