Long descending cervical propriospinal neurons differ from thoracic propriospinal neurons in response to low thoracic spinal injury

Abstract

BackgroundPropriospinal neurons, with axonal projections intrinsic to the spinal cord, have shown a greater regenerative response than supraspinal neurons after axotomy due to spinal cord injury (SCI). Our previous work focused on the response of axotomized short thoracic propriospinal (TPS) neurons following a low thoracic SCI (T9 spinal transection or moderate spinal contusion injury) in the rat. The present investigation analyzes the intrinsic response of cervical propriospinal neurons having long descending axons which project into the lumbosacral enlargement, long descending propriospinal tract (LDPT) axons. These neurons also were axotomized by T9 spinal injury in the same animals used in our previous study.ResultsUtilizing laser microdissection (LMD), qRT-PCR, and immunohistochemistry, we studied LDPT neurons (located in the C5-C6 spinal segments) between 3-days, and 1-month following a low thoracic (T9) spinal cord injury. We examined the response of 89 genes related to growth factors, cell surface receptors, apoptosis, axonal regeneration, and neuroprotection/cell survival. We found a strong and significant down-regulation of ~25% of the genes analyzed early after injury (3-days post-injury) with a sustained down-regulation in most instances. In the few genes that were up-regulated (Actb, Atf3, Frs2, Hspb1, Nrap, Stat1) post-axotomy, the expression for all but one was down-regulated by 2-weeks post-injury. We also compared the uninjured TPS control neurons to the uninjured LDPT neurons used in this experiment for phenotypic differences between these two subpopulations of propriospinal neurons. We found significant differences in expression in 37 of the 84 genes examined between these two subpopulations of propriospinal neurons with LDPT neurons exhibiting a significantly higher base line expression for all but 3 of these genes compared to TPS neurons.ConclusionsTaken collectively these data indicate a broad overall down-regulation in the genes examined, including genes for neurotrophic/growth factor receptors as well as for several growth factors. There was a lack of a significant regenerative response, with the exception of an up-regulation of Atf3 and early up-regulation of Hspb1 (Hsp27), both involved in cell stress/neuroprotection as well as axonal regeneration. There was no indication of a cell death response over the first month post-injury. In addition, there appear to be significant phenotypic differences between uninjured TPS and LDPT neurons, which may partly account for the differences observed in their post-axotomy responses. The findings in this current study stand in stark contrast to the findings from our previous work on TPS neurons. This suggests that different approaches will be needed to enhance the capacity for each population of propriospinal neuron to survive and undergo successful axonal regeneration after SCI.

Peripheral nerve graft with immunosuppression modifies gene expression in axotomized CNS neurons

“…Further, the upregulation in LVN neurons was more prolonged than in propriospinal neurons. Interestingly, Siebert et al (2010b) show that gene expression in long propriospinal neurons injured in the same experiment showed a more typical downregulation of genes related to regeneration and less cell death, supporting the idea that a critical factor in the regenerative response may be the distance from the injury to the cell body (Fernandes et al, 1999;Mason et al, 2003a;Siebert et al, 2010b).…”

Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons

“…This may suggest a different response to incision in some large-diameter neurons, with one response signified by short-term ATF3 expression without GAP-43, and another by sustained ATF3 and GAP-43 expression. There is precedent for different ATF3 expression patterns in different cells in the same condition (Ohba et al, 2003; Hai et al, 2010; Siebert et al, 2010; Yin et al, 2010). This may be impactful for post-incision sensation because different types of sensory neurons drive different aspects of sensory perception.…”

Schwann cell transplantation and descending propriospinal regeneration after spinal cord injury

“…A bilateral distribution of retrograde-labeled propriospinal neurons within the spinal cord was observed, with a significantly higher occurrence of labeled cells on the ipsilateral side were reported in both PN nerve graft and isolated SCs graft models (Decherchi and Gauthier, 2000; Iannotti et al, 2003). However, due to the fact that intrinsic spinal cord neurons, especially long projecting propriospinal neurons, have various projection patterns including projection distance, laterality, or branching within the graft (Saywell et al, 2011; Siebert et al, 2010; Tuszynski and Steward, 2012; Verburgh and Kuypers, 1987), analysis of the size, distribution, and cytological features failed to yield specific identification of usual destinations of these labeled neurons. In addition to the anatomical differences,Siebert et al (2010) observed phenotypic variation in the post-injury response to axotomy between ldPST neurons and sdPST neurons.…”

“…However, due to the fact that intrinsic spinal cord neurons, especially long projecting propriospinal neurons, have various projection patterns including projection distance, laterality, or branching within the graft (Saywell et al, 2011; Siebert et al, 2010; Tuszynski and Steward, 2012; Verburgh and Kuypers, 1987), analysis of the size, distribution, and cytological features failed to yield specific identification of usual destinations of these labeled neurons. In addition to the anatomical differences,Siebert et al (2010) observed phenotypic variation in the post-injury response to axotomy between ldPST neurons and sdPST neurons. The ldPST neurons lacked both cell death and regenerative responses, and down-regulated many genes important for regrowth.…”

“…The ldPST neurons lacked both cell death and regenerative responses, and down-regulated many genes important for regrowth. Instead of mounting a robust early response exhibited by short thoracic propriospinal neurons, ldPST neurons become relatively dormant or quiescent (Siebert et al, 2010). This study demonstrated that ldPST neurons respond more like supraspinal neurons than sdPST neurons following low thoracic axotomy.…”