Contributions of Parallel Nigrostriatal Dopamine Circuits to Reward Learning and Habit Formation

 描述（由申请人提供）：习惯允许快速，流畅，几乎毫不费力地执行复杂的任务，但它们也可能是有害的，例如在它们导致强迫症的强迫行为或药物滥用和成瘾复发的行为模式的情况下。习惯的形成需要纹状体，基底神经节的输入核，以及从黑质丘脑部（SNc）到纹状体的多巴胺输入。然而，更好地了解纹状体和SNc多巴胺能回路支持习惯形成的机制将是阐明习惯形成过程在健康和疾病中的作用的关键下一步。SNc多巴胺神经元很容易被它们向背内侧纹状体（DMS）或背外侧纹状体（DLS）的传出投射所分割，几十年的研究表明，这些区域在操作性学习中发挥着不同的作用：DMS介导早期目标导向任务的获得，而DLS介导后期习惯的形成。SNc多巴胺神经元仅投射到DMS或DLS的事实表明，不同的信号可能被传递到每个区域，导致DMS和DLS在行为期间的不同时间点经历多巴胺依赖性可塑性。事实上，我们已经发现，DMS和DLS投射SNc多巴胺神经元对无条件厌恶刺激的反应相反。虽然这一发现令人震惊，但关于发送到DMS和DLS的独立多巴胺能信息流，特别是在学习的背景下，还有很多问题需要理解。本提案的目标是建立电路动力学控制显着的刺激在SNc多巴胺神经元的亚群定义的传出目标在DMS和DLS，时间特异性和细胞分辨率，在一个复杂的行为过程中的差异处理：从目标导向的奖励寻求习惯性反应的缓慢过渡。为实现这一目标，提出了三个具体目标。每个目标都集中在阐明SNc多巴胺能回路动力学的三个关键但未知的方面之一：可变性的决定因素，行为转变过程中的进化和传入控制。首先，为了确定传出靶点是否是SNc亚群内变异性的主要决定因素，我们将在清醒小鼠中对传出定义的SNc多巴胺神经元进行体内双光子钙成像。其次，我们将在自由行为的动物体内进行多纤维光度测定，以评估在行为向习惯转变的过程中单个动物内DMS和DLS中的天然多巴胺能投射动力学。第三，我们将结合联合收割机光度学和光遗传学来剖析传出定义的SNc多巴胺神经元的传入调制机制。总的来说，这些方法将使SNc多巴胺神经元参与学习和习惯形成的第一个功能性的，以回路为中心的调查，为理解多巴胺能回路动力学的畸变如何成为一系列神经和精神疾病（包括强迫症和药物成瘾）的基础提供必要的基础。这项研究将在斯坦福大学进行，这是一个领先的R1研究机构，为博士后研究员提供了令人印象深刻的物质和智力资源。斯坦福大学神经科学系由神经科学各子领域的杰出研究人员组成，神经科学研究生课程一直是全国最好的。斯坦福大学的神经科学社区是一个高效的环境，具有相似兴趣和互补技术专长的研究人员可以自由合作。斯坦福大学不仅提供世界一流的科研环境，还为职业和专业发展提供了宝贵的资源。斯坦福大学的资源将使候选人能够追求她眼前的职业目标-获得额外的实验和数据分析技术，学习和磨练独立所需的关键技能，如granische，谈判，资源预算，沟通和指导-以及她的长期职业目标-作为一个强大的生物医学研究机构的终身神经科学教授，通过建立一个独立的小组，通过解剖电路，测试它们的功能，以及确定单个电路组件的特性以及系统的涌现特性如何随着学习而演变，并随着年龄、性别、压力和健康状况而不同。

 DESCRIPTION (provided by applicant): Habits allow for the fast, fluid, nearly effortless execution of complex tasks, yet they can also be detrimental, for example in cases where they lead to compulsive behaviors in OCD or to behavioral patterns of drug abuse and relapse in addiction. Habit formation requires the striatum, the input nucleus of the basal ganglia, as well as dopamine inputs to the striatum from the substantia nigra pars compacta (SNc). However, a better understanding of the mechanisms by which striatal and SNc dopaminergic circuitry support habit formation will be a crucial next step in elucidating the roles of habit formation processes in health and disease. SNc dopamine neurons are readily divisible by their efferent projections to the dorsomedial striatum (DMS) or the dorsolateral striatum (DLS), regions that decades of research have shown play distinct roles in operant learning: the DMS mediates early goal-directed task acquisition, while the DLS mediates later habit formation. The fact that SNc dopamine neurons project only to the DMS or the DLS suggests that different signals may be relayed to each area, causing the DMS and DLS to experience dopamine-dependent plasticity at different time points during behavior. Indeed, we have found that DMS- and DLS-projecting SNc dopamine neurons respond oppositely to unconditioned aversive stimuli. Although striking, this finding leaves much to be understood about the independent dopaminergic information streams being sent to the DMS and the DLS, especially in the context of learning. The goal of this proposal is to establish the circuit dynamics controlling differential processing of salient stimuli in subpopulations of SNc dopamine neurons defined by their efferent targets in the DMS and DLS, with temporal specificity and cellular resolution, over the course a complex behavior: the slow transition from goal-directed reward-seeking to habitual responding. In service of this goal, three specific aims are proposed. Each aim is focusing on elucidating one of three crucial yet unknown aspects of SNc dopaminergic circuit dynamics: determinants of variability, evolution over the course of a behavioral shift, and afferent control. First, to determine whether efferent targets are the main determinant of variability within SNc subpopulation, we will perform in vivo two-photon calcium imaging of efferent-defined SNc dopamine neurons in awake mice. Second, we will perform in vivo multi-fiber photometry in freely behaving animals to assess natural dopaminergic projection dynamics in both the DMS and the DLS within a single animal over the course of a behavioral transition to habit. Third, we will combine photometry with optogenetics to dissect mechanisms of afferent modulation of efferent-defined SNc dopamine neurons. Collectively, these approaches will enable the first functional, circuit-focused investigations of SNc dopamine neurons' involvement in learning and habit formation, providing a necessary foundation for understanding how aberrations in dopaminergic circuit dynamics could underlie an array of neurological and psychiatric disorders including OCD and drug addiction. This research will be pursued at Stanford University, a leading R1 research institution with an impressive arsenal of material and intellectual resources available for postdoctoral fellows. The Stanford neuroscience faculty is made up of preeminent researchers in a broad array of neuroscience subfields and the neuroscience graduate program is consistently ranked among the nation's best. The Stanford neuroscience community is a highly productive environment where researchers with similar interests and complementary technical expertise freely collaborate. Stanford not only offers a world-class scientific research environment, but also provides invaluable resources for career and professional development. Stanford's resources will enable the candidate to pursue both her immediate career goals - the acquisition of additional experimental and data analysis techniques and the learning and honing of key skills necessary for independence such as grantsmanship, negotiation, resource budgeting, communication and mentorship - and her long-term career goal - to succeed as a tenured neuroscience professor at a strong biomedical research institution by developing an independent group studying the regulation of brain-wide dopaminergic signaling by dissecting circuits, testing their functionality, and determining how the properties of individual circuit components as well as the emergent properties of the system evolve with learning and differ with age, gender, stress, and health status.