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.

摘要 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 频率编码的信息传递到肌肉纤维引起收缩。人们通常认为， 运动神经元以与所接收的兴奋性突触输入成比例的速率产生尖峰。现在 然而，认识到运动神经元有活跃的过程，如持续性内向电流（PIC）， 这可能会显著改变突触输入和放电率输出之间的关系。太平洋岛屿国家代表了 神经调节剂介导的膜去极化的内在来源，甚至可以导致自我维持 运动神经元的放电，即，在缺乏突触输入的情况下延长尖峰。有几个想法 关于PIC的功能意义，无论是在正常运动功能的控制方面， 一种导致各种神经紊乱的受损过程。事实上，一些研究人员 表明PIC在所有形式的运动过程中为运动神经元提供去极化电流的主要来源。 然而，其他人推测PIC只在高压力和唤醒期间活跃。然而 PIC对天然运动神经元活动的贡献程度尚不清楚。因此，这一目标 一个项目是利用动物直接确定PICs在随意肌肉收缩过程中所起的作用 模型，其中被认为是运动神经元PIC的主要介质的离子通道（L-型钙）是 选择性禁用（目标1）或启用（目标2）。我们将通过记录足底屈肌的运动单位活动来做到这一点 在存在和不存在鞘内注射的情况下自发地施加目标等长力的大鼠肌肉 尼莫地平，一种L-型Ca+2通道阻滞剂（Aim 1），和5-羟色胺，一种已知的PIC促进剂（Aim 2）。 在药物条件下记录的运动单位放电率（和募集）的变化将与 给药前记录的单位相同，同时动物保持相同的力。这些比较将 提供直接了解PIC在塑造自然运动单位活动中所起的作用-这是一个争论的话题，因为 太平洋岛屿国家的发现此外，本研究将增加我们对PIC的理解 功能障碍，涉及神经系统疾病，如痉挛和肌萎缩侧索硬化。