Dissecting the role of cortico-basal ganglia circuit diversity in action learning from reinforcement

剖析皮质基底神经节回路多样性在强化行动学习中的作用

• 批准号: 10425617
• 负责人: Alice Mosberger
• 金额: $ 13.62万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425617
• 关键词: Anatomy; Animals; Area; Axon; Basal Ganglia; Behavior; Behavior Control; Behavioral; Brain; Brain Stem; Calcium; Cells; Cerebellum; Complex; Corpus striatum structure; Dopamine; Forelimb; Head; Heterogeneity; Image; Individual; Joystick; Learning; Limb structure; Link; Maps; Measures; Mentors; Methods; Modeling; Motor; Movement; Mus; Neurons; Outcome; Paper; Pathway interactions; Phase; Photons; Play; Population; Positioning Attribute; Postdoctoral Fellow; Process; Psychological reinforcement; Publishing; Pyramidal Tracts; Red nucleus structure; Research; Research Training; Rewards; Role; Spinal Cord; Stroke; Synapses; Techniques; Tennis; Testing; Thalamic structure; base; behavior measurement; career development; cell type; central nervous system injury; experience; experimental study; limb movement; motor control; motor learning; motor recovery; neural network; novel; optogenetics; programs; rabies viral tracing; relating to nervous system; skills; skills training; theories; transmission process; two-photon

Project Summary/Abstract To learn novel actions through reinforcement, a fundamental mechanism of motor learning, the brain needs to causally link previously performed movements to their resulting outcomes. But even single limb movements consist of multiple aspects, which poses what is known as the credit assignment problem: ‘What was it that I just did that led to the desired outcome?’ Through repeated reselection of the movement the brain converges on which aspects are relevant, and variability is reduced in those aspects, refining the action into a skill. Current theories suggest that this process is implemented in the cortico-basal ganglia-thalamo-cortical loop. Cortical information about planned and ongoing movements is conveyed to the striatum via corticostriatal projections. If the movement leads to a desired outcome, dopamine is released in striatum, strengthening the activated corticostriatal synapses. This plasticity, in turn, is thought to allow the reselection of the movement through the basal ganglia-thalamo-cortical loop. It is unclear however how different aspects of the action are distinguished such that the relevant ones are refined. The anatomical heterogeneity of the corticostriatal sensorimotor command may provide a circuit-level mechanism of this process. In the K99 mentored phase, I will dissect this mechanism. I hypothesize that distinct corticostriatal projections convey different aspects of the motor command and what is learned is determined by which projections are reinforced. I have developed a head-fixed behavior task in which mice get rewarded for moving a joystick into a defined circular target area. In this task, a specific movement direction, a position of the rewarded endpoint, or both may be reinforced and learned by mice. I use behavioral measurements and manipulations, and neural decoding of the different corticostriatal motor commands to probe what individual animals learn. I will be mentored by Dr. Rui Costa, Dr. Daniel Wolpert, and collaborator Dr. James Murray to hone my behavior analysis skills and train in cutting-edge methods for neural decoding, such as the use of neural networks. Then I use optogenetic manipulation to directly test if anatomically distinct corticostriatal commands determine what animals learn. Besides reselection of cortical motor commands through thalamus, the basal ganglia control movement by disinhibiting brainstem motor centers, providing a parallel pathway for action refinement. One such center, the red nucleus, is directly involved in forelimb control, as previously shown by me and others, and is also innervated by the cerebellum. In the R00 phase, I will start my independent research by investigating if action refinement also depends on basal ganglia control of brainstem motor centers, particularly the red nucleus. As I transition to independence, Dr. Megan Carey will advise me in questions of cerebellum-related motor control. All mentors will promote my career development. These research and training experiences will place me as a competitive candidate to become a successful independent PI and give me the needed support to achieve milestones of getting my first R01 and publishing the first independent paper from my lab.

项目概要/摘要 为了通过强化（运动学习的基本机制）来学习新动作，大脑需要 将先前执行的动作与其产生的结果联系起来。但即使是单肢动作 由多个方面组成，这就提出了所谓的学分分配问题：“我刚才是什么？” 这是否达到了预期的结果？”通过反复重新选择大脑集中的运动 哪些方面是相关的，并且减少了这些方面的可变性，从而将行动细化为技能。 目前的理论表明，这个过程是在皮质-基底节-丘脑-皮质环路中实现的。 有关计划和正在进行的运动的皮质信息通过皮质纹状体传递到纹状体 预测。如果运动达到了预期的结果，纹状体就会释放多巴胺，从而加强 激活皮质纹状体突触。反过来，这种可塑性被认为允许运动的重新选择 通过基底神经节-丘脑-皮质环。但目前尚不清楚该行动的不同方面有何不同 区分，从而细化相关内容。皮质纹状体的解剖异质性 感觉运动命令可以提供该过程的电路级机制。在K99辅导阶段，我会 剖析这个机制。我假设不同的皮质纹状体投射传达了不同的方面 运动指令和学到的东西取决于强化的预测。 我开发了一项头部固定行为任务，其中小鼠因将操纵杆移动到定义的位置而获得奖励 圆形目标区域。在此任务中，特定的移动方向、奖励端点的位置或两者都可以 被老鼠强化和学习。我使用行为测量和操作以及神经解码 不同的皮质纹状体运动命令来探究个体动物学习的内容。我将接受芮博士的指导 Costa、Daniel Wolpert 博士和合作者 James Murray 博士磨练了我的行为分析技能并进行了培训 神经解码的尖端方法，例如神经网络的使用。然后我用光遗传学 直接测试解剖学上不同的皮质纹状体命令是否决定动物学习的内容。 除了通过丘脑重新选择皮质运动命令外，基底神经节还通过 抑制脑干运动中心，为动作细化提供并行途径。一个这样的中心， 红核，直接参与前肢控制，如我和其他人之前所示，并且也受到神经支配 由小脑。在R00阶段，我将通过调查动作细化是否可以开始我的独立研究 还取决于基底神经节对脑干运动中枢，特别是红核的控制。当我过渡到 独立性，梅根·凯里博士将就小脑相关的运动控制问题向我提供建议。所有导师都会 促进我的职业发展。这些研究和培训经验将使我成为一名有竞争力的人 成为一名成功的独立 PI 的候选人，并为我提供实现里程碑所需的支持 获得我的第一个 R01 并发表我实验室的第一篇独立论文。