Ionic currents and spiking in cerebellar nuclear neurons

描述（由申请人提供）：小脑的许多神经元自发活动，即使在没有突触输入的情况下，每秒也能发射10到100个动作电位。这种高基础活性与信息编码机制相关，这与回路中通常处于静止状态直到突触兴奋的细胞不同。例如，在小脑核中，兴奋性突触输入强度的长期变化不是由经典的突触兴奋和突触后放电一致的Hebbian规则产生的。相反，突触电流是由抑制和兴奋相结合的刺激模式增强的，其方式类似于预测在小脑联想学习任务中发生的（抑制性）浦肯野传入事件和（兴奋性）苔藓纤维传入事件。这些结果支持了小脑回路具有信息传递和存储规则的观点，这些规则将其与其他研究充分的大脑区域区分开来。目前的建议是由自发放电如何设置的阶段，是独立于脉冲时间的可塑性的问题。在本研究中，实验将在小鼠小脑切片的小脑核神经元上进行。电压钳和电流钳对突触反应、离子电流和动作电位的记录，以及核细胞树突中Ca信号的成像，将用于确定苔藓纤维输入的兴奋性突触反应增强的机制，以及检查浦肯野传入和核细胞的自发活动对可塑性的影响。所得数据将提供关于跨脑区信号编码的基本特性的一般信息，以及关于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。公共卫生相关性：在目前的工作中，我们正在研究小脑中的细胞，小脑是大脑中控制协调肌肉运动的学习和执行的一部分，其电信号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被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对运动学习很重要的小脑信号的持久变化。这些数据可用于比较由于离子通道基因突变而导致共济失调的动物小脑中的干扰信号，目的是了解在病理生理条件下出现的问题，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.