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

项目摘要/摘要 要通过强化来学习新动作，这是运动学习的基本机制，大脑需要 将先前进行的运动与其结果之间存在因果关系。但即使是单一的肢体运动 包括多个方面，这就提出了所谓的信用分配问题：‘我刚刚是什么 这是否导致了预期的结果？通过对运动的反复选择，大脑集中在 哪些方面是相关的，这些方面的可变性被减少，将动作提炼成一项技能。 目前的理论认为，这一过程是在皮质-基底节-丘脑-皮质环中实现的。 有关计划的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 投射。如果运动导致预期的结果，多巴胺就会在纹状体中释放，从而加强 激活了皮质纹状体突触。这种可塑性，反过来又被认为允许运动的重新选择 穿过基底节-丘脑-皮质环路。然而，目前还不清楚行动的不同方面有多大 有特色的，以便相关的都是精炼的。皮质纹状体的解剖异质性 感应器运动命令可以提供该过程的电路级机制。在K99指导阶段，我将 剖析这一机制。我假设不同的皮质纹状体投射传达了 运动指令和学习的内容取决于哪些投射得到加强。 我已经开发了一个头部固定行为任务，在这个任务中，老鼠将操纵杆移动到定义的 圆形目标区域。在该任务中，特定移动方向、奖励终点的位置或这两者可以 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指令来探测单个动物学习什么。我将得到瑞博士的指导 科斯塔、丹尼尔·沃尔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并在 神经解码的前沿方法，例如使用神经网络。然后我用光生技术 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的操作。 除了通过丘脑重新选择皮质运动指令外，基底节还通过 解除脑干运动中枢的抑制，为动作优化提供一条平行的途径。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那样，它也受到神经支配 通过小脑。在R00阶段，我将开始我的独立研究，首先调查动作细化 也依赖于基底节对脑干运动中枢的控制，特别是红核。当我过渡到 独立后，梅根·凯里博士将就与小脑相关的运动控制问题向我提供建议。所有导师都会 促进我的事业发展。这些研究和培训经验将使我成为一个有竞争力的人 成为一名成功的独立PI的候选人，并为我实现以下里程碑提供必要的支持 获得了我的第一个R01，并发表了我实验室的第一篇独立论文。

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.