Serotonergic Modulation of Spinal Circuits for Flexible Motor Control

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。通过神经元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运动行为中的神经元能系统的作用。直接控制外周肌肉活动的脊髓运动神经元由脑干5-羟色胺神经元密集支配。此外，电生理学研究已经确定，5-羟色胺是运动神经元兴奋性的有效调节剂。然而，在行为背景下，多巴胺能调节在控制运动输出中的作用尚不清楚。我将在小鼠中使用新的遗传和病毒方法来研究遗传定义的多巴胺能回路在运动控制中的功能。在K99的目的中，我将研究运动行为中脊髓运动神经元的多巴胺能输入的功能。首先，我将使用顺行和逆行追踪策略系统地解剖脊髓运动神经元的多巴胺能输入的解剖组织。第二，我将在体内进行电生理学测试是否神经肽脊髓输入调节运动神经元突触输入的增益。最后，我将测试这一假设，即在快速运动过程中增加的多巴胺能神经元的活性是产生剧烈运动所需的增加的肌肉活性。我将进行功能扰动和成像研究，以确定运动神经元的多巴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图（EMG）记录，提供精确的肌肉活动读数，以确定多巴胺能系统如何调节运动输出。在R 00的目标，我建议实验来定义的细胞机制，神经调节剂作用于靶神经元介导的行为效应，以及上下文依赖性调节的神经调节通路。首先，我将剖析在运动行为过程中，代谢型与离子型兴奋性5-羟色胺受体在运动神经元中的作用。第二，我将检验一个假设，即控制运动的大脑区域驱动5-羟色胺-脊髓通路的活动，以促进行为背景下适当的肌肉输出。总之，这些实验和培训经验将为运动控制中遗传定义的神经调节群体的细胞，电路和行为水平调查奠定基础。拟议的研究将提供新的见解，在运动控制中的5-羟色胺的功能，超越了经典的生理和药理学方法以前使用的领域。此外，这项工作旨在激发新的临床方法，用于治疗影响运动产生的脊髓疾病或损伤。

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.