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  • Chemogenetic Stimulation of the Lumbar Locomotor Network Enhances Motor Function Following Experimental Cervical Spinal Cord Injury: Translational Relevance for a Novel Therapeutic Strategy

    Final Number:
    179

    Authors:
    Spyridon K Karadimas MD PhD; Kajana Satkunendrarajah; Michael G. Fehlings MD PhD FRCS(C) FACS

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2016 Annual Meeting

    Introduction: Cervical spinal cord injury (SCI), the most common type of SCI, results in substantial motor impairment. No effective treatment options currently exist to restore motor function. The neural network responsible for locomotion resides within the lumbar region of the spinal cord. Interestingly, we discovered for first time significant neural degeneration of the lumbar locomotor network during the chronic phase of cSCI. Here, we hypothesized that early chemogenetic stimulation of the lumbar glutamatergic cells may prevent degeneration of the locomotor central pattern generator and the associated motor decline after cSCI.

    Methods: Using intersectional technology we specifically expressed hM3Dq within the lumbar glutamatergic cells of mice. Following cSCI induction we administered clozapine N-oxide (CNO) intraperitonealy to activate hM3Dq. hM3Dq activation leads to depolarization, and enhanced neuronal excitability resulting in burst-like firing. Control mice with hM3Dq expression received saline. The effectiveness of stimulation was assessed using detailed gait and kinematic analysis and anatomical examination.

    Results: At 12 weeks post cSCI, mice that underwent chemogenetic stimulation of the lumbar glutamatergic neurons demonstrated higher locomotor ability compared to controls. Specifically, chemogenetic stimulation attenuated the loss of speed, cadence and stride length during overground locomotion compared to controls. Moreover, abatement of locomotor deficits was associated with preservation of interneurons and motoneurons within the lumbar locomotor neural network compared to controls. Thus, indicating the effectiveness of stimulation therapy in preventing the degeneration of the distal locomotor network after sSCI.

    Conclusions: Early artificial replacement of the supraspinal input on lumbar glutamatergic preserves the anatomical and functional integrity of the locomotor neural network and attenuated the extent of locomotor dysfunction. Our novel and exciting work suggests that chemogenetic modulation of the lumbar locomotor network can prevent the loss of motor function following cSCI.

    Patient Care: Spinal cord injury (SCI) results in devastating motor, sensory and autonomic impairment below the injury site for which there are limited treatment options. This results in significant physical, emotional, and financial burdens. Optimism regarding spinal cord injury treatment stems from this study shedding light on the status of locomotor neural networks known as central pattern generators (CPGs) that exist in the lumbar spinal cord..Barring injury of the spinal cord directly to the segments housing the locomotor CPG, it is presumed that this neural network remains intact after rostral injury. Thus, many approaches for restoring motor function below the injury site have focused on either coaxing axons across the lesion to their synaptic partners, or directly activating these neurons using electrical stimulation. Here, for the first time we show that the locomotor CPG does not remain intact after traumatic SCI but undergoes specific degeneration. Perhaps it is not surprising that we have had very modest success in repairing the injured spinal cord. Here in this session we will not only provide an accurate depiction of the locomotor network following injury, but also provide a means of minimizing this injury induced degeneration of distal locomotor network. Further, findings of this study can incite us to decipher alternate ways of preserving the locomotor neural network residing in the lumbar spinal cord after injury to the cervical or thoracic regions.

    Learning Objectives: Here we describe the importance of providing artificial and selective input to the electrically deprived neurons knowing that the distal locomotor network after cervical SCI is damaged. We will inform the field for a novel effective treatment for acute and traumatic cervical spinal cord injury

    References:

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