D2 receptors in cholinergic interneurons: role in striatal circuitry & motivation

 描述（由申请人提供）：我的长期目标是指导和进行原创的，富有成效的和令人信服的研究，促进该领域的进步，寻找治疗大脑疾病的方法。我有兴趣从事研究事业，旨在通过研究有助于其功能的潜在细胞机制，了解特定神经回路如何在神经精神疾病中受损。随着我对这些目标的关注，我在不久的将来的主要目标是获得必要的技能，知识和指导，以制定一个有凝聚力和创新性的研究计划，旨在阐明介导动机行为的细胞机制。通过这个奖励机制，我将研究D2多巴胺受体（D2 R）的功能和行为的后果，特别是在胆碱能中间神经元的改变。我将通过学习应用先进的工具来解决这个关键问题 在电生理学、光遗传学、体内药物遗传学和动机的行为模型方面，在精选的指导团队的帮助下。为了补充我的基础研究训练，我还将寻求以动机异常为特征的疾病的临床和翻译方面的基本指导。这一新的科学知识将与专业发展的指导计划相匹配，该计划侧重于建立独立和有竞争力的研究计划的必要步骤。几种神经精神疾病，包括注意力缺陷多动障碍和慢性药物滥用-显示出显着的动机缺陷-与奖励相关的大脑区域的D2 R功能降低有关。然而，人们对D2 R水平和动机之间是否存在因果关系知之甚少。此外，尚未确定介导这种D2 R对动机的影响的细胞类型。我们小组最近的证据表明，增加D2 R水平在核丘脑增强激励动机，但这种全球性的方法并没有区分在这个区域的关键细胞群体。在这个建议中，我将测试有趣的可能性，D2 R水平的胆碱能中间神经元的核纹状体电路功能和动机行为的调节至关重要。为此，我将使用细胞选择性策略，结合电生理学和行为分析。具体来说，我将测试的假设，D2 R上调胆碱能中间神经元改变与强化学习的放电模式。此外，我将确定这些神经元中D2 R水平的增加是否不仅对纹状体输出通路的功能具有关键影响，而且也是激励动机的关键调节器。 从这项工作中获得的信息将增加我们对动机机制的理解，同时为动机失调的潜在新治疗目标提供帮助。

 DESCRIPTION (provided by applicant): My long-term goals are to direct and conduct original, productive, and compelling research that promotes the advancement of the field towards finding cures for brain disorders. I am interested in pursuing a research career aimed at understanding how specific neural circuits may become impaired in neuropsychiatric disorders by studying the underlying cellular mechanisms contributing to their function. With my sight set on these goals, my main objective in the near future is to obtain the necessary skillset, knowledge, and mentorship to develop a cohesive and innovative research plan aimed at elucidating the cellular mechanisms mediating motivated behavior. Through this award mechanism, I will study the functional and behavioral consequences of D2 dopamine receptor (D2R) alterations specifically in cholinergic interneurons. I will address this critical issue by learning to apply advanced tools in electrophysiology, optogenetics, in vivo pharmacogenetics, and behavioral models of motivation with the assistance of a select mentoring team. To complement my basic research training, I will also seek essential guidance in clinical and translational aspects of disorders characterized by motivational abnormalities. This new scientific knowledge will be matched by a mentored plan for professional development focused on the necessary steps towards establishing an independent and competitive research program. Several neuropsychiatric disorders, including attention-deficit hyperactivity disorder and chronic drug abuse - which display significant motivational deficits - are associated with reduced D2R function in brain regions involved in reward. However, it is poorly understood whether there is a causal relationship between D2R levels and motivation. In addition, the cell type(s) mediating this D2R effect on motivation has not been identified. Recent evidence from our group suggests that increasing D2R levels in the nucleus accumbens enhances incentive motivation, but this global approach did not distinguish between key cell populations in this region. In this proposal, I will test the intriguing possibility that D2R levels in cholinergic interneurons of the nucleus accumbens are critically involved in the regulation of striatal circuit function and motivated behaviors. To do this, I will use cell-selective strategies, in combination with electrophysiologicl and behavioral analysis. Specifically, I will test the hypothesis that D2R upregulation in cholinergic interneurons alters firing patterns linked to reinforcement learning. Further, I will determine whether increased D2R levels in these neurons not only have key consequences on the function of striatal output pathways, but are also critical regulators of incentive motivation. The information derived from this work will increase our understanding of the mechanisms underlying motivation, while shedding light on potential new treatment targets for motivational dysregulation.