ScRNA-seq generates a molecular map of emerging cell subtypes after sciatic nerve injury in rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE216665 | GEO | 2022/10/27
REPOSITORIES: GEO
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Project description:Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury. Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 3,7,21,40 hours after three different sciatic nerve lesions [Spared Nerve Injury (SNI); Chronic Constriction Injury (CCI); Spinal Nerve Ligation (Ch) with Sham controls (SH)].
2011-07-14 | E-GEOD-30691 | biostudies-arrayexpress
Project description:Neuropathic pain is an apparently spontaneous experience triggered by abnormal physiology of the peripheral or central nervous system, which evolves with time. Neuropathic pain arising from peripheral nerve injury is characterized by a combination of spontaneous pain, hyperalgesia and allodynia. There is no evidence of this type of pain in human infants or rat pups; brachial plexus avulsion, which causes intense neuropathic pain in adults, is not painful when the injury is sustained at birth. Since infants are capable of nociception from before birth and display both acute and chronic inflammatory pain behaviour from an early neonatal age, it appears that the mechanisms underlying neuropathic pain are differentially regulated over a prolonged postnatal period. We used microarrays to detail the global programme of gene expression underlying the differences in nerve injury between along the postnatal development and identified distinct classes of regulated genes during the injury Experiment Overall Design: We have performed a microarray analysis of the rat L4/L5 dorsal root ganglia, 7 days post spared nerve injury, a model of neuropathic pain. Genes that are regulated in adult rats displaying neuropathic behaviour were compared to those regulated in young rats (10 days old) that did not show the same neuropathic behaviour.
2010-01-30 | E-GEOD-15041 | biostudies-arrayexpress
Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries. To identify the miRs that were differentially dysregulated between Tibial-SNI and Sural-SNI, we first performed 12 microarrays in a limited number of samples (in four individual DRGs per group: Sham, Tibial-SNI and Sural-SNI; two L3-DRG and two L4-DRG). Then, miRs identified as having differential expression were corroborated with real time qRT-PCR in RNA isolated from individual DRGs (L3, L4 and L5) derived from 4 rats per group (not presented here, but in the manuscript).
2014-09-29 | E-GEOD-60033 | biostudies-arrayexpress
Project description:We produced single-cell transcriptomes from the mouse spinal cord using Drop-seq in animals modeling neuropathic pain and superficial injury (SI) controls. We used the spared nerve injury (SNI) model of neuropathic pain. ~10,000 cells from sham surgery controls and ~9,000 cells from SNI animals were sequenced. Unbiased cell clustering yielded 66 spinal cell subtypes sequenced at relatively low depth (~1200 transcripts/cell). Comparisons between SI and SNI cells were performed to investigate cell-specific differences during a neuropathic pain state.
2021-03-04 | GSE134003 | GEO
Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries.
2014-09-29 | GSE60033 | GEO
Project description:Purpose: Nerve injury-induced hyperactivity of primary sensory neurons in the dorsal root ganglion (DRG) contributes critically to chronic pain development, but its underlying mechanisms remain incompletely understood. Chronic neuropathic pain has a clear epigenetic component, however, most studies so far have focused on histone modifications. We determined changes of DNA methylation in the rat DRG, spinal cord, and prefrontal cortex after spinal nerve ligation (SNL).
2018-07-05 | GSE114865 | GEO
Project description:Purpose: Nerve injury-induced hyperactivity of primary sensory neurons in the dorsal root ganglion (DRG) contributes critically to chronic pain development, but its underlying mechanisms remain incompletely understood. Chronic neuropathic pain has a clear epigenetic component, however, most studies so far have focused on histone modifications. We determined changes of DNA methylation in the rat DRG, spinal cord, and prefrontal cortex after spinal nerve ligation (SNL).
2018-06-29 | GSE100641 | GEO
Project description:Maladaptive changes of nerve injury–associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury–specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury–induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury–induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.
2022-06-15 | GSE206043 | GEO
Project description:Here we show that importin alpha (α) 3 (KPNA4) controls pain responsiveness in peripheral sensory neurons. An importin α3 knockout mouse showed reduced responsiveness to noxious heat or chemical pain, as well as greater tolerance to neuropathic pain. Similar findings were obtained upon acute knockdown of importin α3 in peripheral sensory neurons. Transcriptome analyses and immunohistochemistry indicated that importin α 3 deficient neurons were impaired in nuclear import of c-Fos. Forty days after spared nerve injury acute down-regulation of importin α3, c-FOS, Jun and the dominat negative AAV9 viruses rescue the neuropathic pain phenotype. In silico screens identified importin α3 deficiency mimicking drug leads that attenuated neuropathic pain and reduced c-Fos nuclear localization. Hence, perturbing c-Fos nuclear import by importin α3 can provide analgesia at peripheral loci in the nervous system
2020-08-17 | GSE137515 | GEO
Project description:Dorsal root ganglion (DRG) neurons provide connectivity between peripheral tissues and spinal cord. Transcriptional plasticity within DRG sensory neurons after peripheral nerve injury contributes to nerve repair but also leads to maladaptive plasticity, including the development of neuropathic pain. This study presents tissue and neuron specific expression profiling of both known and novel Long Non-Coding RNAs (LncRNAs) in rodent DRG following nerve injury. We have identified a large number of novel LncRNAs expressed within rodent DRG, a minority of which were syntenically conserved between mouse and rat and which including both- intergenic and antisense LncRNAs. We have also identified neuron type-specific LncRNAs in mouse DRG, and LncRNAs that are expressed in human IPS cell-derived sensory neurons. We show significant plasticity in LncRNA expression following nerve injury, which in mouse is strain dependant. This resource is publicly available and will aid future studies of DRG neuron identity and the transcriptional landscape in both naïve and injured DRG.
2017-11-21 | GSE107180 | GEO