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Brainstem control of transcription after spinal cord injury (SCI)

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, can influence these transcriptional changes. Rats received 2 hours of low-frequency electrical stimulation in the raphé magnus three 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 spinal cord injury. Thus, the initial transcriptional response of 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE133093 | GEO | 2019/11/03

REPOSITORIES: GEO

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Project description:Purpose: The goal of this study was to determine the gene expression changes that occur over 7 days in parralyzed muscle in response to isometric contraction elicited by electrical stimulation initiated 4 months after spinal cord injury and to compare such changes to those observed in a normal muscle subjected to overload. Methods: Electrical stimulation of the soleus and plantaris muscle was stimulated in female rats with complete transection of the spinal cord at the interspace between the 9th and 10th thoracic vertebrae. Stimulation was begun 16 weeks after spinal cord transection and produced near-isometric contraction of soleus, plantaris and tibialis anterior. Muscle was analyzed at 1, 2 and 7 days after starting exercise with electrical stimulation. To provide a baseline reference for gene expression at 16 weeks after spinal cord injury, muscle was also analysed from an additional group of spinal cord transected animals. One additional group of animals with a sham-spinal cord injury was included to provide information about gene expression in neurologically intact animals of similar age. In parallel studies, rats underwent bilateral gastrocnemius ablation to overload soleus and plantaris, or a sham ablation as a control. Muscle was analyzed at 1, 3 and 7 days after gastrocnemius ablation or sham-ablation. Gene expression was determined using Affymetrix Rat Exon microarrays. For each group of animals, microarray analysis was performed for soleus muscle for each of 3 separate animals, using one array per animal. Control sammples for the spinal cord injured groups included a group of animals with a Sham-spinal cord injury, and a group of spinal cord injured animals that did not get electrical stimulation. The comparator for determining fold-change expression values was the spinal cord injured group that did not receive electrical stimulation. For each day after gastrocnemius ablation, a control was included that received all procedures needed for this ablation except cutting the distal insertion of the gastrocnemius into the Achilles tendon to control for effects of the surgery on gene expression.

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Brainstem control of transcription after spinal cord injury (SCI)

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