Physiological Function of Persistent Inward Currents in Motor Neurons

运动神经元持续内向电流的生理功能

• 批准号: 10663030
• 负责人: ANDREW J FUGLEVAND
• 金额: $ 40.84万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663030
• 关键词: Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Arousal; Automobile Driving; Axon; Bipolar Disorder; Brain; Calcium; Catheters; Central Nervous System; Characteristics; Code; Dendrites; Disabled Persons; Disease; Disparity; Dose; Drug Delivery Systems; Elements; Epilepsy; Flexor; Frequencies; Functional disorder; Goals; Human; Huntington Disease; Impairment; Ion Channel; Isometric Exercise; Knowledge; Lead; Learning; Lumbar spinal cord structure; Measures; Mediating; Mediator; Membrane; Mental Depression; Motor; Motor Neurons; Movement; Muscle; Muscle Contraction; Muscle Fibers; Nervous System control; Neuromodulator; Neurons; Nifedipine; Nimodipine; Norepinephrine; Output; Parkinson Disease; Pharmaceutical Preparations; Physiological; Play; Preparation; Procedures; Process; Published Comment; Ramp; Rattus; Research Personnel; Role; Schizophrenia; Serotonin; Serotonin Receptor Binding; Shapes; Skeletal Muscle; Source; Stress; Structure; Synapses; Time; Training; awake; channel blockers; chronic pain; experimental study; human subject; indexing; insight; monoamine; motor behavior; muscle strength; nervous system disorder; neural; operation; promoter; recruit; response; spasticity; virtual; voltage

ABSTRACT Motor neurons receive synaptic inputs from many other neurons and convert these inputs into frequency-coded messages that are relayed to muscle fibers to cause contraction. It is often assumed that motor neurons generate spikes at rates in proportion to the excitatory synaptic input received. It is now recognized, however, that motor neurons have active processes, such as persistent inward currents (PICs), that may markedly alter the relationship between synaptic input and firing rate output. PICs represent a neuromodulator-mediated intrinsic source of membrane depolarization that can even lead to self-sustained firing of motor neurons, i.e., prolonged spiking in the absence of synaptic input. Several ideas have been forwarded as to the functional significance of PICs, both in terms of the control of normal motor function and as an impaired process contributing to various neurological disorders. Indeed, some investigators have suggested that PICs provide the primary source of depolarizing current to motor neurons during all forms of activity, whereas others speculate that PICs are only active during periods of high stress and arousal. Yet the extent to which PICs contribute to natural motor neuron activity is not known. Therefore, the goal of this project is to directly ascertain the role that PICs play during voluntary muscle contraction using an animal model wherein the ion channels (L-type calcium), thought to be primary mediators of motor neuron PICs, are selectively disabled (Aim 1) or enabled (Aim 2). We will do this by recording motor unit activity in plantar flexor muscles of rats voluntarily exerting target isometric forces in the presence and absence of intrathecally injected nimodipine, an L-type Ca+2 channel blocker (Aim 1), and serotonin, a known promotor of PICs (Aim 2). Changes in motor unit firing rate (and recruitment) recorded under drug conditions will be compared to the same units recorded prior to drug delivery while the animal holds the same force. These comparisons will provide direct knowledge of the role PICs play in shaping natural motor unit activity – a topic of debate since the discovery of PICs in the late 1970s. Furthermore, this study will add to our understanding of PIC dysfunction, implicated in neurological disorders such as spasticity and amyotrophic lateral sclerosis.

抽象的 运动神经元接收来自许多其他神经元的突触输入，并将这些输入转换为 传递到肌肉纤维引起收缩的频率编码的消息。经常假定 运动神经元与接收到的兴奋性突触输入成正比生成峰值。现在 然而，认识到运动神经元具有活跃的过程，例如持续的内向电流（图片）， 这可能明显改变合成输入和发射速率输出之间的关系。图片代表 神经调节剂介导的膜沉积的固有来源，甚至可以导致自我维持 运动神经元的发射，即在没有突触输入的情况下长时间的尖峰。有几个想法 在正常运动函数的控制方面，都转发了图片的功能意义和 导致各种神经系统疾病的过程受损。确实，一些调查人员有 建议在各种形式的情况下，图片为运动神经元推出电流的主要来源 活性，而其他人则推测图片仅在高应力和唤醒期间是活跃的。但是 图片促进自然运动神经元活性的程度尚不清楚。因此，目标的目标 项目是直接确定图片使用动物在自愿性肌肉收缩过程中扮演的角色 其中的模型（L型钙），被认为是运动神经元图的主要介体的模​​型是 有选择地禁用（AIM 1）或已启用（AIM 2）。我们将通过记录足底屈肌中的运动单元活动来做到这一点 大鼠的肌肉在存在和不存在胸前注​​射的情况下自愿发挥目标等距力 Nimodipine，L型CA+2通道阻滞剂（AIM 1）和5-羟色胺，是已知的图片启动子（AIM 2）。 将记录在药物条件下记录的电机发射率（和招募）的变化与 在动物持有相同力的同时，在药物输送前记录的相同单位。这些比较会 直接了解图片在塑造自然运动单元活动中所扮演的角色 - 自从 在1970年代后期发现图片。此外，这项研究将增加我们对图片的理解 功能障碍，在神经系统疾病（如痉挛和肌萎缩性侧面硬化症）中实施。