scholarly journals Spared Nerve Injury Causes Sexually Dimorphic Mechanical Allodynia and Differential Gene Expression in Spinal Cords and Dorsal Root Ganglia in Rats

2021 ◽  
Author(s):  
F.H.G. Ahlström ◽  
K. Mätlik ◽  
H. Viisanen ◽  
K.J. Blomqvist ◽  
X. Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Nerve Injury ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Female Rats ◽  
Sexually Dimorphic ◽  
Spared Nerve Injury ◽  
Rna Seq

AbstractNeuropathic pain is more prevalent in women. However, females are under-represented in animal experiments, and the mechanisms of sex differences remain inadequately understood. We used the spared nerve injury (SNI) model in rats to characterize sex differences in pain behaviour, unbiased RNA-Seq and proteomics to study the mechanisms. Male and female rats were subjected to SNI- and sham-surgery. Mechanical and cold allodynia were assessed. Ipsilateral lumbar dorsal root ganglia (DRG) and spinal cord (SC) segments were collected for RNA-seq analysis with DESeq2 on Day 7. Cerebrospinal fluid (CSF) samples for proteomic analysis and DRGs and SCs for analysis of IB-4 and CGRP, and IBA1 and GFAP, respectively, were collected on Day 21. Females developed stronger mechanical allodynia. There were no differences between the sexes in CGRP and IB-4 in the DRG or glial cell markers in the SC. No CSF protein showed change following SNI. DRG and SC showed abundant changes in gene expression. Sexually dimorphic responses were found in genes related to T-cells (cd28, ctla4, cd274, cd4, prf1), other immunological responses (dpp4, c5a, cxcr2 and il1b), neuronal transmission (hrh3, thbs4, chrna4 and pdyn), plasticity (atf3, c1qc and reg3b), and others (bhlhe22, mcpt1l, trpv6). We observed significantly stronger mechanical allodynia in females and numerous sexually dimorphic changes in gene expression following SNI in rats. Several genes have previously been linked to NP, while some are novel. Our results suggest gene targets for further studies in the development of new, possibly sex-specific, therapies for NP.

scholarly journals Spared nerve injury causes sexually dimorphic mechanical allodynia and differential gene expression in spinal cords and dorsal root ganglia in rats

2020 ◽  
Author(s):  
Fredrik H.G. Ahlström ◽  
Kert Mätlik ◽  
Hanna Viisanen ◽  
Kim B. Blomkvist ◽  
Xiaonan Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Nerve Injury ◽  
Differential Gene Expression ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Sexually Dimorphic ◽  
Spared Nerve Injury ◽  
Cell Counts ◽  
Differential Gene

Abstract BACKGROUND Neuropathic pain (NP) is more prevalent in women. However, females are under-represented in animal experiments, and the mechanisms of sex differences remain inadequately understood. Using the spared nerve injury (SNI) model in rats, we characterized sex differences in behaviour, analysed dorsal root ganglion (DRG) and spinal cord (SC) tissues with transcriptomics and immunohistochemistry assays, and examined the proteome of cerebrospinal fluid (CSF). METHODS The study comprised two experiments, with male and female Sprague-Dawley rats subjected to SNI- and sham-surgeries. Mechanical and cold allodynias were assessed using von Frey filaments and the acetone test, respectively. Samples were extracted on Day 21 for CSF proteome and DRG and SC analysis for neuronal markers (IB4 and CGRP) and glial cell markers (IBA1 and GFAP), respectively, in Experiment I. Lumbar 4-5 DRGs and SC segments were collected for RNA-seq analysis on Day 7 in Experiment II. Differential gene expression in DRG and SC was calculated using DESeq2, and pathway analyses were conducted using iPathwayguide. RESULTS Females developed stronger mechanical allodynia in both experiments. Equivalent decreases in CGRP and IB-4 positive cell counts in DRG and increases in glial cells markers in the SC were seen in both sexes. No CSF protein showed change following SNI in any group. RNASeq of DRG and SC showed abundant changes in gene expression. Sexually dimorphic responses were found in genes related to T-cells (cd28, ctla4, cd274, cd4, prf1), other immunological responses (dpp4, c5a, cxcr2 and il1b), neuronal transmission (hrh3, thbs4, chrna4 and pdyn), plasticity (atf3, c1qc and reg3b), and others (bhlhe22, mcpt1l, trpv6). Analyses of biological processes revealed differences in T and B cell functions in DRG and neuronal processes in both DRG and SC. CONCLUSIONS We observed significantly stronger mechanical allodynia in females and many sexually dimorphic changes in gene expression, following SNI in rats. Several genes have previously been linked to NP, while some are novel. Our results suggest gene targets for further studies in the development of new, possibly sex-specific, therapies for NP and underline the importance of investigating NP in both sexes.

scholarly journals Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury

2021 ◽  
Vol 14 ◽  
Author(s):  
Andrei V. Chernov ◽  
Veronica I. Shubayev
Keyword(s):  
Immune Response ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Dorsal Root Ganglia ◽  
Peripheral Nerve Injury ◽  
Dorsal Root ◽  
Sexually Dimorphic ◽  
Matrix Remodeling ◽  
Immune Functions ◽  
Transcriptional Reprogramming

Peripheral nerve injury induces genome-wide transcriptional reprogramming of first-order neurons and auxiliary cells of dorsal root ganglia (DRG). Accumulating experimental evidence suggests that onset and mechanistic principles of post-nerve injury processes are sexually dimorphic. We examined largely understudied aspects of early transcriptional events in DRG within 24 h after sciatic nerve axotomy in mice of both sexes. Using high-depth RNA sequencing (>50 million reads/sample) to pinpoint sexually dimorphic changes related to regeneration, immune response, bioenergy, and sensory functions, we identified a higher number of transcriptional changes in male relative to female DRG. In males, the decline in ion channel transcripts was accompanied by the induction of innate immune cascades via TLR, chemokine, and Csf1-receptor axis and robust regenerative programs driven by Sox, Twist1/2, and Pax5/9 transcription factors. Females demonstrated nerve injury-specific transcriptional co-activation of the actinin 2 network. The predicted upstream regulators and interactive networks highlighted the role of novel epigenetic factors and genetic linkage to sex chromosomes as hallmarks of gene regulation post-axotomy. We implicated epigenetic X chromosome inactivation in the regulation of immune response activity uniquely in females. Sexually dimorphic regulation of MMP/ADAMTS metalloproteinases and their intrinsic X-linked regulator Timp1 contributes to extracellular matrix remodeling integrated with pro-regenerative and immune functions. Lexis1 non-coding RNA involved in LXR-mediated lipid metabolism was identified as a novel nerve injury marker. Together, our data identified unique early response triggers of sex-specific peripheral nerve injury regulation to gain mechanistic insights into the origin of female- and male-prevalent sensory neuropathies.

scholarly journals Expression of a novel versican variant in dorsal root ganglia from spared nerve injury rats

2019 ◽  
Vol 15 ◽  
pp. 174480691987455 ◽  
Author(s):  
Oliver Bogen ◽  
Olaf Bender ◽  
Pedro Alvarez ◽  
Marie Kern ◽  
Stefan Tomiuk ◽  
...  
Keyword(s):  
Nerve Injury ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Spared Nerve Injury

scholarly journals Sex differences in gene regulation in the dorsal root ganglion after nerve injury

2017 ◽  
Author(s):  
Kimberly E. Stephens ◽  
Weiqiang Zhou ◽  
Zhicheng Ji ◽  
Shaoqiu He ◽  
Hongkai Ji ◽  
...  
Keyword(s):  
Sex Differences ◽  
Nerve Injury ◽  
Dorsal Root ◽  
Gene Networks ◽  
Subjective Experience ◽  
Female Rats ◽  
Complex Interactions ◽  
Male And Female Rats ◽  
Pain Models ◽  
Pain Prevalence

ABSTRACTPain is a subjective experience derived from complex interactions among biological, environmental, and psychosocial pathways. Sex differences in pain sensitivity and chronic pain prevalence are well established. However, the molecular causes underlying these sex dimorphisms are poorly understood particularly with regard to the role of the peripheral nervous system. Here we sought to identify shared and distinct gene networks functioning in the peripheral nervous systems that may contribute to sex differences of pain after nerve injury. We performed RNA-seq on dorsal root ganglia following chronic constriction injury of the sciatic nerve in male and female rats. Analysis from paired naive and injured tissues showed that 1456 genes were differentially expressed between sexes. Appreciating sex-related gene expression differences and similarities in neuropathic pain models may help to improve the translational relevance to clinical populations and efficacy of clinical trials of this major health issue.

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