Circuit mechanisms of cerebellar control of reaching movements

项目总结/摘要 伸展运动是人类与环境互动的基础。小脑损伤损害 达到精确度和准确度，但小脑达到控制的机制贡献尚不清楚。 最近的研究阐明了小脑前馈控制的原理，其中浦肯野细胞学习预测 突发事件，称为前向模型，但我们对小脑发出的控制信号的理解 核，特别是提高到达精度，是穷人。拟议中的研究利用了我们在 上一个资助周期，识别和表征内部运动复制途径，以测试 小脑预测控制这些研究的结果将调和小脑运动的各种假设， 控制和识别产生前馈电动机控制的电路机制。我们已经确定 在到达小鼠的小脑间置核中， 使用闭环光遗传学，这种活动对肢体施加因果拉动，雕刻达到终点。在 建议的研究，我们将探讨这一代码，以测试其在实时控制，学习和排序的作用。在 目的1我们将鉴定产生这种活动的细胞类型及其在试验中形成伸展运动学的作用- 在试验的基础上提高精度。在aim 2中，我们探索了reach适应是否会改变神经模式， 与终点控制相关的小脑核。最后，在目标3中，我们利用了以前的研究结果， 格兰特周期，我们的特点是解剖和生理特性的反馈途径， 小脑输出神经元返回小脑皮质，终末为苔藓纤维。我们会研究 这一内部反馈途径的贡献，达到控制，测试假设，这种快速反馈 调节随时间变化的神经和行为序列。这些研究的结果将推动我们长期的 长期目标是了解哺乳动物前馈运动控制的电路机制，这是至关重要的 精确的运动，并假设在涉及小脑的运动障碍中受损。

PROJECT SUMMARY/ABSTRACT Reaching movements are fundamental to human interactions with the environment. Cerebellar damage impairs reach precision and accuracy, but the mechanistic contribution of cerebellum to reach control is unclear. Recent work has illuminated principles of cerebellar feedforward control, where Purkinje cells learn predictive contingencies, termed forward models, but our understanding of control signals issued from the cerebellar nuclei, particularly to improve reach precision, is poor. The proposed studies leverage our discoveries made in the previous grant cycle, identifying and characterizing internal motor copy pathways, to test mechanisms of cerebellar predictive control. Outcomes of these studies will reconcile diverse hypotheses of cerebellar motor control and identify circuit mechanisms by which feedforward motor control is produced. We have identified strong endpoint-aligned neural activity in the cerebellar interposed nucleus of reaching mice and showed, using closed-loop optogenetics that this activity exerts a causal pull on the limb, sculpting reach endpoint. In the proposed studies we will explore this code to test its role in real-time control, learning and sequencing. In aim 1 we will identify the cell-types that produce this activity and its role in shaping reach kinematics on a trial- by-trial basis to improve precision. In aim 2, we explore whether reach adaptation changes neural patterns in the cerebellar nuclei associated with endpoint control. Finally, in Aim 3 we leverage findings from the previous grant cycle where we characterized anatomical and physiological properties of a feedback pathway from cerebellar output neurons back to the cerebellar cortex ending as mossy fibers. We will examine the contribution of this internal feedback pathway in reach control, testing the hypothesis that this fast feedback regulates time-varying neural and behavioral sequencing. The outcomes of these studies will advance our long term goal of understanding the circuit mechanisms of feedforward motor control in mammals, which is critical for precise movement and hypothesized to be impaired in movement disorders that involve the cerebellum.