Zhang, Mengliang

Lateral spinal cord injury including lateral hemisection (LHS) leads to asymmetric postural and motor deficits. After traumatic brain injury, asymmetric postural deficits are partly developed through activation of opioid receptors. We here characterized the effects of LHS on hindlimb postural asymmetry (HL-PA), a proxy for neurological impairments, and assessed the involvement of opioid system. In acute experiments on rats, high lumbar LHS induced HL-PA, characterized by ipsilateral hindlimb flexion. This asymmetry persisted after complete spinal cord transection at the hemisection level. Treatment with naloxone, a general opioid antagonist, abolished HL-PA both before and after transection, suggesting that the LHS effects are mediated through opioid receptors and that neuroplasticity of lumbar opioid circuits underlies the persistent asymmetry. Surprisingly, cervical LHS performed after complete lumbar spinal cord transection also led to HL-PA. However, the hindlimb was flexed on the contralateral side, and the effect was resistant to naloxone treatment. This asymmetry may be caused by endocrine factors, which convey side-specific messages through the humoral pathway after their release from supraspinal structures. Thus, after lateral spinal cord injury, the asymmetric postural deficits may be driven by an interplay between opposing lumbar opioid and neuroendocrine non-opioid mechanisms.

Abstract A neurological dogma is that the contralateral effects of brain injury are set through crossed descending neural tracts. We have recently identified a novel topographic neuroendocrine system (T-NES) that operates via a humoral pathway and mediates the left-right side-specific effects of unilateral brain lesions. In rats with completely transected thoracic spinal cords, unilateral injury to the sensorimotor cortex produced contralateral hindlimb flexion, a proxy for neurological deficit. Here, we investigated in acute experiments whether T-NES consists of left and right counterparts and whether they differ in neural and molecular mechanisms. We demonstrated that left- and right-sided hormonal signaling is differentially blocked by the δ-, κ- and µ-opioid antagonists. Left and right neurohormonal signaling differed in targeting the afferent spinal mechanisms. Bilateral deafferentation of the lumbar spinal cord abolished the hormone-mediated effects of the left-brain injury but not the right-sided lesion. The sympathetic nervous system was ruled out as a brain-to-spinal cord-signaling pathway since hindlimb responses were induced in rats with cervical spinal cord transections that were rostral to the preganglionic sympathetic neurons. Analysis of gene–gene co-expression patterns identified the left- and right-side-specific gene co-expression networks that were coordinated via the humoral pathway across the hypothalamus and lumbar spinal cord. The coordination was ipsilateral and disrupted by brain injury. These findings suggest that T-NES is bipartite and that its left and right counterparts contribute to contralateral neurological deficits through distinct neural mechanisms, and may enable ipsilateral regulation of molecular and neural processes across distant neural areas along the neuraxis.