Co-regulation of striatal dopamine and acetylcholine in associative reward learning

项目摘要 2019年全国药物使用和健康调查（NSDUH）报告称，超过2000万美国人遭受 物质使用障碍（SUD）2018年然而，只有370万有需要的人得到了治疗， 60%接受治疗的人在康复后的第一年内复发。虽然遗传学和 环境因素可以大大增加一个人患SUD的风险， 仍然需要识别潜在的SUD。因此，我认为，这一领域需要采取多学科办法， 包括药理学、电路神经科学、遗传学和行为神经科学，以了解 大脑受到SUD的影响。 虽然SUD背后的神经机制知之甚少，但联想学习的中断是 被认为扮演了一个角色。联想学习是指将奖励和厌恶刺激与 预测这些刺激发生的先验线索。识别调节神经系统的神经机制 因此，联想学习为理解物质使用障碍提供了希望。在我的PhD期间， 研究了控制小鼠线索相关奖励学习的神经机制。具体来说，我的论文 该项目研究了两种神经调质多巴胺（DA）和乙酰胆碱（ACh）之间的共同调节， 联想奖励学习 我在目标1中概述的初步发现表明：1）纹状体DA和ACh同时受到奖励的调节 提示诱发的DA和ACh变化高度相关; 与行为相关。总之，这些发现使我的假设，纹状体DA和ACh是共同的- 相互调节以驱动关联奖励学习。我将在本提案的目标2中检验我的假设。我 我相信，这些实验将揭示新的机制，潜在的联想学习，我将建立 根据从本研究中获得的知识和技能， 有助于目标3所述的物质使用障碍。

PROJECT SUMMARY The 2019 National Survey on Drug Use and Health (NSDUH) reported that over 20 million Americans suffered from a substance use disorder (SUD) in 2018. Yet, only 3.7 million people in need received treatment, and up to 60% of people that received treatment relapsed within the first year of recovery. While genetics and environmental factors can greatly increase a person’s risk for developing a SUD, the specific neural circuits underlying SUDs still need to be identified. Thus, I believe that the field requires a multidisciplinary approach, including pharmacology, circuit neuroscience, genetics, and behavioral neuroscience, to understand how the brain is affected by SUDs. Although the neural mechanisms underlying SUDs are poorly understood, disruption in associative learning is thought to play a role. Associative learning refers to the ability to associate rewarding and aversive stimuli with prior cues that predict the occurrence of these stimuli. Identifying the neural mechanisms that regulate associative learning therefore holds promise for understanding substance use disorders. During my PhD I have studied the neural mechanisms that govern cue-associated reward learning in mice. Specifically, my thesis project investigates co-regulation between two neuromodulators, dopamine (DA) and acetylcholine (ACh), during associative reward learning. My preliminary findings outlined in Aim 1 show that 1) striatal DA and ACh are concurrently modulated by rewards and reward predicting cues, 2) cue evoked changes in DA and ACh are highly correlated with each other and 3) correlated with behavior. Together, these findings lead me to my hypothesis that striatal DA and ACh are co- regulating each other to drive associative reward learning. I will test my hypothesis in Aim 2 of this proposal. I am confident that these experiments will reveal novel mechanisms underlying associative learning and I will build upon the knowledge and skill sets obtained from this study to address how dysregulation in associative learning contributes to substance use disorders as described in Aim 3.