The role of striatal dopamine and acetylcholine activity in adaptive reward-seeking behaviors

项目摘要 环境奖励预测线索为奖励寻求行为提供了一个主要的动机来源。这 动机受自我平衡和认知控制因素的调节。这些控制因素的失调 产生适应不良的奖赏寻求行为，这是各种心理健康的共同特征 疾病，如重度抑郁症，强迫性暴饮暴食，物质使用障碍， 精神分裂症然而，很少有人知道的神经生物学机制，调节稳态和 线索驱动行为的认知控制。我们实验室和其他人之前的工作已经确定了多巴胺 释放在核丘脑核心（NAc）作为线索动机的奖励寻求的关键基板。我们也 最近证实NAc胆碱能中间神经元作用于含b2的烟碱乙酰胆碱受体（b2- nAChRs）对NAc多巴胺提供终末调节影响，这可能对其在 动机如何调节这些动机系统，以确保适应性稳态和认知控制 过度线索动机行为仍有待充分理解。该提案的主要目标是调查 多巴胺的释放受内稳态和认知因素的调节，以促进 NAc终末中的适应性动机信息，以及NAc胆碱能活性通过β2-nAChRs门控局部 多巴胺释放以确保适应性奖励寻求。在目的1中，我将研究线索诱发的NAc的调节 通过自我平衡和认知控制释放多巴胺，以促进自适应线索动机的奖励寻求。在 目的2，我将研究NAc胆碱能信号是如何被稳态和认知控制因子调节的 以及这种活动是否独立于中脑多巴胺神经元调节终末多巴胺释放， 促进NAc终端中的自适应激励消息。为了解决这些假设， 相关的巴甫洛夫-仪器（PIT）测定将用于所有目的，以确定神经生物学 线索动机行为的适应性调节机制。在这项任务中，初步研究表明， 大鼠能够抑制探索性的奖励寻求，而有利于情境有利的等待策略。 目标1中的实验将利用实时多巴胺测量，并在体内纤维光度成像， 遗传编码的荧光多巴胺传感器、化学发生抑制或VTA的光学刺激 NAc中的多巴胺终末，以揭示NAc多巴胺的内源性活性、必要性和充足性 在适应性线索驱动的行为中释放。目标2将利用体内光纤光度法进行实时测量 乙酰胆碱水平，并评估NAc b2-nAChR失活对线索激发行为的影响。 总的来说，这些研究的新发现确定了行为和神经化学机制， 潜在的适应性调节的奖励寻求行为，并提供机械的理解， 适应不良的动机出现在心理健康疾病中。

PROJECT SUMMARY Environmental reward-predictive cues provide a major source of motivation for reward-seeking behaviors. This motivation is regulated by homeostatic and cognitive control factors. Dysregulation of these control factors produce maladaptive reward-seeking behaviors, which is a common feature of a variety of mental health illnesses, such as major depressive disorder, compulsive overeating, substance use disorder, and schizophrenia. However, little is known of the neurobiological mechanisms that regulate homeostatic and cognitive control of cue-motivated behavior. Previous work from our lab and others have identified dopamine release in the nucleus accumbens core (NAc) as a critical substrate of cue-motivated reward seeking. We also recently demonstrated NAc cholinergic interneurons acting at b2-containing nicotinic acetylcholine receptors (b2- nAChRs) provide a terminal regulatory influence on NAc dopamine that may be crucial to its function in motivation. How these motivational systems are regulated to ensure adaptive homeostatic and cognitive control over cue-motivated behavior remains to be fully understood. The principal goals of this proposal are to investigate the novel hypotheses that dopamine release is regulated by homeostatic and cognitive factors to promote an adaptive motivational message in NAc terminals, and that NAc cholinergic activity via β2-nAChRs gates local dopamine release to ensure adaptive reward seeking. In Aim 1, I will examine the regulation of cue-evoked NAc dopamine release by homeostatic and cognitive control to promote adaptive cue-motivated reward seeking. In Aim 2, I will examine how NAc cholinergic signaling is regulated by homeostatic and cognitive control factors and whether this activity regulates terminal dopamine release, independently of midbrain dopamine neurons, to promote an adaptive motivational message in NAc terminals. To address these hypotheses, a translationally relevant Pavlovian-to-instrumental (PIT) assay will be used in all aims to determine the neurobiological mechanisms underlying adaptive regulation of cue-motivated behavior. In this task, preliminary studies show rats are able to suppress exploratory reward seeking in favor of a situationally advantageous waiting strategy. Experiments in Aim 1 will utilize real-time dopamine measurements with in vivo fiber photometry imaging of a genetically encoded fluorescent dopamine sensor, chemogenetic inhibition, or optical stimulation of VTA dopamine terminals in the NAc to reveal the endogenous activity, necessity, and sufficiency of NAc dopamine release in adaptive cue-motivated behavior. Aim 2 will utilize in vivo fiber photometry to measure real-time acetylcholine levels and assess the influence of NAc b2-nAChR inactivation on cue-motivated behavior. Collectively, the novel findings from these studies identify the behavioral and neurochemical mechanisms underlying adaptive regulation of reward-seeking behaviors and provide mechanistic understanding of how maladaptive motivation arises in mental health illnesses.