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: 10605243
• 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/10605243
• 关键词: Anatomy; Animals; Area; Axon; Basal Ganglia; Behavior; Behavior Control; Behavioral; Brain; Brain Stem; Calcium; Cells; Cerebellum; Complex; Corpus striatum structure; Disinhibition; Dopamine; Forelimb; Ganglia; Head; Heterogeneity; Image; Individual; Joystick; Learning; Learning Skill; Limb structure; Link; Maps; Measures; Mentors; Methods; Modeling; Motor; Motor Cortex; 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; Rewards; Role; Spinal Cord; Stroke; Synapses; Techniques; Tennis; Testing; Thalamic structure; Training; behavior measurement; career development; cell type; central nervous system injury; experience; experimental study; limb movement; motor control; motor learning; motor recovery; neural; neural network; novel; optogenetics; programs; rabies viral tracing; skills; 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.

项目总结/摘要 通过强化学习新的动作，这是运动学习的基本机制，大脑需要 将先前执行的动作与其结果因果联系起来。但即使是单一的肢体动作 由多个方面组成，这就提出了所谓的学分分配问题：“我刚刚 是否达到了预期的效果通过反复重新选择大脑集中注意的动作 哪些方面是相关的，并且在这些方面减少可变性，将动作精炼成技能。 目前的理论认为，这一过程是在皮质-基底节-丘脑-皮质回路中实现的。 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。如果运动产生了预期的结果，纹状体中就会释放多巴胺， 激活皮质纹状体突触这种可塑性，反过来，被认为是允许重新选择的运动 穿过基底节丘脑皮质环然而，目前还不清楚该行动的不同方面是如何运作的。 区分，以便细化相关的。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，我将 剖析这个机制。我假设不同的皮质纹状体投射传达了不同方面的信息。 运动指令和学到的东西取决于哪些投射得到加强。 我已经开发了一个头部固定的行为任务，在这个任务中，老鼠将操纵杆移动到一个定义的位置， 圆形目标区域在该任务中，特定移动方向、奖励端点的位置或两者可以 被老鼠强化和学习。我使用行为测量和操纵，以及神经解码， 不同的皮质纹状体运动指令来探测个体动物学习什么。我将由芮博士指导 科斯塔，丹尼尔沃伯特博士和合作者詹姆斯默里博士磨练我的行为分析技能和培训， 神经解码的尖端方法，例如使用神经网络。然后我用光遗传学 操作，以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什么。 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 解除对脑干运动中心的抑制，为动作的精细化提供平行的途径。一个这样的中心， 红核，直接参与前肢控制，正如我和其他人之前所展示的，也受神经支配 被小脑在R 00阶段，我将开始我的独立研究调查，如果行动细化 也依赖于基底神经节控制脑干运动中枢，特别是红核。当我过渡到 独立后，梅根·凯里博士将在小脑相关的运动控制问题上为我提供建议。所有导师将 促进我的职业发展。这些研究和培训经验将使我成为一个有竞争力的 候选人成为一名成功的独立PI，并为我提供实现里程碑所需的支持 得到了我的第一个R 01，发表了我实验室的第一篇独立论文。