Ionic currents and spiking in cerebellar nuclear neurons

描述(申请人提供)：许多小脑神经元是自发活跃的，即使在没有突触输入的情况下，每秒也会发出10到100个动作电位。这种高度的基础活动与信息编码机制有关，这种编码机制不同于电路中细胞的编码机制，后者通常处于静止状态，直到突触兴奋。例如，在小脑核团中，兴奋性突触输入强度的长期变化不是由突触兴奋和突触后激发的经典Hebbian规则产生的。相反，突触电流通过结合抑制和兴奋的刺激模式来增强，其方式类似于(抑制性)浦肯野传入和(兴奋性)苔藓纤维传入的活动，预计将在小脑联想学习任务中发生。这些结果支持这样一种观点，即小脑回路有信息传递和存储的规则，这些规则将它们与其他经过充分研究的大脑区域区分开来。目前的建议是出于这样一个问题，即自发放电如何为与尖峰时间无关的可塑性奠定基础。在这项拟议的研究中，将对小鼠小脑片中的小脑核神经元进行实验。电压钳和电流钳记录突触反应、离子电流和动作电位，以及核细胞树突中钙信号的成像，将旨在确定苔藓纤维输入增强兴奋性突触反应的机制，以及研究浦肯野传入和核细胞的自发活动对可塑性的影响。由此产生的数据将提供关于跨脑区域信号编码的基本特性的一般信息，以及关于在正常和病理生理条件下小脑突触可塑性的离子机制的具体信息。与公共健康相关：在目前的工作中，我们正在研究小脑中的细胞，小脑是大脑的一部分，控制协调肌肉运动的学习和执行，其电和化学信号模式在共济失调、肌张力障碍、阅读障碍和自闭症中被破坏。由于脑细胞的信号模式依赖于称为离子通道的特殊蛋白质，我们正在研究这些离子通道的特性，目的是了解它们的活动如何导致小脑信号的长期变化，而小脑信号对运动学习非常重要。这些数据可以用来与由于离子通道基因突变而患有共济失调的动物的小脑中的干扰信号进行比较，目的是了解在病理生理条件下发生了什么问题，以及离子通道是否可以作为治疗干预的目标。

DESCRIPTION (provided by applicant): Many neurons of the cerebellum are spontaneously active, firing 10 to 100 action potentials per second even in the absence of synaptic input. This high basal activity correlates with information coding mechanisms that differ from those of cells in circuits that are generally quiescent until excited synaptically. For example, in the cerebellar nuclei, long-term changes in the strength of excitatory synaptic inputs are not generated by classical Hebbian rules of coincident synaptic excitation and postsynaptic firing. Instead, synaptic currents are potentiated by patterns of stimulation that combine inhibition and excitation, in a manner that resembles the activity of (inhibitory) Purkinje afferents and (excitatory) mossy fiber afferents predicted to occur during cerebellar associative learning tasks. Such results support the idea that cerebellar circuits have rules for information transfer and storage that distinguish them from other well studied brain regions. The present proposal is motivated by the question of how spontaneous firing sets the stage for plasticity that is independent of spike timing. In the proposed research, experiments will be performed on neurons of the cerebellar nuclei in cerebellar slices of mice. Voltage-clamp and current-clamp recordings of synaptic responses, ionic currents, and action potentials, as well as imaging of Ca signals in nuclear cell dendrites, will be directed toward identifying the mechanisms of potentiation of excitatory synaptic responses to mossy fiber input, as well as toward examining the influence of spontaneous activity in Purkinje afferents and nuclear cells on plasticity. The resulting data will provide general information about the fundamental properties of signal encoding across brain regions, as well as specific information about the ionic mechanisms underlying cerebellar synaptic plasticity under normal and pathophysiological conditions. PUBLIC HEALTH RELEVANCE: In the present work, we are studying cells in the cerebellum, a part of the brain that controls the learning and execution of coordinated muscle movements, and whose electrical and chemical signaling patterns are disrupted in ataxia, dystonia, dyslexia, and autism. Because signaling patterns by brain cells depend on specialized proteins called ion channels, we are studying the properties of these ion channels, with the goal of understanding how their activity leads to long-lasting changes in cerebellar signals that are important for motor learning. These data can be used to make comparisons to disrupted signals in the cerebella of animals that have ataxia as a result of genetic mutations of ion channels, with the goal of understanding what goes wrong under pathophysiological conditions and whether ion channels can serve as a target for therapeutic interventions.