title: Peripheral nerve injury is accompanied by chronic transcriptome-wide changes in the mouse prefrontal cortex.
abstract: BACKGROUND
  Peripheral nerve injury can have long-term consequences including pain-related manifestations, such as hypersensitivity to cutaneous stimuli, as well as affective and cognitive disturbances, suggesting the involvement of supraspinal mechanisms. Changes in brain structure and cortical function associated with many chronic pain conditions have been reported in the prefrontal cortex (PFC). The PFC is implicated in pain-related co-morbidities such as depression, anxiety and impaired emotional decision-making ability. We recently reported that this region is subject to significant epigenetic reprogramming following peripheral nerve injury, and normalization of pain-related structural, functional and epigenetic abnormalities in the PFC are all associated with effective pain reduction. In this study, we used the Spared Nerve Injury (SNI) model of neuropathic pain to test the hypothesis that peripheral nerve injury triggers persistent long-lasting changes in gene expression in the PFC, which alter functional gene networks, thus providing a possible explanation for chronic pain associated behaviors.
  
  
  RESULTS
  SNI or sham surgery where performed in male CD1 mice at three months of age. Six months after injury, we performed transcriptome-wide sequencing (RNAseq), which revealed 1147 differentially regulated transcripts in the PFC in nerve-injured vs. control mice. Changes in gene expression occurred across a number of functional gene clusters encoding cardinal biological processes as revealed by Ingenuity Pathway Analysis. Significantly altered biological processes included neurological disease, skeletal muscular disorders, behavior, and psychological disorders. Several of the changes detected by RNAseq were validated by RT-QPCR and included transcripts with known roles in chronic pain and/or neuronal plasticity including the NMDA receptor (glutamate receptor, ionotropic, NMDA; grin1), neurite outgrowth (roundabout 3; robo3), gliosis (glial fibrillary acidic protein; gfap), vesicular release (synaptotagmin 2; syt2), and neuronal excitability (voltage-gated sodium channel, type I; scn1a).
  
  
  CONCLUSIONS
  This study used an unbiased approach to document long-term alterations in gene expression in the brain following peripheral nerve injury. We propose that these changes are maintained as a memory of an insult that is temporally and spatially distant from the initial injury.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Faculty of Medicine, 3655 Promenade Sir William Osler, Montréal, Québec H3G 1Y6, Canada.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Alvarado
authors.forename: Maral
authors.initials: M
authors.lastname: Tajerian
authors.forename: Magali
authors.initials: M
authors.lastname: Millecamps
authors.forename: Mathew
authors.initials: M
authors.lastname: Suderman
authors.forename: Laura S
authors.initials: LS
authors.lastname: Stone
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015536:Down-Regulation / Q000235:genetics; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000235:genetics / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D059348:Peripheral Nerve Injuries / Q000235:genetics* / Q000473:pathology*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D012333:RNA, Messenger