A mouse DRG genetic toolkit reveals morphological and physiological diversity of somatosensory neuron subtypes

Cell, Год журнала: 2024, Номер 187(6), С. 1508 - 1526.e16

Опубликована: Март 1, 2024

Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG neuron subtypes relay neural signals from periphery to CNS has been challenging with existing tools. Here, we develop curate mouse genetic toolkit that allows for interrogating properties functions distinct cutaneous targeting subtypes. These tools have enabled broad morphological analysis, which revealed axon arborization areas branching patterns transcriptionally Moreover, in vivo physiological analysis each subtype threshold range responses mechanical and/or thermal stimuli. findings support model morphologically physiologically sensory tile stimulus space collectively encode wide natural

Язык: Английский

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A transcriptional atlas of gut-innervating neurons reveals activation of interferon signaling and ferroptosis during intestinal inflammation

Neuron, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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scRNA-sequencing reveals subtype-specific transcriptomic perturbations in DRG neurons of PirtEGFPf mice in neuropathic pain condition

eLife, Год журнала: 2022, Номер 11

Опубликована: Окт. 20, 2022

Functionally distinct subtypes/clusters of dorsal root ganglion (DRG) neurons may play different roles in nerve regeneration and pain. However, details about their transcriptomic changes under neuropathic pain conditions remain unclear. Chronic constriction injury (CCI) the sciatic represents a well-established model pain, we conducted single-cell RNA-sequencing (scRNA-seq) to characterize subtype-specific perturbations transcriptomes lumbar DRG on day 7 post-CCI. By using PirtEGFPf mice that selectively express an enhanced green fluorescent protein neurons, established highly efficient purification process enrich for scRNA-seq. We observed emergence four prominent CCI-induced clusters loss marker genes injured neurons. Importantly, portion from several were spared injury-induced identity loss, suggesting Moreover, uninjured which are necessary mediating evoked also demonstrated cell-type-specific these clusters, but not others. Notably, male female showed differential multiple neuronal after CCI, sexual dimorphism injury. Using Fgf3 as proof-of-principle, RNAscope study provided further evidence increased supporting scRNA-seq analysis, calcium imaging unraveled functional role excitability. These findings contribute identification new target development neuron therapies optimizing treatment regeneration.

Язык: Английский

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Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Апрель 10, 2024

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common off-target adverse effects caused by various chemotherapeutic agents, such as cisplatin, oxaliplatin, paclitaxel, vincristine and bortezomib. CIPN characterized a substantial loss of primary afferent sensory axonal fibers leading to disturbances in patients. An estimated 19-85% patients developed during course chemotherapy. The lack preventive measures limited treatment options often require dose reduction or even early termination life-saving chemotherapy, impacting efficacy patient survival. In this Review, we summarized current understanding on pathogenesis CIPN. One prominent change induced agents involves disruption neuronal cytoskeletal architecture transport dynamics largely influenced interference microtubule stability neurons. Due an ineffective blood-nerve barrier our nervous system, exposure some causes mitochondrial swelling nerves, which lead opening permeability transition pore cytochrome c release resulting degeneration fibers. exacerbated nociceptive signaling pain transmission linked increased excitability due elevated expression ion channels dorsal root ganglion Another important contributing factor neuroinflammation infiltration immune cells production inflammatory cytokines. central also induce hyperexcitability spinal horn anterior cingulate cortex development sensitization that Emerging evidence suggests composition diversity gut microbiota (dysbiosis) could have direct impact progression Collectively, all these aspects contribute Recent advances RNA-sequencing offer solid platform for

Язык: Английский

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Analgesic Effect of Dehydrocorydaline on Chronic Constriction Injury-Induced Neuropathic Pain via Alleviating Neuroinflammation

Chinese Journal of Integrative Medicine, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

Язык: Английский

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Autoreactive IgG levels and Fc receptor γ subunit upregulation drive mechanical allodynia after nerve constriction or crush injury

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 24, 2025

Abstract B cells contribute to the development of pain after sciatic nerve chronic constriction injury (CCI) via binding immunoglobulin G (IgG) Fc gamma receptors (FcγRs) in lumbar dorsal root ganglia (DRG) and spinal cord. Yet contribution different types peripheral is uncertain. Using male female mice, we demonstrate a divergent role for cell-IgG-FcγR signaling underlying mechanical allodynia between CCI, crush (NC), spared (SNI), ligation (SNL). Depletion (monoclonal anti-CD20) or genetic deletion (muMT mice) prevented following NC but not SNI SNL. In apparent contradiction, circulating levels autoreactive IgG immune complexes were increased all models, though more prominent CCI. Passive transfer from donor mice induced CCI muMT recipient demonstrating that secreted pronociceptive. To investigate why pronociceptive did SNI, evaluated receptor γ subunit. SNL increase subunit DRG cord, whereas did, agreement with cell-dependent these models. Together, results suggest traumatic drives secretion cells. However, cognate FcγRs are crush, transection, differentially regulate through axis.

Язык: Английский

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Targeting sensory neuron GPCRs for peripheral neuropathic pain

Trends in Pharmacological Sciences, Год журнала: 2023, Номер 44(12), С. 1009 - 1027

Опубликована: Ноя. 11, 2023

Язык: Английский

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The dorsal root ganglion as a target for neurorestoration in neuropathic pain

Neural Regeneration Research, Год журнала: 2023, Номер 19(2), С. 296 - 301

Опубликована: Июль 7, 2023

Abstract Neuropathic pain is a severe and chronic condition widely found in the general population. The reason for this extensive variety of damage or diseases that can spark unpleasant constant feeling patients. During processing pain, dorsal root ganglia constitute an important region where ganglion neurons play crucial role transmission propagation sensory electrical stimulation. Furthermore, have recently exhibited regenerative capacity should not be neglected understanding development resolution neuropathic elucidation innovative therapies. Here, we will review complex interplay between cells (satellite glial inflammatory cells) factors (cytokines, neurotrophic genetic factors) takes place within accounts generation aberrant excitation primary occurring pain. More importantly, summarize updated view current pharmacologic nonpharmacologic therapies targeting treatment

Язык: Английский

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TET1-Lipid Nanoparticle Encapsulating Morphine for Specific Targeting of Peripheral Nerve for Pain Alleviation

International Journal of Nanomedicine, Год журнала: 2024, Номер Volume 19, С. 4759 - 4777

Опубликована: Май 1, 2024

Background: Opioids are irreplaceable analgesics owing to the lack of alternative that offer opioid-like pain relief. However, opioids have many undesirable central side effects. Restricting peripheral opioid receptors could reduce those effects while maintaining analgesia. Methods: To achieve this goal, we developed Tet1-LNP (morphine), a neural-targeting lipid nanoparticle encapsulating morphine specifically activate receptor in dorsal root ganglion (DRG) and significantly caused by activation brain. (morphine) were successfully prepared using thin-film hydration method. In vitro, uptake was assessed differentiated neuron-like PC-12 cells primary cells. The DRGs brain vivo. Von Frey filament Hargreaves tests used assess antinociception chronic constriction injury (CCI) neuropathic model. Morphine concentration blood evaluated ELISA. Results: had an average size 131 nm. showed high cellular targeted DRG vitro. CCI mice treated with experienced prolonged analgesia for nearly 32 h compared 3 free ( p < 0.0001). Notably, group eight-fold lower than Conclusion: Our study presents system neural delivery morphine. We anticipate will safe formulation treatment, promise further development clinical applications. Keywords: nanoparticle, Tet1, nerve-targeted, management,

Язык: Английский

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Mrgprb4-lineage neurons indispensable in pressure induced pleasant sensation are polymodal

iScience, Год журнала: 2025, Номер 28(2), С. 111940 - 111940

Опубликована: Фев. 1, 2025

Pharmacogenetic activation of the Mas-related G-protein-coupled receptor b4 (Mrgprb4) neurons in dorsal root ganglia is positively reinforcing, and these can be activated by innocuous or noxious mechanical stimuli. However, direct evidence regarding role how they encode diverse somatic inputs remains unclear. To address this, mild pressure conditioned place preference (MP-CPP) was conducted to evaluate indispensability Mrgprb4-lineage pleasantness caused pressure. Mice without lost for The number significantly higher than that brush pinch. Ca2+ transients were Further analysis co-activating mechano-thermosensitive showed evoked fluorescence 0°C 43°C. In brief, are needed transmit pleasant sensation exhibit functional polymodality.

Язык: Английский

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