NIH/NINDS R01 NS130799; 09/30/2022 - 07/31/2027
PIs: Dougherty KJ, Rybak IA

Locomotion is a fundamental behavior that allows humans and animals to move through their environments and is critically involved in all aspects of life. This behavior is impeded in a number of diseases, disorders, and injuries, including spinal cord injury, stroke, and various ataxias. All of the essential circuity to generate locomotor rhythm and pattern is located in the thoracolumbar spinal cord, most often below the level of neural damage. These circuits can be accessed directly via various central and peripheral stimulation methods, including but not limited to epidural stimulation. Rhythm generating circuits are the entry point for initiation and control of locomotion, affect all downstream neurons related to locomotion, and, therefore, are the first step in establishing spinal control of locomotion.

Successful activation of the rhythm generator clinically has been hampered because the mechanisms by which spinal neuronal circuits generate coordinated rhythmic output remain poorly understood and represents a major gap in our understanding of neural control of movement. The generation of rhythmic motor behaviors is based on a triad involving: (1) specific “rhythmogenic” properties allowing individual neurons to generate rhythmic oscillations, (2) mutual excitatory interactions to synchronize neuronal activity into rhythmic populational bursting, and (3) network inhibition to coordinate activity between different neuronal populations, which can both shape locomotor pattern and control frequency. Triad components are highly interconnected and the involvement of each component is condition-dependent.

The proposed study will use highly integrated electrophysiological, pharmacological, genetic, and computational approaches to systematically explore the specific contributions of these mechanisms and the interactions between them, in the generation and patterning of the locomotor rhythm. Utilizing spinal neurons identified in transgenic mice by the transcription factor Shox2 as a representative rhythm generating population, we will test the overarching hypothesis that rhythm generating mechanisms in the spinal cord involve interplay between the triad of cellular, population, and network properties, whose contribution to rhythmogenesis is interdependent, leading to flexibility and adaptability seen as alterations in the relative balance of the triad in different conditions. We will first determine the voltage-gated currents underlying spontaneous cellular oscillations in adult Shox2 neurons. We will then assess excitatory interactions between rhythm generating neurons. Lastly, we will establish the role of ipsilateral and contralateral network interactions in regulating locomotor frequency and determine the operation of these pathways during afferent-evoked locomotion.

Together, our multidisciplinary study will reveal mechanisms of rhythm generation, establish the first mammalian locomotor neural network model based on “real” rhythm generating cellular and network properties, and determine the ways by which afferent stimulation may influence the locomotor rhythm and pattern generated in the spinal cord. The results of these studies will identify specific neural targets for the future devices and strategies aimed at restoration of locomotion following injury or motor disorders.