Sensorimotor integration in mammalian cerebellum

描述（由申请人提供）：推论放电（CD），或传出运动命令的副本，是许多小脑运动控制模型的组成部分。假设CD提供了一个参考信号来更新当前运动状态的内部模型，并修改由运动命令预测的传入感觉输入，将其置于感觉运动整合的中心。然而，由于解剖学上的限制，我们对哺乳动物小脑中CD的特定解剖和生理回路的理解是有限的，这使得研究运动皮层来源的CD信号变得复杂。我们的方法通过关注从运动前小脑核到小脑颗粒细胞层的侧枝组成的被忽视的途径来绕过这些障碍。这种实验上可获得的“核皮质”通路具有CD通路的所有特征，因为它由运动输出神经元组成，这些神经元也投射到感觉接受区。我们建议通过研究小鼠中这一通路的组织和功能，来了解在哺乳动物小脑感觉加工过程中必然放电的机制和作用。为了验证CD既更新内部模型又抑制感觉参照的假设，我们将使用解剖学和生理学的方法来检查核皮质通路是否在前馈兴奋性颗粒神经元和前馈抑制性高尔基神经元上形成兴奋性突触。这种安排将为CD在电机控制中的拟议作用提供一种机制。为了进一步验证CD可以改变感觉参照的预测，我们将研究颗粒细胞层的感觉反应是否对核皮质通路的同时激活或失活敏感。我们预计，来自小脑核的运动CD通路与颗粒细胞和高尔基细胞接触，与其他感觉小脑传入事件汇合，并通过颗粒细胞层改变感觉加工。这些研究将有助于我们理解哺乳动物前馈运动控制回路机制的长期目标，这对精确运动至关重要，并且假设在涉及小脑的运动障碍中受损。

DESCRIPTION (provided by applicant): Corollary discharge (CD), or a copy of efferent motor commands, is integral to numerous models cerebellar motor control. CD is hypothesized to provide a reference signal to update internal models of current motor state and modify reafferent sensory input that is predicted by the motor command, placing it at the center of sensorimotor integration. Our understanding of the specific anatomical and physiological circuitry of CD in the mammalian cerebellum is limited, however, owing to anatomical constraints that complicate studying motor cortex-derived CD signals. Our approach bypasses these obstacles by focusing on a neglected pathway consisting of collaterals from the premotor cerebellar nuclei to the cerebellar granule cell layer. This experimentally accessible "nucleocortical" pathway has all of the hallmarks of a CD pathway in that it consists of motor output neurons that also project to sensory receptive areas. We propose to investigate the organization and function of this pathway in mice as a means to understand the mechanisms and role of corollary discharge in sensory processing in mammalian cerebellum. To test the hypothesis that CD both updates internal models and suppresses sensory reafference, we will use anatomical and physiological approaches to examine whether the nucleocortical pathway forms excitatory synapses onto feedforward excitatory granule neurons and feedforward inhibitory Golgi neurons. This arrangement would provide a mechanism for the proposed roles of CD in motor control. To further test the prediction that CD can modify sensory reafference, we will examine whether sensory responses in the granule cell layer are sensitive to concurrent activation or inactivation of the nucleocortical pathway. We expect that the motor CD pathway from the cerebellar nuclei contacts granule cells and Golgi cells, converges with other sensory cerebellar afferents, and modifies sensory processing by the granule cell layer. These studies will aid in 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.