Abstract
The spinal cord after injury shows altered transcription in numerous genes. We tested in a pilot study whether the nucleus raphé magnus, a descending serotonergic brainstem region whose stimulation improves recovery after incomplete spinal cord injury (SCI), can influence these transcriptional changes. Rats received 2 h of low-frequency electrical stimulation in the raphé magnus 3 days after an impact contusion at segment T8. Comparison groups lacked injuries or activated stimulators or both. Immediately following stimulation, spinal cords were extracted, their RNA transcriptome sequenced, and differential gene expression quantified. Confirming many previous studies, injury primarily increased inflammatory and immune transcripts and decreased those related to lipid and cholesterol synthesis and neuronal signaling. Stimulation plus injury, contrasted with injury alone, caused significant changes in 43 transcripts (39 increases, 4 decreases), all protein-coding. Injury itself decreased only four of these 43 transcripts, all reversed by stimulation, and increased none of them. The non-specific 5-HT7 receptor antagonist pimozide reversed 25 of the 43 changes. Stimulation in intact rats principally caused decreases in transcripts related to oxidative phosphorylation, none of which were altered by stimulation in injury. Gene ontology (biological process) annotations comparing stimulation with either no stimulation or pimozide treatment in injured rats highlighted defense responses to lipopolysaccharides and microorganisms, and also erythrocyte development and oxygen transport (possibly yielding cellular oxidant detoxification). Connectivity maps of human orthologous genes generated in the CLUE database of perturbagen-response transcriptional signatures showed that drug classes whose effects in injured rats most closely resembled stimulation without pimozide include peroxisome proliferator-activated receptor agonists and angiotensin receptor blockers, which are reportedly beneficial in SCI. Thus the initial transcriptional response of the injured spinal cord to raphé magnus stimulation is upregulation of genes that in various ways are mostly protective, some probably located in recently arrived myeloid cells.
Highlights
Mechanical spinal cord injury (SCI) causes numerous molecular, cellular and structural changes that vary in duration and onset, both at the site of injury and beyond (Dulin et al, 2015; O’Shea et al, 2017)
3https://david.ncifcrf.gov/tools.jsp confirmed protein-coding RNAs; further details are given in the Supplementary Figure 1
The differential gene expression (DGE) software applications EdgeR and DESEq2 were of roughly equal leniency, and showed mean overlap of 75% for selected transcripts
Summary
Mechanical SCI causes numerous molecular, cellular and structural changes that vary in duration and onset, both at the site of injury and beyond (Dulin et al, 2015; O’Shea et al, 2017) These include changes in gene transcription that collectively and individually could influence recovery via protein synthesis and downstream molecules. Raphé neurons receive sensory, chemical and central-state signals indicative of recent injury (e.g., pain, vestibular input, hypothermia, circulating cytokines). Their evoked electrical activity causes axonal release of serotonin and co-release of neuropeptide transmitters from terminals that, collectively, innervate almost the entire CNS (Molliver, 1987; Hornung, 2003). As in the response to infection which is frequently concurrent with injury, an endogenous repair system from the perspective of natural selection should promiscuously exploit (facilitate or depress) multiple molecular and cellular mechanisms
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