Selective Corticospinal Tract Injury in the Rat Induces Primary Afferent Fiber Sprouting in the Spinal Cord and Hyperreflexia

Abstract

The corticospinal tract (CST) has dense contralateral and sparse ipsilateral spinal cord projections that converge with proprioceptive afferents on common spinal targets. Previous studies in adult rats indicate that the loss of dense contralateral spinal CST connections after unilateral pyramidal tract section (PTX), which models CST loss after stroke or spinal cord injury, leads to outgrowth from the spared side into the affected, ipsilateral, spinal cord. The reaction of proprioceptive afferents after this CST injury, however, is not known. Knowledge of proprioceptive afferent responses after loss of the CST could inform mechanisms of maladaptive plasticity in spinal sensorimotor circuits after injury. Here we hypothesize that the loss of the contralateral CST results in a reactive increase in muscle afferents from the impaired limb and enhancement of their physiological actions within the cervical spinal cord. We found that ten days after PTX, proprioceptive afferents sprout into cervical gray matter regions denervated by the loss of CST terminations. Further, VGlut1 positive boutons, indicative of group 1A afferent terminals, increased on motoneurons. PTX also produced an increase in microglial density within the gray matter regions where CST terminations were lost. These anatomical changes were paralleled by reduction in frequency-dependent depression of the H-reflex, suggesting hyperreflexia. Our data demonstrate for the first time that selective CST injury induces maladaptive afferent fiber plasticity remote from the lesion. Our findings suggest a novel structural reaction of proprioceptive afferents to the loss of CST terminations and provide insight into mechanisms underlying spasticity.

Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury

“…Undirected plasticity of denervated circuits leads to the development of neuronal dysfunction in the chronic stage of injury Previous investigations in animal models of SCI documented the progressive upregulation of receptor, synapse and fibre density in spinal circuitries deprived of supraspinal input (Krenz and Weaver, 1998;Kitzman, 2006;Boulenguez et al, 2010;Ichiyama et al, 2011;Kapitza et al, 2012;Tan et al, 2012;Bos et al, 2013). In the present study, we also found a multiplicity of plastic changes in spinal segments caudal to a staggered lateral hemisection SCI.…”

“…However, the regained excitability in motor neurons contributed to the development of abnormal reflex responses (Murray et al, 2010). Likewise, the depletion of corticospinal tract associated vGlut1 terminals after a pyramidotomy induced a specific sprouting of vGlut1 proprioceptive afferent fibres, but also in this condition, the synaptic reorganization adversely altered proprioceptive reflex circuits (Tan et al, 2012). Although additional mechanisms such as changes in motor neuron membrane excitability (Lin et al, 2007;Boulenguez et al, 2010) likely contribute to neuronal dysfunction in the chronic stage of SCI, our combined results suggest that undirected compensatory plasticity plays an important role in the emergence of this syndrome.…”

“…Although previous studies reported contrasting and variable conclusions, they consistently highlighted the progressive upregulation of receptor (Murray et al, 2010), synapse (Kitzman, 2006;Ichiyama et al, 2011;Kapitza et al, 2012;Tan et al, 2012), and fibre density (Krenz and Weaver, 1998;Ballermann and Fouad, 2006;Hou et al, 2008Hou et al, , 2009) in response to the interruption of supraspinal input. Likewise, ablation of afferent pathways in the brain provokes the formation of new fibre arborizations and spines in the affected region (Kirov and Harris, 1999).…”

“…Various studies in experimental animals uncovered a mosaic of injury-induced molecular and cellular changes in segments caudal to a SCI (Krenz and Weaver, 1998;Ballermann and Fouad, 2006;Kitzman, 2006Kitzman, , 2007Soares et al, 2007;Hou et al, 2008;Tan et al, 2008;Hou et al, 2009;Boulenguez et al, 2010;Murray et al, 2010;Ichiyama et al, 2011;Singh et al, 2011;Kapitza et al, 2012;Tan et al, 2012). Depending upon the SCI model and specific functional assessments, these alterations in the properties of neuronal circuits have alternatively been classified as beneficial or detrimental.…”

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

“…Additional perspective may be gained by characterizing the intrinsic proteomic mechanisms driving compensatory sprouting of both injured and intact CNS projections following injury (175). This includes corticospinal (176 -178), rubrospinal (179), reticulospinal, and propriospinal axons (180,181). Finally, exploring the identified signaling networks activated within injured CNS neurons that regenerate into permissive cellular grafts discussed below may yield novel insight into the molecular switches that enable growth of an axon previously incapable of regeneration.…”