Project description:Expression of DREAM in dorsal root ganglia and spinal cord is related to endogenous control mechanisms of acute and chronic pain. In primary sensory trigeminal neurons high levels of endogenous DREAM protein are preferentially localized in the nucleus, suggesting a major transcriptional role. Here, we show that DREAM participates in the control of trigeminal pain perception through the regulation of prodynorphin and BDNF. Furthermore, genome-wide analysis of trigeminal neurons in daDREAM transgenic mice revealed that cathepsin L (CTSL) and the monoglyceride lipase (MGLL) are new DREAM downstream targets and have a role in the regulation of trigeminal nociception.
Project description:Little is known about the molecular mechanisms underlying mammalian touch transduction. To identify novel candidate transducers, we examined the molecular and cellular basis of touch in one of the most sensitive tactile organs in the animal kingdom, the star of the star-nosed mole. Our findings demonstrate that the trigeminal ganglia innervating the star are enriched in tactile-sensitive neurons, resulting in a higher proportion of light touch fibers and lower proportion of nociceptors compared to the dorsal root ganglia innervating the rest of the body. We exploit this difference using transcriptome analysis of the star-nosed mole sensory ganglia to identify novel candidate mammalian touch and pain transducers. The most enriched candidates are also expressed in mouse somatosesensory ganglia, suggesting they may mediate transduction in diverse species and are not unique to moles. These findings highlight the utility of examining diverse and specialized species to address fundamental questions in mammalian biology. Examination of the transcriptome of 3 trigeminal and 3 dorsal root ganglia
Project description:Purpose: In this study, we aimed to analyze lncRNA expression in the whole transcriptome of trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) in a chronic inflammatory TMJ pain mouse model. Chronic inflammatory TMJ pain was induced by intra-TMJ injection of complete Freund's adjuvant (CFA). The lncRNA expression patterns in the whole transcriptome of TG and Sp5C were profiled with RNA sequencing.
Project description:The trigeminal nerve is primarily responsible for facial sensation and exhibits the highest expression of CGRP. Here, we explored the impact of Rimegepant on the transcriptome of the trigeminal ganglion in mice and found that the transcription profiles changed significantly following treatment compared to the control group. Following Rimegepant administration, we observed a significant downregulation of innate immune-related items within the trigeminal ganglia, as well as functional items directly associated with pain perception and calcium signaling pathways.The activation of innated immune within the trigeminal ganglia is known to enhance nociceptive responses, which were also directly linked to the activation of calcium signaling pathways. These results suggest that Rimegepant alleviates OSCC-related pain by mitigating the inflammatory condition within the trigeminal ganglion. We then categorized the genes enriched in these functional groups. Genes that promote the proliferation and differentiation of innate immune cells, and those related to the expression of proinflammatory mediators, were significantly downregulated, while those associated with anti-inflammatory functions were significantly upregulated. Additionally, genes from various chemokine receptor families and ion channel genes linked to neuronal activity were significantly downregulated. Collectively, these results suggest that CGRP influences OSCC-related pain by modulating the innate immune status of the trigeminal nerve.
Project description:RNA-sequencing identifies the expression profile of miRNAs in the trigeminal ganglia of mice with or without trigeminal neuropathic pain
Project description:The expression profile of lncRNAs, circRNAs, and mRNAs in the trigeminal ganglia of mice with or without trigeminal neuropathic pain
Project description:Chronic pain remains a significant medical challenge with complex underlying mechanisms, and an urgent need for new treatments. Our research built and utilized the iPain single-cell atlas to study chronic pain progression in dorsal root and trigeminal ganglia. We discovered that senescence of a small subset of pain-sensing neurons may be a key driver of chronic pain. This mechanism was observed in animal models after nerve injury and in human patients with chronic pain or diabetic neuropathy. Notably, treatment with senolytics, drugs that remove senescent cells, reversed pain symptoms in mice post-injury. These findings highlight the crucial role of cellular senescence in chronic pain development, demonstrate the therapeutic potential of senolytic treatments, and underscore the value of the iPain atlas for future pain research.
Project description:The cerebral cortex plays a key role in the multi-dimensional human pain experience. However, the neural mechanisms mediating pain-related cortical activity remain largely unknown, particularly in primary somatosensory cortex (S1). We therefore developed a new animal model of trigeminal neuralgia, a prototypical neuropathic pain, which allowed us to evaluate pain-related cortical dynamics with unprecedented translational relevance. Our novel model (FLIT: Foramen Lacerum Impingement of Trigeminal-nerve) displayed robust clinically relevant trigeminal neuralgia-like behaviors, including asymmetric facial grimacing, dental pain-like behaviors, anxiety-like behavior, and sexual dysfunction, capturing many features of the human pain experience. Awake FLIT mice exhibited highly synchronized spontaneous population activity in S1, due to GABAergic interneuron hypoactivity. Remarkably, clinically effective treatments including carbamazepine and trigeminal nerve root decompression abrogated S1 synchronization and alleviated trigeminal neuralgia-like behaviors. These results reveal synchronized S1 activity as a new and important cortical substrate of neuropathic pain, which can be clinically targeted to provide effective therapy.
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
Project description:Nerve injury-induced changes in gene expression in primary sensory neurons, such as trigeminal ganglion (TG) neurons, play a critical role in the genesis of neuropathic pain. Therefore, understanding the molecular mechanisms underlying these changes in the TGs following peripheral nerve injury will enable us to develop a new avenue for managing trigeminal-mediated neuropathic pain. Studies have highlighted the involvement of miRNA-mediated modulation in a wide range of diseases, leading to the exploration of miRNA-based therapeutics as a potential treatment strategy. Here, in this RNA-seq database, we have found that microRNA-216a-3p (miR-216a-3p) and miR-32-5p (miR-32-5p), which are downregulated in injured TGs, are novel functional RNAs involved in regulating trigeminal-mediated neuropathic pain. Histone methylation-mediated miRNA downregulation in TG neurons regulates trigeminal neuropathic pain by targeting either STIM1 (H3K27me3/SOX10/miR-216a-3p/STIM1) or Cav3.2 (GR/miR-32-5p/Cav3.2) channels. Moreover, we found that miR-323-3p exhibited the most significant upregulation in the injured TG. Understanding the mechanistic role of the PRMT2/FOXA2/miR-323-3p/Kv2.1 signaling axis in sensory neurons may advance the discovery of novel therapeutic strategies for neuropathic pain.