The Effects of Neuronal Stimulation on Sympathetic Regeneration after Peripheral Nerve Injury
Tina Tian, BS1,2,3 and Patricia J. Ward, PhD1,3, 1Emory University School of Medicine, Department of Cell Biology, Atlanta, GA, 2Emory University School of Medicine, Medical Scientist Training Program, Atlanta, GA, 3Emory University Laney Graduate School, Neuroscience Graduate Program, Atlanta, GA
Introduction: Peripheral nerve injuries are common and result in motor, sensory, and autonomic functional deficits that can lead to lifelong disabilities. After surgical reconstruction, spontaneous regeneration is slow and inadequate, and developing adjunctive therapeutic options is critical for functional recovery. The effects of neuronal stimulation-based interventions that complement surgical repair on the regeneration of sympathetic neurons, however, has rarely been studied.
Materials & Methods: Thy-1-YFP-16 mice received a unilateral transection of the sciatic nerve with subsequent repair with fibrin glue alongside concurrent saphenous nerve ligation. The sciatic nerves received either 1 hour of electrical stimulation (ES) or a crush conditioning lesion 1 week prior to the transection. Two weeks post-injury, the sciatic nerves were harvested and immunostained for tyrosine hydroxylase to visualize sympathetic axons.
Transgenic mice were developed to specifically stimulate sympathetic neurons via bioluminescent optogenetics. Mice received bilateral sciatic nerve transection injuries followed by intraperitoneal injection of coelenterazine (CTZ). Two weeks later, sympathetic regeneration was assessed via immunohistochemistry and retrograde tracing via sciatic nerve soak. Additionally, the postganglionic lumbar sympathetic neurons of these mice were cultured in the presence of CTZ, and Sholl analysis was performed on the cultured neurons that were allowed to grow for 3 days.
Results: ES and the conditioning lesion resulted in improved motor and sensory axon regeneration with no improvement in sympathetic axon regeneration compared to no treatment. Selective sympathetic activation in vivo and in vitro also yields no enhancement of sympathetic axon elongation via immunohistochemistry but results in a decrease in the number of sympathetic neurons that have grown 5 mm from the injury site.
Conclusions: These data indicate that neuronal stimulation enhances motor and sensory axons but may be detrimental to sympathetic axon growth. Further understanding of the mechanistic processes underlying different neuronal subtypes after injury will be necessary to develop therapeutic options that will enhance the regeneration of all neurons.
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