Serotonergic Modulation of Spinal Circuits for Flexible Motor Control

用于灵活运动控制的脊髓回路的血清素调节

• 批准号: 10188666
• 负责人: Sara J. Fenstermacher
• 金额: $ 10.8万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188666
• 关键词: Adaptive Behaviors; Address; Affect; Anatomy; Anxiety; Behavior; Behavioral; Brain; Brain Stem; Brain region; Cell Nucleus; Cells; Chronic; Clinical; Critical Pathways; Data; Disease; Electromyography; Electrophysiology (science); Fiber; Functional Imaging; Generations; Genetic; Goals; Hindlimb; Injury; Investigation; Lateral; Limb structure; Locomotion; Maps; Mediating; Moods; Motor; Motor Activity; Motor Neurons; Motor output; Movement; Mus; Muscle; Neuraxis; Neuromodulator; Neurons; Neurotransmitters; Output; Pathway interactions; Pattern; Peripheral; Pharmacology; Phase; Physiological; Plant Roots; Play; Population; Production; Recovery of Function; Regulation; Role; Serotonergic System; Serotonin; Source; Speed; Spinal; Spinal Cord; Spinal Cord Diseases; Spinal cord injury; Synapses; System; Testing; Therapeutic; Training; Viral; Work; career; cell type; environmental change; experience; experimental study; flexibility; genetic manipulation; imaging study; improved; in vivo; insight; motor behavior; motor control; neuroregulation; novel; optogenetics; rabies viral tracing; raphe nuclei; receptor; receptor expression; recruit; response; serotonin receptor; spinal pathway

Neuromodulation is essential for producing adaptive behaviors in response to changing environmental demands. Modulation by the serotonergic system is important for the control of movement, the root of all behavior. The overall goal of this project is to elucidate the role of the serotonergic system in motor behavior. Spinal motor neurons, which directly control peripheral muscle activity, are densely innervated by brainstem serotonin neurons. Furthermore, electrophysiological studies have established that serotonin is a potent regulator of motor neuron excitability. However, the role of serotonergic modulation in controlling motor output within a behavioral context is unclear. I will use novel genetic and viral approaches in mice to investigate the function of genetically defined serotonergic circuits in motor control. In the K99 Aims, I will examine the function of serotonergic input to spinal motor neurons during locomotor behavior. First, I will systematically dissect the anatomical organization of serotonergic inputs to spinal motor neurons using anterograde and retrograde tracing strategies. Second, I will perform in vivo electrophysiology to test whether serotonin-spinal inputs regulate the gain of synaptic input to motor neurons. Finally, I will test the hypothesis that increased activity of serotonergic neurons during fast locomotion is required for producing the increased muscle activity for vigorous movement. I will perform functional perturbation and imaging studies to determine how serotonergic input to motor neurons affect muscle output and locomotor behavior. I will use chronic electromyography (EMG) recordings from limb muscles during these experiments providing precise readout muscle activity to determine how the serotonergic system adjusts motor output. In the R00 aims, I propose experiments to define the cellular mechanisms by which neuromodulators act upon target neurons to mediate behavioral effects, as well as the context-dependent regulation of neuromodulatory pathways. First, I will dissect the role of metabotropic vs. ionotropic excitatory serotonin receptors in motor neurons during motor behavior. Second, I will test the hypothesis that brain regions controlling locomotion drive activity of serotonin- spinal pathways to facilitate appropriate muscle output for the behavioral context. Together, these experiments and training experience will set the stage for a career in cellular, circuit and behavioral level investigation of genetically-defined neuromodulatory populations in motor control. The proposed studies will provide new insight to the function of serotonin in motor control, beyond the classic physiological and pharmacological approaches used previously by the field. Furthermore, this work aims to inspire new clinical approaches for treatment of disorders or injury of the spinal cord that influence production of movement.

神经调节对于产生适应性行为以响应不断变化的环境需求至关重要。血清素能系统的调节对于控制运动很重要，运动是所有行为的根源。该项目的总体目标是阐明血清素能系统在运动行为中的作用。直接控制外周肌肉活动的脊髓运动神经元受到脑干血清素神经元的密集支配。此外，电生理学研究已经证实，血清素是运动神经元兴奋性的有效调节剂。然而，血清素调节在行为背景下控制运动输出中的作用尚不清楚。我将在小鼠中使用新颖的遗传和病毒方法来研究基因定义的血清素回路在运动控制中的功能。在 K99 目标中，我将检查运动行为期间脊髓运动神经元的血清素输入的功能。首先，我将使用顺行和逆行追踪策略系统地剖析脊髓运动神经元的血清素输入的解剖结构。其次，我将进行体内电生理学来测试血清素脊髓输入是否调节运动神经元突触输入的增益。最后，我将检验以下假设：快速运动期间血清素能神经元的活动增加是产生剧烈运动所需的肌肉活动增加所必需的。我将进行功能扰动和成像研究，以确定运动神经元的血清素输入如何影响肌肉输出和运动行为。在这些实验中，我将使用肢体肌肉的慢性肌电图 (EMG) 记录，提供精确的肌肉活动读数，以确定血清素能系统如何调整运动输出。在 R00 目标中，我提出实验来定义神经调节剂作用于目标神经元以介导行为效应的细胞机制，以及神经调节途径的上下文依赖性调节。首先，我将剖析运动行为过程中运动神经元中代谢型与离子型兴奋性血清素受体的作用。其次，我将检验以下假设：控制运动的大脑区域驱动血清素-脊髓通路的活动，以促进针对行为环境的适当肌肉输出。总之，这些实验和培训经验将为运动控制中基因定义的神经调节群体的细胞、回路和行为水平研究奠定基础。拟议的研究将为血清素在运动控制中的功能提供新的见解，超越该领域之前使用的经典生理和药理学方法。此外，这项工作旨在激发新的临床方法来治疗影响运动产生的脊髓疾病或损伤。