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.

神经调节对于响应不断变化的环境需求而产生适应性行为至关重要。血清素能系统的调节对于控制运动的根源至关重要。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。直接控制周围肌肉活性的脊柱运动神经元被脑干5-羟色胺神经元密集地支配。此外，电生理研究已经确定5-羟色胺是运动神经元兴奋性的有效调节剂。但是，尚不清楚血清素能调节在控制运动输出中的作用。我将在小鼠中使用新型的遗传和病毒方法研究运动控制中遗传定义的血清素能电路的功能。在K99的目标中，我将检查运动行为期间脊柱运动神经元的血清素能输入的功能。首先，我将使用同步和逆行跟踪策略系统地剖析脊柱运动神经元的血清素能输入的解剖组织。其次，我将执行体内电生理学，以测试5-羟色胺脊柱输入是否调节突触输入对运动神经元的增益。最后，我将测试以下假设：在快速运动过程中，血清素能神经元的活性增加以产生增加的肌肉活性以增加剧烈运动。我将执行功能性扰动和成像研究，以确定5-羟色胺能对运动神经元的输入如何影响肌肉输出和运动行为。在这些实验期间，我将使用肢体肌肉的慢性肌电图（EMG）录音，从而提供精确的读数肌肉活动，以确定血清素能系统如何调节运动输出。在R00的目的中，我提出了实验来定义神经调节剂对靶神经元作用以介导行为效应的细胞机制，以及对神经调节途径的上下文依赖性调节。首先，我将在运动神经元中剖析运动神经元中代谢性兴奋性5-羟色胺受体的作用。其次，我将检验以下假设：控制5-羟色胺 - 脊柱途径的运动驱动活性以促进行为环境中适当的肌肉输出。这些实验和培训经验共同为运动控制中遗传定义的神经调节群体的细胞，电路和行为水平研究的职业奠定了基础。拟议的研究将为5-羟色胺在运动控制中的功能提供新的见解，除了该领域先前使用的经典生理和药理方法之外。此外，这项工作旨在激发治疗疾病或影响运动产生的脊髓损伤的新临床方法。