Sex-Specific Transcriptomic Signatures in Brain Regions Critical for Neuropathic Pain-Induced Depression

Abstract

Neuropathic pain is a chronic debilitating condition with a high comorbidity with depression. Clinical reports and animal studies have suggested that both the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC) are critically implicated in regulating the affective symptoms of neuropathic pain. Neuropathic pain induces differential long-term structural, functional, and biochemical changes in both regions, which are thought to be regulated by multiple waves of gene transcription. However, the differences in the transcriptomic profiles changed by neuropathic pain between these regions are largely unknown. Furthermore, women are more susceptible to pain and depression than men. The molecular mechanisms underlying this sexual dimorphism remain to be explored. Here, we performed RNA sequencing and analyzed the transcriptomic profiles of the mPFC and ACC of female and male mice at 2 weeks after spared nerve injury (SNI), an early time point when the mice began to show mild depressive symptoms. Our results showed that the SNI-induced transcriptomic changes in female and male mice were largely distinct. Interestingly, the female mice exhibited more robust transcriptomic changes in the ACC than male, whereas the opposite pattern occurred in the mPFC. Cell type enrichment analyses revealed that the differentially expressed genes involved genes enriched in neurons, various types of glia and endothelial cells. We further performed gene set enrichment analysis (GSEA), which revealed significant de-enrichment of myelin sheath development in both female and male mPFC after SNI. In the female ACC, gene sets for synaptic organization were enriched, and gene sets for extracellular matrix were de-enriched after SNI, while such signatures were absent in male ACC. Collectively, these findings revealed region-specific and sexual dimorphism at the transcriptional levels induced by neuropathic pain, and provided novel therapeutic targets for chronic pain and its associated affective disorders.

The basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice

“…Prompted by these consistent transcriptomic, histological and imaging findings, we then asked whether myelin dysregulation might also occur during chronic pain. To address this possibility, we took advantage of recent work by Dai and collaborators in a chronic neuropathic pain model (spared nerve injury), which provided transcriptomic analysis in both the PFC and ACC 47 . For consistency, these data were reprocessed in our differential expression analysis pipeline, and compared to those obtained after optogenetic stimulations (using RRHO2).…”

Environmental enrichment promotes resilience to neuropathic pain-induced depression and correlates with decreased excitability of the anterior cingulate cortex

“…Therefore, EE might restore cellular changes that control excitability, so that the neuronal network function is improved, protecting the brain against deleterious effects of insults, including chronic pain. Indeed, chronic pain leads to changes in transcriptional patterns ( Su et al, 2021 ; Wang et al, 2021 ; Dai et al, 2022 ), together with epigenetic changes ( Mauceri, 2022 ), along the pain neuraxis that could contribute to alterations in excitability and network activity, all of which could be potentially reversed by EE. Overall, EE is a promising approach for restoring neuronal excitability in rodents and may have potential applications for the treatment of neurological disorders in humans ( Kimura et al, 2022 ).…”

“…It has been shown that the development of chronic pain in female mice diverges from that of male through specific mechanisms ( Melchior et al, 2016 ; Mapplebeck et al, 2018 ). Indeed, sexual dimorphism in chronic pain has been observed in transcriptomic profiles in the ACC and in the medial prefrontal cortex ( Dai et al, 2022 ), which may lead to differential susceptibilities and re-configurations by EE. It is therefore imperative to evaluate in future research the mechanisms of EE-promoted resilience to neuropathic pain-induced comorbid symptoms in female mice ( Girbovan and Plamondon, 2013 ).…”

Neuroinflammation in the medial prefrontal cortex exerts a crucial role in bone cancer pain

“…The mPFC is a main cortical area involved in processing both pain and consequent negative emotion ( Salomons et al, 2015 ; Mecca et al, 2021 ), notably, it has been reported that dysfunction of mPFC neurons may be implicated in neuropathic pain-related anxiety ( Du et al, 2022 ). Most, recently, Dai et al (2022) performed a gene set enrichment analysis in the mPFC of neuropathic pain, and they found that there are 49 different expression genes. To further explore the potential targets in the mPFC of BCP, we established a comprehensive transcription sequence.…”

“…In the analysis of neuropathic pain, the most significantly regulated gene sets included oligodendrocyte differentiation, semaphoring plexin signaling pathway, negative regulation of gliogenesis, neuron fate commitment, intrinsic component of external side of plasma membrane, and germ cell nucleus ( Dai et al, 2022 ). While, in our study, different from neuropathic pain, we found that the BP, CC, and MF was related to the MHC complex and antigen process in the mPFC of BCP rats.…”