Wednesday, April 2, 2025
4/2/2025
The role of propriospinal neurons in the recovery of posture after spinal cord injury - Project Summary Neurons that control rhythmic movements like walking reside within the spinal cord in the central pattern generator (CPG), and thus understanding this CPG has been a major focus of rehabilitation efforts after spinal cord injury (SCI). However, the prerequisites for walking are steady postural tone and ability to stand, which are permanently lost following spinal cord injury. While standing to reach or make wheelchair transfers is arguably a more important function to restore than walking after SCI, little is known about the spinal circuits that control posture. However, in the course of our recent survey of neurons that generate muscle spasms in mice, we unexpectedly found that excitatory propriospinal commissural neurons (PSC neurons) that express the Sim1 transcription factor (V3 neurons) produce robust standing when they are optogenetically, including in mice that are otherwise paralysed after SCI. PSC neurons may be ideally suited to maintaining posture, as they directly innervate extensor motoneurons throughout the limb and axial muscles, and are innervated extensively by sensory and supraspinal inputs, seemingly bypassing the CPG, though we know little about their control. Since PSC neurons (including V3) have unique anatomical and functional connections and properties, they can be readily identified in mice and cats, and so we will start by recording the firing properties of these neurons prior to injury in the decerebrate unanesthetized animals that spontaneously exhibit a standing posture. We will test the hypothesis that prior to SCI, PSC neurons are driven tonically by supraspinal inputs to maintain posture and phasically by sensory feedback to correct for disturbances, but this supraspinal drive is lost with acute SCI. We also hypothesize that after chronic SCI increased excitability in these neurons helps restore some phasic sensory-evoked postural tone that may be promoted by stimulating nerves that innervate PSC neurons or by direct optogenetic V3 activation. This will be examined both in awake mice with optogenetic activation or inhibition of V3 neurons where we will record limb kinematics and EMG, and in the isolated whole adult in vitro spinal cord where we will making direct intracellular recordings from V3 neurons and the motoneurons they innervate. Finally, we will examine whether the postural standing that can be obtained by sensory evoked V3 neuron activation can be used as a basis for training mice to walk after SCI, and explore whether the action of treatments like epidural spinal cord stimulation function by activating PSC neurons. Overall, these experiments will shed light on how spinal postural motor circuits are controlled by propriospinal neurons, and how these neurons can be harnessed to develop new treatments for SCI.
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