Peripheral Nerve Injury is Accompanied by Chronic Transcriptome-Wide Changes in the Mouse Prefrontal Cortex

Abstract

BackgroundPeripheral 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.ResultsSNI 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).ConclusionsThis 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.

Brain Neuroplastic Changes Accompany Anxiety and Memory Deficits in a Model of Complex Regional Pain Syndrome

“…These data are in agreement with previous findings showing that decreased levels of synaptophysin are accompanied by impairment in cognitive function and memory 84 and vice versa. 85 In contrast, some brain regions (such as the prefrontal cortex) display increased levels of synaptic proteins, 86 including synaptophysin, 87 following chronic painful conditions.…”

“…Epigenetic mechanisms are well suited to modulate the long-lasting CNS changes that accompany chronic pain. 86,99,101 …”

The role of the extracellular matrix in chronic pain following injury

“…40 Alterations in the ECM may modulate pain chronification by changing pain-processing centers in the brain. After chronic pain, brain neuroplasticity (functional, morphologic, and anatomical) is observed both in various preclinical models 2,23,45,46 and in human subjects, 3,42 suggesting the requisite for a more plastic ECM (Fig. 1C, third panel).…”

Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy

“…For pan-neuronal inducible progranulin overexpression, SLICK-H-cre mice were used (Young et al, 2008) (SLICK-Grn-OE mice: supporting information). The PFC is a major site of pain processing (Alvarado et al, 2013;Seifert and Maihofner, 2007) and affected by progranulin deficiency. In total, 7018 proteins were identified excluding contaminants.…”