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].

小脑疾病使普通运动变得非常困难，经常导致终点错误。为 例如，对蚓部小叶VII的损伤使得扫视眼球运动不规则。这些症状 他认为，小脑会监控正在进行的命令，并调整它们，特别是当运动接近时， 目标.然而，单个浦肯野细胞（P-细胞）的放电模式的调制时间远长于 运动因此，很难解码P细胞及其下游核神经元的活动， 关于控制运动所必需的计算。 解开这个谜团的一个关键是，下橄榄核监控着小脑的输出，并返回到小脑 信息似乎编码错误[1-4]。这一输入到小脑组织P细胞和核神经元 分为称为微簇的解剖组[5-7]。微簇内的细胞可能具有共同的功能：它们 对错误的反应类似。通过Shadmehr、Soetedjo和Kojima之间的合作，我们利用这个想法， 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而被组织成组，那么 他们作为一个群体的简单尖峰产生了一个速率编码，预测正在进行的运动的参数， [8，9]。结果产生了一个新的想法：小脑中的基本计算单位可能不是个人 细胞，而是一群共享错误偏好的细胞。 在这里，我们提出，对错误做出类似反应的P细胞是网络的一部分， 性质：在这个网络中，P细胞不仅协调它们的放电率，而且在时间上对齐它们的放电率。 特别是在运动的减速阶段。也就是说，P细胞将信息传递到细胞核 通过调节它们的放电频率和同步它们的峰值。在我们的假设中，P细胞将联合收割机解除抑制与 当运动应该停止时，同步以发出信号[10]。为了实现这个想法，2016年，我们建立了一个 绒猴实验室，开创了训练动物的技术，然后用硅探针记录了许多 神经元同时[10，11]。然后，我们建立了新的工具来精确分析小脑棘波[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 响应，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。 我们提出的实验有可能同时记录P细胞、MLI和 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， 检验我们假设的解剖学基础，即下橄榄将小脑组织成细胞集合体。 这些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，阐明诸如辨距障碍和震颤等病症，这些病症似乎不是由 P细胞放电率的错误调节，而是尖峰时间的混乱[13-16]。