Control of movements by the cerebellum

小脑对运动的控制

• 批准号: 10585632
• 负责人: REZA SHADMEHR
• 金额: $ 73.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585632
• 关键词: Algorithms; Anatomy; Animals; Axon; Behavior; Brain; Callithrix; Cell Nucleus; Cells; Cerebellar Cortex; Cerebellar Diseases; Cerebellar Nuclei; Cerebellar vermis structure; Cerebellum; Code; Collaborations; Complex; Data; Deceleration; Dendrites; Disease; Disinhibition; Dysmetria; Ensure; Exhibits; Eye; Grouping; Individual; Inferior; Interneurons; Laboratories; Learning; Light; Link; Lobule; Macaca; Measures; Molecular; Monitor; Motion; Movement; Neurons; Nucleus fastigii; Olives - dietary; Output; Pathologic; Pathologic Nystagmus; Pathology; Pattern; Phase; Play; Population; Primates; Procedures; Property; Purkinje Cells; Role; Saccades; Sensory; Signal Transduction; Silicon; Structure; Symptoms; Techniques; Testing; Training; Tremor; cell assembly; experimental study; improved; innovation; neural; neurophysiology; nonhuman primate; optogenetics; population based; preference; response; tool; transmission process

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].

小脑病使普通运动非常困难，通常会导致终点错误。为了 例如，对vii的爱的损害使阳性的眼动动作异常。这些符号具有 建议小脑监视正在进行的命令并调整它们，尤其是在运动接近时 目标。然而，单个purkinje细胞（P细胞）的发射模式比 移动。那是很难解码P细胞的活性及其下游核神经元的活性 关于控制运动所需的计算。 这个难题的关键是下橄榄监测小脑的输出并返回它 似乎编码错误[1-4]的信息。小脑的输入组织P细胞和核神经元 分成称为微群体的解剖组[5-7]。微簇中的单元可能具有共同的特征：它们 对错误的响应类似。通过Shadmehr，Soetedjo和Kojima之间的合作，我们使用了这个想法 在猕猴中表明，如果P细胞根据其复杂的尖峰对错误的响应组织为组，则 他们的简单峰值作为人口产生了预测正在进行运动参数的速率编码 [8,9]。结果是一个新想法：小脑中的基本计算单元可能不是个体 细胞，但具有共同偏爱误差的细胞群。 在这里，我们建议对错误做出类似响应的P细胞是一个表现出特殊的网络的一部分 属性：在该网络中，P细胞不仅协调其点火率，而且还暂时对齐他们 尖峰，尤其是在运动阶段。也就是说，P细胞将信息传输到核 通过调节点火率并同步其尖峰。在我们的假设中，P细胞将抑制作用与 同步以何时停止运动[10]。为了追求这个想法，我们在2016年建立了一个 马尔莫塞特实验室，启动训练动物的技术，然后使用硅问题来记录许多 神经元[10,11]。然后，我们建立了新的工具，用于精确的小脑尖峰临时分析[12]。 在这里，我们建议从P细胞，分子层中间神经元（MLI）和核神经元记录记录它们的误差 响应将细胞组织到种群中，然后在运动过程中量化点火速率和尖峰时间。 我们提出的实验有可能产生简单的P细胞，MLI和MLI和 细胞核神经元，私人中前所未有的东西。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组件。 数据将使我们能够确定健康的小脑是否依赖于同步编码 信息，阐明诸如障碍和震颤之类的疾病，似乎不是从 P细胞发射速率的调节误导，而是尖峰计时的混乱[13-16]。