Role of the kappa opioid receptor system in learning and substance use disorders

项目摘要 尽管其患病率很高，但物质使用障碍的潜在神经生物学仍然不清楚， 限制了有效的药物治疗选择。以学习过程中断为特征， 物质使用障碍被认为是从积极的动机转变而来的， 强化效果的物质，以负强化，其中使用发生，以避免或减轻厌恶 在禁欲期间。据推测，物质诱导的κ阿片受体（KOR）上调 信号在驱动负强化的焦虑中起着因果作用。为了支持这一观点， 拮抗剂在慢性使用或依赖模型中减少药物摄入， 对强化学习和动机行为至关重要，是物质使用的区域之一， 显示上调KOR系统。尽管有证据表明KOR信号在物质使用中起着因果作用， 疾病，这个系统的功能，在适应性强化过程和充分的上调， 驾驶适应不良学习仍然是未知的。在这里，我们旨在通过直接调查解决这些问题 KOR系统在正强化学习和负强化学习中的作用， 操纵，体内强啡肽动力学的亚秒级测量，以及KOR的光遗传学激活 系统在目标1中，我将把KOR系统的系统性拮抗作用与正强化和负强化配对 操作性条件反射任务来阐明KOR信号在适应性学习中的作用。在目标2中，我将进行 亚秒分辨率，在体光学成像的强啡肽释放在核延髓，以揭示 内源性KOR系统活动在强化学习过程中编码信息的作用。 最后，在目标3中，我将通过光遗传学方法引起脑内强啡肽的释放，以确定 增强KOR系统在驱动成瘾基础的适应不良学习中的作用。通过 完成这一建议，我将接受全面的培训，进行独立的研究， 有助于成瘾神经科学领域对KOR系统的机制的理解。 涉及适应性和适应不良的强化学习过程。

Project Summary Despite their high prevalence, the underlying neurobiology of substance use disorders is still not understood, limiting effective pharmacological treatment options. Characterized by disruptions in learning processes, substance use disorders are thought to develop with the transition from being motivated by the positive reinforcing effects of the substance, to negative reinforcement where use occurs to avoid or alleviate an aversive state during abstinence. It is hypothesized that substance-induced upregulations in kappa opioid receptor (KOR) signaling play a causal role in the dysphoria that drives negative reinforcement. In support of this idea, KOR antagonists decrease drug intake in models of chronic use or dependence and the nucleus accumbens, a region critical to reinforcement learning and motivated behaviors, is one of the regions in which substance use has been shown to upregulate the KOR system. Despite this evidence of a causal role for KOR signaling in substance use disorders, this system’s function in adaptive reinforcement processes and the sufficiency of its upregulation in driving maladaptive learning remains unknown. Here, we aim to address these issues through direct investigation of the role of the KOR system in positive and negative reinforcement learning through pharmacological manipulation, sub-second measurement of in vivo dynorphin dynamics, and optogenetic activation of the KOR system. In aim 1, I will pair systemic antagonism of the KOR system with positive and negative reinforcement operant conditioning tasks to elucidate the role of KOR signaling in adaptive learning. In aim 2, I will conduct sub-second resolution, in vivo optical imaging of dynorphin release in the nucleus accumbens to uncover the role of endogenous KOR system activity in encoding information during reinforcement learning processes. Finally, in aim 3, I will optogenetically evoke accumbal dynorphin release to determine the sufficiency of augmentation of the KOR system in driving the maladaptive learning that underlies addiction. Through the completion of this proposal, I will receive well-rounded training in conducting independent research and contribute to the field of addiction neuroscience’s understanding of the mechanism by which the KOR system is involved in adaptive and maladaptive reinforcement learning processes.