Wednesday, January 15, 2025
1/15/2025
DESCRIPTION (provided by applicant): A primary goal for recovery following spinal cord injury (SCI) is restoration of locomotor capacity (e.g. walking). This is feasible because the core neuronal circuitry for locomotion resides within the spinal cord, and usually remains intact with spinal cord injury. However, a major problem for restoration of locomotion is that sensory input to the spinal cord often induces muscle spasms that can interfere with locomotion. On the other hand, intense locomotor training has been reported to inhibit spasms. We suggest that these opposing actions of locomotion and spasms arise from separate mutually inhibitory neuronal mechanisms in the spinal cord, including separate networks of interneurons and separate ionic currents in motoneurons. Thus, these differing mechanisms can be selectively targeted to promote locomotion and at the same time reduce spasms. Aim 1: In our previous studies, we showed that L-type calcium channels on motoneurons produce large persistent inward currents (Ca PICs) that are fundamental for generating long-lasting spasms after SCI. We have also demonstrated that NMDA receptors on motoneurons induce equally large persistent inward currents (NMDA PICs), but these are followed by large persistent outward currents (NMDA POCs), which terminate all PICs. These NMDA currents potentially contribute to controlling the amplitude and duration of rhythmic locomotor activity. Thus, in this proposal we examine the hypothesis that after SCI activation of NMDA receptors on motoneurons during rhythmic locomotor activity amplifies motor output (via NMDA PICs) and at the same time terminates Ca PIC driven spasms (via NMDA POCs). Aim 2: Our preliminary studies suggest that after SCI interneurons in the deep dorsal horn generate a burst of firing following sensory stimulation, which could trigger PICs in motoneurons and spasms. We hypothesize that: bursting interneurons in the deep dorsal horn are strongly involved in triggering of spasms, but at the same time inhibit locomotor activity. Aim 3: If the interneurons involved in locomotion and spasm are mutually inhibitory, then increasing the activation of locomotor interneurons should decrease spasms. To test this idea we examine the V3 interneurons known to be involved in locomotion in normal mice, and hypothesize that after SCI the V3 interneurons promote locomotion and inhibit spasms, transforming tonic spastic activity to coordinated locomotor drive. We employ optogenetic activation of V3 neurons after SCI. The novel concept that the interneurons that generate locomotion are different and mutually inhibitory to the interneurons that generate spasms opens up promising new avenues to treating spasms and promoting locomotion after SCI, especially when combined with potential therapeutic viral/genetic manipulation of these interneurons. From a general point of view, the tonic spasm generating interneurons and ionic currents (Ca PICs) are likely related to normal postural activity, and thus our studies shed light on the general interplay of neuronal circuits that differentially control posture and locomotion.
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