Contributions of Parallel Nigrostriatal Dopamine Circuits to Reward Learning and Habit Formation
平行黑质纹状体多巴胺回路对奖励学习和习惯形成的贡献
基本信息
- 批准号:9086170
- 负责人:
- 金额:$ 11.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-15 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAgeAnimalsAreaAversive StimulusAxonBasal GangliaBehaviorBehavioralBiomedical ResearchBrainBrain regionBudgetsCalciumCell NucleusCellsCommunicationCommunitiesComplexCompulsive BehaviorCorpus striatum structureDataData AnalysesDevelopmentDiseaseDopamineDrug AddictionDrug abuseEmployee StrikesEnvironmentEvolutionFacultyFiberFluorescenceFoundationsFunctional disorderFutureGenderGoalsHabitsHealthHealth StatusImageImaging TechniquesIndividualInstitutionInvestigationLeadLearningLiquid substanceLogicMediatingMediationMental disordersMentorsMentorshipMethodsMonitorMusNatureNeuronsNeurosciencesObsessive-Compulsive DisorderPatternPhasePhotometryPlayPopulation DynamicsPostdoctoral FellowProcessPropertyRegulationResearchResearch PersonnelResolutionResourcesRewardsRoleServicesShockSignal TransductionSpecificityStimulusStreamStressSubstantia nigra structureSystemTechnical ExpertiseTechniquesTechnologyTestingTimeUniversitiesaddictionarea striataawakebasebehavioral outcomecalcium indicatorcareerdopaminergic neurondrug relapseexperienceexperimental analysishabit learningin vivoinsightinterestnervous system disorderneuromechanismnext generationoptogeneticspars compactaprofessorprogramspublic health relevanceresearch studyresponseskillstwo-photon
项目摘要
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.
描述(由申请人提供):习惯可以快速、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,它们会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。习惯的形成需要纹状体(基底神经节的输入核)以及从黑质致密部(SNc)到纹状体的多巴胺输入。然而,更好地理解纹状体和 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通过其对背内侧纹状体 (DMS) 或背外侧纹状体 (DLS) 的传出投射进行划分,数十年的研究表明,这些区域在操作性学习中发挥着独特的作用:DMS 介导早期目标导向任务的习得,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,不同的信号可能会传递到每个区域,导致 DMS 和 DLS 在行为过程中的不同时间点经历多巴胺依赖性可塑性。事实上,我们发现 DMS 和 DLS 投射的 SNc 多巴胺神经元对无条件厌恶刺激的反应相反。尽管令人震惊,但这一发现对于发送到 DMS 和 DLS 的独立多巴胺能信息流还有很多需要理解的地方,尤其是在学习的背景下。该提案的目标是建立控制 SNc 多巴胺神经元亚群中显着刺激差异处理的电路动力学,该亚群由 DMS 和 DLS 中的传出目标定义,具有时间特异性和细胞分辨率,在整个复杂行为过程中:从目标导向的奖励寻求到习惯性反应的缓慢过渡。为了实现这一目标,提出了三个具体目标。每个目标都集中于阐明 SNc 多巴胺能回路动力学的三个关键但未知的方面之一:变异性的决定因素、行为转变过程中的进化以及传入控制。首先,为了确定传出目标是否是 SNc 亚群内变异的主要决定因素,我们将对清醒小鼠中传出定义的 SNc 多巴胺神经元进行体内双光子钙成像。其次,我们将对自由行为的动物进行体内多纤维光度测定,以评估单个动物在行为向习惯转变过程中 DMS 和 DLS 中的自然多巴胺能投射动态。第三,我们将结合光度测量和光遗传学来剖析传出定义的 SNc 多巴胺神经元的传入调节机制。总的来说,这些方法将能够首次对 SNc 多巴胺神经元参与学习和习惯形成进行功能性、以回路为中心的研究,为理解多巴胺能回路动力学的畸变如何导致一系列神经和精神疾病(包括强迫症和药物成瘾)提供必要的基础。这项研究将在斯坦福大学进行,斯坦福大学是一家领先的 R1 研究机构,为博士后研究员提供了大量的材料和智力资源。斯坦福大学神经科学系由神经科学各个子领域的杰出研究人员组成,神经科学研究生项目始终名列全美最佳。斯坦福大学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宝贵的资源。斯坦福大学的资源将使候选人能够实现她的近期职业目标——获得额外的实验和数据分析技术,以及学习和磨练独立所需的关键技能,如资助、谈判、资源预算、沟通和指导——以及她的长期职业目标——通过建立一个研究全脑调节的独立小组,成为一家强大的生物医学研究机构的终身神经科学教授。 通过剖析电路、测试其功能并确定各个电路组件的特性以及系统的新兴特性如何随着学习而演变以及随年龄、性别、压力和健康状况而变化的多巴胺能信号传导。
项目成果
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Talia Newcombe Lerner其他文献
Talia Newcombe Lerner的其他文献
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