Noradrenergic Components of Locomotor Recovery Induced by Intraspinal Grafting of the Embryonic Brainstem in Adult Paraplegic Rats

Abstract

Intraspinal grafting of serotonergic (5-HT) neurons was shown to restore plantar stepping in paraplegic rats. Here we asked whether neurons of other phenotypes contribute to the recovery. The experiments were performed on adult rats after spinal cord total transection. Grafts were injected into the sub-lesional spinal cord. Two months later, locomotor performance was tested with electromyographic recordings from hindlimb muscles. The role of noradrenergic (NA) innervation was investigated during locomotor performance of spinal grafted and non-grafted rats using intraperitoneal application of α2 adrenergic receptor agonist (clonidine) or antagonist (yohimbine). Morphological analysis of the host spinal cords demonstrated the presence of tyrosine hydroxylase positive (NA) neurons in addition to 5-HT neurons. 5-HT fibers innervated caudal spinal cord areas in the dorsal and ventral horns, central canal, and intermediolateral zone, while the NA fiber distribution was limited to the central canal and intermediolateral zone. 5-HT and NA neurons were surrounded by each other’s axons. Locomotor abilities of the spinal grafted rats, but not in control spinal rats, were facilitated by yohimbine and suppressed by clonidine. Thus, noradrenergic innervation, in addition to 5-HT innervation, plays a potent role in hindlimb movement enhanced by intraspinal grafting of brainstem embryonic tissue in paraplegic rats.

Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus

“…Human patients with GPT2 Deficiency display cognitive as well as motor abnormalities including spastic paraplegia ( Ouyang et al, 2016 ). LC projects to virtually the entire central nervous system and descending noradrenergic tracts have been shown to influence motor function ( Amaral and Sinnamon, 1977 ; Foote et al, 1983 ; Harro et al, 2008 ; Kwasniewska et al, 2020 ; Loughlin et al, 1986 ; Rekling et al, 2000 ). LC neurons that project to the cortex are spread out along the dorsal-ventral axis of LC and those that project to the hippocampus remain dorsally whereas the spinal cord-projecting LC neurons reside at the ventral most region of LC ( Loughlin et al, 1986 ; Mason and Fibiger, 1979 ; O’Donnell et al, 2012 ; Schwarz and Luo, 2015 ).…”

Role of Descending Serotonergic Fibers in the Development of Pathophysiology after Spinal Cord Injury (SCI): Contribution to Chronic Pain, Spasticity, and Autonomic Dysreflexia

“…Superficial dorsal horn and deeper laminae, and lamina X [17]; motoneurons [356] Antinociception [17,362,363]; inhibits sympathetic outflow [17] Locomotor recovery [364]; mediates bowel dysfunction [365]; reflex/muscle spasticity [366,367]; neurological recovery [368] α 2B Dorsal horn [17] α 2C Dorsal horn and DRG [17]; motoneurons [356] β β 1…”

Perspectives in the Cell-Based Therapies of Various Aspects of the Spinal Cord Injury-Associated Pathologies: Lessons from the Animal Models

“…Many reports contribute to building the growing body of evidence that both noradrenergic [ 19 , 177 , 178 ] and serotonergic [ 18 , 20 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 ] innervation play an important role in the control of locomotion. Noradrenergic and serotonergic neurons that send projections to the spinal cord are located in locus coeruleus and locus subcoeruleus (noradrenergic neurons) [ 188 , 189 ] and three nuclei of the brain stem: n. raphe pallidus , n. raphe obscurus , n. raphe magnus [ 190 ], and the parapyramidal region (serotonergic neurons).…”

“…The beneficial effects were abolished by application of antagonists for both 5-HT 2 [ 186 , 195 ] and 5-HT 7 [ 186 ] serotonin receptors, suggesting that those receptors play a pivotal role in the modulation of spinal cord networks and restoration of the locomotor ability after SCI. We also demonstrated the role of noradrenergic neurons present in the intraspinally grafted embryonic brainstem tissue for the recovery of locomotor hindlimb function of paraplegic rats [ 181 ]. Recently, we expanded serotonergic precursors derived from embryonic brain stem in a neurosphere assay in vitro and transplanted them into the rat spinal cord one segment below total transection.…”