Sensorimotor integration in mammalian cerebellum

描述(由申请人提供)：推论放电(CD)，或传出运动指令的副本，是许多模型小脑运动控制的组成部分。CD被假设为提供参考信号，以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，我们对哺乳动物小脑中CD的特定解剖和生理回路的了解是有限的，这是因为解剖学上的限制使研究运动皮质来源的CD信号变得复杂。我们的方法绕过了这些障碍，重点放在一条被忽视的路径上，该路径由从运动前小脑核到小脑颗粒细胞层的侧支组成。这种可通过实验获得的“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。我们建议在小鼠中研究这一通路的组织和功能，以此来了解哺乳动物小脑感觉加工中必然的放电机制和作用。为了验证CD既更新内部模型又抑制感觉再传入的假设，我们将使用解剖学和生理学的方法来检验核皮质通路是否形成与前馈兴奋性颗粒神经元和前馈抑制性高尔基神经元的兴奋性突触。这一安排将为CD在马达控制方面的拟议作用提供一个机制。为了进一步验证CD可以改变感觉再传入的预测，我们将检查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。我们认为来自小脑核的运动CD通路接触颗粒细胞和高尔基细胞，与其他感觉传入小脑汇聚，并通过颗粒细胞层改变感觉加工。这些研究将有助于我们了解哺乳动物前馈运动控制的电路机制，这是精确运动的关键，并被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.