Serotonergic Modulation of Spinal Circuits for Flexible Motor Control

神经调节对于产生适应不断变化的环境需求的行为至关重要。5-羟色胺能系统的调节对于运动的控制是重要的，运动是所有行为的根源。这个项目的总体目标是阐明5-羟色胺能系统在运动行为中的作用。脊髓运动神经元直接控制外周肌肉活动，由脑干5-羟色胺神经元密集支配。此外，电生理学研究已经证实，5-羟色胺是运动神经元兴奋性的有力调节器。然而，5-羟色胺能调节在行为背景下控制运动输出的作用尚不清楚。我将在老鼠身上使用新的遗传和病毒方法来研究遗传定义的5-羟色胺能回路在运动控制中的功能。在K99 AIMS中，我将研究5-羟色胺能输入脊髓运动神经元在运动行为中的功能。首先，我将使用顺行和逆行追踪策略，系统地剖析5-羟色胺能神经传入脊髓运动神经元的解剖结构。其次，我将在体内进行电生理学，以测试5-羟色胺-脊髓输入是否调节运动神经元突触输入的获得。最后，我将验证这一假设，即快速运动期间5-羟色胺能神经元的活性增加是产生剧烈运动所需的肌肉活动增加的必要条件。我将进行功能扰动和成像研究，以确定运动神经元的5-羟色胺能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(EMG)记录，提供准确的肌肉活动读数，以确定5-羟色胺能系统如何调节运动输出。在R00目标中，我提议通过实验来定义神经调节剂作用于目标神经元以调节行为效应的细胞机制，以及神经调节通路的上下文相关调节。首先，我将剖析运动神经元中代谢型和离子型兴奋性5-羟色胺受体在运动行为中的作用。其次，我将测试一个假设，即控制运动的大脑区域驱动5-羟色胺-脊髓通路的活动，以促进适当的肌肉输出，以适应行为背景。总而言之，这些实验和培训经验将为在运动控制中对遗传定义的神经调节群体进行细胞、电路和行为水平的研究奠定基础。这些拟议的研究将为5-羟色胺在运动控制中的功能提供新的见解，而不是该领域以前使用的经典生理学和药理学方法。此外，这项工作旨在启发治疗影响运动产生的脊髓紊乱或损伤的新的临床方法。

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.