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

Cell, Journal Year: 2024, Volume and Issue: 187(6), P. 1508 - 1526.e16

Published: March 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

Language: Английский

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

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Oct. 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.

Language: Английский

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

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: April 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

Language: Английский

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

Chinese Journal of Integrative Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Language: 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), Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

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Targeting sensory neuron GPCRs for peripheral neuropathic pain

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(12), P. 1009 - 1027

Published: Nov. 11, 2023

Language: Английский

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

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 19(2), P. 296 - 301

Published: July 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

Language: Английский

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

iScience, Journal Year: 2025, Volume and Issue: 28(2), P. 111940 - 111940

Published: Feb. 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.

Language: Английский

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Characterizing a new rat model of chronic pain after spine surgery

Bone Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: March 12, 2025

Abstract Chronic pain after spine surgery (CPSS) is a complex disorder characterized by multifactorial pathogenesis that occurs in 8%–40% of patients undergoing lumbar surgery. We aimed to develop rat model mimics clinical CPSS conditions taking two sequential surgical procedures. Step 1: A plastic rod was inserted into the left L5 intervertebral foramen produce steady compression on dorsal root ganglion (DRG) and spinal nerve, common cause low back (LBP). 2: The removed 7 days when rats exhibited mechanical heat hypersensitivity ipsilateral hindpaw, followed full laminectomy mimic decompression LBP patients. retention induced prolonged LBP-like behavior but quickly resolved removal without laminectomy. However, received developed heightened sensitivity impaired gait, reduced spontaneous exploration activity, indicating CPSS. Patch clamp recording revealed significant augmentation intrinsic excitability small-diameter DRG neurons rats. Administration Dermorphin [D-Arg2, Lys4] (1–4) amide (DALDA, 5 mg /kg, i.p.), peripherally acting mu-opioid receptor (MOR)-preferred agonist, attenuated hypersensitivity, capsaicin-induced [Ca 2+ ]i rising increased from Our findings suggest this new model, which mirrors nature patients, may be useful for future studies underlying mechanisms.

Language: Английский

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