Early life adversity amplifies behavioral opportunism by altering striatal dopamine signaling

项目摘要 早期生活逆境（ELA）与物质使用障碍风险的显着增加有关。但 ELA增加物质使用障碍风险的机制尚不清楚。在这里，我将测试假设 关于ELA如何通过改变纹状体多巴胺系统， 在小鼠模型中。在初步的数据中，我证明ELA增加了“行为机会主义”， 立即可用的和更可能的奖励，以及更少的努力，更遥远的，不太可能的奖励，相比之下， 对照我假设ELA通过改变相对静态的受体表达和 动态纹状体多巴胺信号。在目的1中，我将检验这一假设，即ELA诱导的多巴胺受体的改变， D1表达（传统上与奖励/利益敏感性相关）和D2表达（传统上与 努力/成本敏感性）足以改变成本效益权衡计算，以产生行为机会主义。 具体来说，我将利用一个生物学上知情的行为计算模型来评估纹状体的影响。 多巴胺信号对成本效益计算的影响。接下来，我将测试该模型是否具有普遍性，是否可以预测行为 在概率强盗任务中的机会主义，在富有和贫穷的奖励环境之间转换。独立于相对 在多巴胺受体的停滞改变（目的1），我假设ELA陡峭的多巴胺斜坡动态 产生行为机会主义（目标2）。在目标2中，我将建立一个动物瞬时感知的动态模型 状态值（环境在特定时刻的回报程度）来预测离散的行为， 试验内行为（例如试验启动和奖励检索）。该模型将被设计为概括我的初步 数据显示，ELA动物表现出延迟启动“更难”的试验，但随后表现出更陡峭的速度增加， 奖励是接近或现成的。基于先前的工作表明多巴胺音调跟踪状态值，我将在体内使用 纤维光度法测量真实的时间多巴胺释放以检验纹状体多巴胺产生动态 行为机会主义通过编码更多的动态变化的状态值。 通过研究和培训计划，我将加深我的行为， 认知和神经机制的基础学习和行为，同时获得先进的系统神经科学和 定量技术，包括体内纤维光度测定，计算建模和复杂的行为分析。 通过该补助金获得的培训将使申请人在解决如何使用跨学科的方法时， 早期生活经历塑造了动机和决策。总的来说，拟议的工作将告知丰富的文献 关于早期生活经历导致动机和纹状体多巴胺改变的机制。这项工作 将提供对ELA脆弱性的深入了解，这可能有助于解释为什么早期生活创伤会增加 物质使用障碍

PROJECT SUMMARY Early life adversity (ELA) is associated with a significant increase in risk for substance use disorder. However, the mechanisms by which ELA increases the risk for substance use disorder are not well understood. Here, I will test hypotheses about how ELA shapes motivation for reward as a function of reward availability by altering the striatal dopamine system in a mouse model. In preliminary data, I demonstrate ELA increases “behavioral opportunism”, exerting more effort on immediately available and more probable rewards, and less effort on more distant, less probable rewards, compared to controls. I hypothesize the ELA amplifies behavioral opportunism by altering both relatively static receptor expression and dynamic striatal dopamine signaling. In Aim 1, I will test the hypothesis that ELA-induced alterations in dopamine receptor D1 expression (traditionally associated with reward/benefit sensitivity) and D2 expression (traditionally associated with effort/cost sensitivity) are sufficient to alter cost-benefit trade off calculations to produce behavioral opportunism. Specifically, I will leverage a biologically informed computational model of behavior to assess the impact of striatal dopamine signaling on cost-benefit calculations. Next, I will test whether the model generalizes and can predict behavioral opportunism in a probabilistic bandit task, altering between rich and poor reward environments. Independent of relatively stagnant alterations in the dopamine receptors (Aim 1), I hypothesize that ELA steepens the dopamine ramp to dynamically produce behavioral opportunism (Aim 2). In Aim 2, I will build a dynamic model of an animal’s instantaneous perception of state value (how rewarding the environment is at a particular moment) to make predictions about behavior in discrete, within-trial behaviors (e.g. trial initiation, and reward retrieval). This model will be designed to recapitulate my preliminary data showing that ELA animals exhibit delays to initiate “harder” trials, but then exhibit steeper increases in speed when reward is near or readily available. Based on prior work showing that dopamine tone tracks state value, I will use in vivo fiber photometry to measure real time dopamine release to test the hypothesis that striatal dopamine produces dynamic behavioral opportunism by encoding more dynamic changes in state value. Through the Research and Training Plan, the I will deepen my theoretical and conceptual knowledge of behavioral, cognitive and neural mechanisms underlying learning and behavior, while acquiring advanced systems neuroscience and quantitative techniques, including in-vivo fiber photometry, computational modeling and sophisticated behavioral analysis. The training acquired through this grant will allow the applicant to use an interdisciplinary approach when addressing how early life experience shapes motivation and decision-making. Overall, the proposed work will inform a rich literature regarding the mechanisms by which early life experiences lead to alterations in motivation and striatal dopamine. This work will provide insight into ELA vulnerabilities that could help explain why early life trauma increases the propensity for substance use disorder.