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.

Public Health Relevance

The proposed research is designed to understand the interaction of the neuronal circuits that control locomotion (walking, swimming) and muscle spasms after spinal cord injury. We use novel transgenic and pharmacological methods to activate selected neurons (V3 neurons) and receptors (NMDA receptors) that promote locomotion and minimize unwanted muscle spasms. Once successfully developed in our animal preparations, these transgenic and pharmacological methods can be adapted to human subjects with spinal cord injury, allowing the possibility of exciting new therapies for recovery o function after spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047567-13
Application #
9412194
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jakeman, Lyn B
Project Start
2004-09-15
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
13
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alberta
Department
Type
DUNS #
208095844
City
Edmonton
State
AB
Country
Canada
Zip Code
T6 2E1
Li, Yaqing; Lucas-Osma, Ana M; Black, Sophie et al. (2017) Pericytes impair capillary blood flow and motor function after chronic spinal cord injury. Nat Med 23:733-741
Fenrich, Keith K; May, Zacincte; Torres-Espín, Abel et al. (2016) Single pellet grasping following cervical spinal cord injury in adult rat using an automated full-time training robot. Behav Brain Res 299:59-71
Thaweerattanasinp, Theeradej; Heckman, Charles J; Tysseling, Vicki M (2016) Firing characteristics of deep dorsal horn neurons after acute spinal transection during administration of agonists for 5-HT1B/1D and NMDA receptors. J Neurophysiol 116:1644-1653
Li, Yaqing; Li, Lisa; Stephens, Marilee J et al. (2014) Synthesis, transport, and metabolism of serotonin formed from exogenously applied 5-HTP after spinal cord injury in rats. J Neurophysiol 111:145-63
D'Amico, Jessica M; Murray, Katherine C; Li, Yaqing et al. (2013) Constitutively active 5-HT2/ýý1 receptors facilitate muscle spasms after human spinal cord injury. J Neurophysiol 109:1473-84
D'Amico, Jessica M; Li, Yaqing; Bennett, David J et al. (2013) Reduction of spinal sensory transmission by facilitation of 5-HT1B/D receptors in noninjured and spinal cord-injured humans. J Neurophysiol 109:1485-93
Manuel, Marin; Li, Yaqing; Elbasiouny, Sherif M et al. (2012) NMDA induces persistent inward and outward currents that cause rhythmic bursting in adult rodent motoneurons. J Neurophysiol 108:2991-8
Murray, Katherine C; Stephens, Marilee J; Ballou, Edmund W et al. (2011) Motoneuron excitability and muscle spasms are regulated by 5-HT2B and 5-HT2C receptor activity. J Neurophysiol 105:731-48
Rank, M M; Murray, K C; Stephens, M J et al. (2011) Adrenergic receptors modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic spinal cord injury. J Neurophysiol 105:410-22
Murray, Katherine C; Stephens, Marilee J; Rank, Michelle et al. (2011) Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors. J Neurophysiol 106:925-43

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