Control of movements by the cerebellum

小脑疾病使正常的动作异常困难，经常导致终点错误。为 例如，蚯蚓小叶VII的损伤导致眼球跳动困难。这些症状有 提示小脑监控正在进行的指令并调整它们，特别是当运动接近的时候 目标。然而，单个浦肯野细胞(P细胞)的放电模式被调制的时间比 有动静。因此，很难破译P细胞及其下游核神经元的活动， 关于运动控制所必需的计算。 这个谜题的一个关键是下层橄榄监测小脑的输出并返回小脑。 似乎编码错误[1-4]的信息。这种对小脑的输入组织P细胞和核神经元 形成称为微簇的解剖群[5-7]。微簇内的细胞可能有一个共同的特征：它们 对错误做出类似的反应。通过Shadmehr、Soetedjo和Kojima之间的合作，我们使用了这个想法 研究表明，在猕猴中，如果P细胞根据它们对错误的复杂尖峰反应被组织成组，那么 它们作为种群的简单尖峰产生了预测正在进行的运动的参数的速率编码 [8，9]。结果产生了一个新的想法：小脑的基本计算单位可能不是个体 单元格，而是一群拥有共同的错误偏好的单元格。 在这里，我们假设对错误做出类似反应的P-细胞是网络的一部分，该网络表现出特殊的 属性：在这个网络中，P细胞不仅协调它们的放电频率，而且还在时间上调整它们的 尖峰，特别是在动作的减速阶段。也就是说，P细胞将信息传递到细胞核 通过调整它们的射速，并同步它们的尖峰。在我们的假设中，P细胞将去抑制与 同步以指示何时应停止移动[10]。为了追求这一理念，我们在2016年建立了一个 绒猴实验室，开创了训练动物的技术，然后使用硅探头记录了许多 神经元同时[10，11]。然后，我们建立了新的工具，用于对小脑棘波进行精确的时间分析[12]。 在这里，我们建议从P细胞、分子层中间神经元(MLI)和核神经元记录，使用它们的误差 反应将细胞组织成群体，然后量化运动过程中的放电率和尖峰时间。 我们提议的实验有可能产生同时记录P细胞、MLI和 核神经元，这在灵长类动物中是前所未有的。我们将使用这种神经生理学方法来 测试我们假设的解剖学基础，即下橄榄将小脑组织成细胞集合。 这些数据将使我们能够确定健康的小脑是否依赖同步编码 信息，揭示了诸如心律失常和震颤等疾病，这些疾病似乎不是由 P细胞放电率的错误调制，而是棘波时序的混乱[13-16]。

Cerebellar disease makes ordinary movements extraordinarily difficult, often resulting in endpoint errors. For example, damage to lobule VII of the vermis makes saccadic eye movements dysmetric. These symptoms have suggested that the cerebellum monitors ongoing commands and adjusts them, particularly as the movement nears the target. Yet, individual Purkinje cells (P-cells) have firing patterns that are modulated much longer than the movement. Thus, it has been difficult to decode the activities of P-cells, and their downstream nucleus neurons, with respect to computations that are necessary for control of movements. A key to this puzzle is that the inferior olive monitors the output of the cerebellum and returns to it information that appears to encode error [1–4]. This input to the cerebellum organizes P-cells and nucleus neurons into anatomical groups called micro-clusters [5–7]. Cells within a micro-cluster likely have a common feature: they respond similarly to error. Through a collaboration between Shadmehr, Soetedjo, and Kojima, we used this idea to show that in macaques, if P-cells were organized into groups based on their complex spike response to error, then their simple spikes as a population produced a rate coding that predicted parameters of the ongoing movement [8,9]. The result was a new idea: the fundamental computational unit in the cerebellum may not be an individual cell, but a population of cells that share a common preference for error. Here, we propose that P-cells that respond similarly to error are part of a network that exhibits a special property: within this network, the P-cells not only coordinate their firing rates, but also temporally align their spikes, especially during the deceleration phase of movements. That is, P-cells transmit information to the nucleus by modulating their firing rates, and synchronizing their spikes. In our hypothesis, P-cells combine disinhibition with synchronization to signal when the movement should be stopped [10]. To pursue this idea, in 2016 we built a marmoset lab, pioneered techniques to train the animals, and then used silicon probes to record from many neurons simultaneously [10,11]. We then built new tools for precise temporal analysis of cerebellar spikes [12]. Here, we propose to record from P-cells, molecular layer interneurons (MLIs), and nucleus neurons, use their error response to organize cells into populations, and then quantify both firing rates and spike timing during movements. Our proposed experiments have the potential to produce simultaneous recordings of P-cells, MLIs, and nucleus neurons, something that is unprecedented in primates. We will use this neurophysiological approach to test the anatomical basis of our hypothesis, that the inferior olive organizes the cerebellum into cell-assemblies. The data will allow us to determine whether the healthy cerebellum relies on synchronization to encode information, shedding light on conditions such as dysmetria and tremor, pathologies that appear to arise not from mis-modulation of P-cell firing rates, but rather disorganization of spike timing [13–16].