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

项目总结 环境奖励--预测性线索为寻求奖励行为提供了一个主要的动机来源。这 动机受动态平衡和认知控制因素的调节。这些控制因素的失调 产生不适应的寻求奖励行为，这是各种心理健康的共同特征 疾病，如严重抑郁障碍，强迫性暴饮暴食，物质使用障碍，以及 精神分裂症。然而，人们对调节体内平衡和代谢的神经生物学机制知之甚少 对线索动机行为的认知控制。我们实验室和其他实验室之前的工作已经确定了多巴胺 伏隔核(NAC)释放作为线索动机奖赏寻求的关键底物。我们也 最近证实NAC胆碱能中间神经元作用于含b2的烟碱型乙酰胆碱受体(b2- NAChRs)对NAC多巴胺产生末端调节影响，这可能对其在 动力。这些动机系统是如何被调节以确保适应性内环境平衡和认知控制的 过度线索动机的行为仍有待于充分理解。这项提案的主要目标是调查 多巴胺释放受体内平衡和认知因素调节的新假说促进了 NAc终末中的适应性激励信息，以及NAc胆碱能活动通过β2-nAChRs局部闸门 释放多巴胺以确保适应性的奖赏寻求。在目标1中，我将研究线索诱发的NAC的调节 多巴胺的释放通过自我平衡和认知控制来促进适应性线索激励的奖赏寻求。在……里面 目标2，我将研究NAC胆碱能信号是如何受内环境平衡和认知控制因素调节的 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，以 在NAC终端中推广适应性激励信息。为了解决这些假设，翻译过来的 相关的巴甫洛夫-仪器(PIT)分析将用于所有AIMS以确定神经生物学 暗示动机行为的适应性调节的潜在机制。在这项任务中，初步研究表明 老鼠能够抑制探索性的奖赏寻求，而倾向于情境有利的等待策略。 目标1的实验将利用体内纤维光度成像的实时多巴胺测量 VTA的基因编码的荧光多巴胺感受器、化学发生抑制或光刺激 NAC中的多巴胺终末揭示NAC多巴胺的内源性活性、必要性和充分性 在适应性提示动机的行为中释放。AIM 2将利用体内纤维光度法实时测量 乙酰胆碱水平，并评估nac b2-nAChR失活对线索动机行为的影响。 总的来说，这些研究的新发现确定了行为和神经化学机制 潜在的对寻求奖励行为的适应性调节，并提供了对如何 不适应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.