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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Interaction of human keratinocytes and nerve fiber terminals at the neuro-cutaneous unit

eLife, Год журнала: 2024, Номер 13

Опубликована: Янв. 16, 2024

Traditionally, peripheral sensory neurons are assumed as the exclusive transducers of external stimuli. Current research moves epidermal keratinocytes into focus sensors and transmitters nociceptive non-nociceptive sensations, tightly interacting with intraepidermal nerve fibers at neuro-cutaneous unit. In animal models, cells establish close contacts ensheath neurites. However, ultrastructural morphological mechanistic data examining human keratinocyte-nerve fiber interface sparse. We investigated this exact in skin applying super-resolution array tomography, expansion microscopy, structured illumination microscopy. show keratinocyte ensheathment afferents adjacent connexin 43 native have applied a pipeline based on microscopy to quantify these parameter sections healthy participants versus patients small neuropathy. further derived fully co-culture system, visualizing plaques vitro. Unraveling potential interaction sites advances These findings crucial way decipher mechanisms cutaneous nociception.

Язык: Английский

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Epigenomic landscape of the human dorsal root ganglion: sex differences and transcriptional regulation of nociceptive genes

Pain, Год журнала: 2025, Номер 166(3), С. 614 - 630

Опубликована: Янв. 23, 2025

Abstract Cell states are influenced by the regulation of gene expression orchestrated transcription factors capable binding to accessible DNA regions. To uncover if sex differences exist in chromatin accessibility human dorsal root ganglion (hDRG), where nociceptive neurons innervating body found, we performed bulk and spatial assays for transposase-accessible technology followed sequencing (ATAC-seq) from organ donors without a history chronic pain. Using ATAC-seq, detected abundant hDRG. In women, differentially regions (DARs) mapped mostly X chromosome, whereas men, they autosomal genes. Hormone-responsive factor motifs such as EGR1/3 were within DARs while JUN, FOS, other activating protein 1 enriched suggesting higher activation state cells compared with women. These observations consistent ATAC-seq data. Furthermore, validated that EGR1 is biased female hDRG using RNAscope. neurons, revealed GABAergic, glutamatergic, interferon-related genes women Ca 2+ -signaling-related men. Strikingly, XIST, responsible inactivating chromosome compacting it maintaining at periphery nucleus, was found be highly dispersed neuronal nuclei. This likely related observed both approaches. We have documented baseline epigenomic which provide important descriptive information test future hypotheses.

Язык: Английский

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Persistent changes in the dorsal root ganglion nociceptor translatome governs hyperalgesic priming in mice: roles of GPR88 and Meteorin

Pain, Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

Abstract Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus–detecting sensory neurons, called nociceptors. A key feature of this following priming, stimuli do not normally cause hyperalgesia now readily provoke state. We hypothesized hyperalgesic occurs because reorganization translation mRNA To test hypothesis, we paclitaxel treatment as the stimulus and translating ribosome affinity purification measure persistent changes Na v 1.8+ Translating sequencing revealed 161 genes with persistently altered primed Among these genes, identified Gpr88 upregulated Metrn downregulated. provide functional evidence for related model, interleukin-6 model. GPR88 agonist injection into paw had no effect naive mice but caused mechanical hypersensitivity grimacing responses female mice. Systemic Meteorin completely reversed established prostaglandin E2 Our work demonstrates nociceptor translatomes are causative producing multiple models

Язык: Английский

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Meningeal regulatory T cells inhibit nociception in female mice

Science, Год журнала: 2025, Номер 388(6742), С. 96 - 104

Опубликована: Апрель 4, 2025

T cells have emerged as orchestrators of pain amplification, but the mechanism by which control processing is unresolved. We found that regulatory (T reg cells) could inhibit nociception through a was not dependent on their ability to regulate immune activation and tissue repair. Site-specific depletion or expansion meningeal (mT in mice led female-specific sex hormone–dependent modulation mechanical sensitivity. Specifically, mT produced endogenous opioid enkephalin exerted an antinociceptive action delta receptor expressed MrgprD + sensory neurons. Although restrains nociceptive processing, it dispensable for cell–mediated immunosuppression. Thus, our findings uncovered sexually dimorphic immunological circuit nociception, establishing sentinels homeostasis.

Язык: Английский

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Leveraging deep single-soma RNA sequencing to explore the neural basis of human somatosensation

Nature Neuroscience, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 4, 2024

Abstract The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes individual human (h)DRG neurons—critical information to decipher their functions—are lacking due technical difficulties. In this study, we isolated somata hDRG neurons and conducted deep RNA sequencing (RNA-seq) detect, on average, over 9,000 unique genes per neuron, identified 16 neuronal types. These results were corroborated validated by spatial transcriptomics RNAscope in situ hybridization. Cross-species analyses revealed divergence among potential pain-sensing the likely existence human-specific Molecular-profile-informed microneurography recordings temperature-sensing properties across sensory afferent summary, employing single-soma RNA-seq transcriptomics, generated an neuron atlas, which provides insights into somatosensory physiology serves as a foundation for translational work.

Язык: Английский

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B cells drive neuropathic pain–related behaviors in mice through IgG–Fc gamma receptor signaling

Science Translational Medicine, Год журнала: 2024, Номер 16(766)

Опубликована: Сен. 25, 2024

Neuroimmune interactions are essential for the development of neuropathic pain, yet contributions distinct immune cell populations have not been fully unraveled. Here, we demonstrate critical role B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury male and female mice. Depletion with a single injection anti-CD20 monoclonal antibody at time prevented allodynia. cell–deficient (muMT) mice were similarly spared from Nerve was associated increased immunoglobulin G (IgG) accumulation ipsilateral lumbar dorsal root ganglia (DRGs) spinal cords. IgG colocalized sensory neurons macrophages DRGs microglia also accumulated DRG samples human donors chronic colocalizing marker satellite glia. RNA sequencing revealed population naive mouse DRGs. A transcriptional signature enriched pain. Passive transfer injured induced allodynia muMT recipient The pronociceptive effects likely mediated through complexes interacting Fc gamma receptors (FcγRs) expressed by neurons, microglia, macrophages, given that both hyperexcitability dissociated abolished nerve-injured FcγR-deficient Consistently, passive lost These data reveal cell–IgG–FcγR axis is required pain

Язык: Английский

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Nociceptor sodium channels shape subthreshold phase, upstroke, and shoulder of action potentials

The Journal of General Physiology, Год журнала: 2025, Номер 157(2)

Опубликована: Янв. 21, 2025

Voltage-gated sodium channels (VGSCs) in the peripheral nervous system shape action potentials (APs) and thereby support detection of sensory stimuli. Most nine mammalian VGSC subtypes are expressed nociceptors, but predominantly, three linked to several human pain syndromes: while Nav1.7 is suggested be a (sub-)threshold channel, Nav1.8 thought fast AP upstroke. Nav1.9, as it produces large persistent currents, attributed role determining resting membrane potential. We characterized gating Nav1.1–Nav1.3 Nav1.5–Nav1.9 manual patch clamp with focus on subthreshold depolarization phase. Nav1.9 exhibited most hyperpolarized activation, its inactivation resembled depolarized Nav1.8. For some VGSCs (e.g., Nav1.1 Nav1.2), positive correlation between ramp current window was detected. Using modified Hodgkin–Huxley model that accounts for time needed occur, we used acquired data simulate two nociceptive nerve fiber types (an Aδ- mechano-insensitive C-nociceptor) containing conductances according published RNAseq data. Our simulations suggest supporting both upstroke shoulder. A reduced threshold generation induced by enhancing conductivity or shifting activation more potentials, observed Nav1.7-related disorders. Here, provide comprehensive, comparative functional characterization relevant nociception describe their Hodgkin–Huxley–like models, which can serve tool study specific contributions channel–related diseases.

Язык: Английский

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Neuroimmune mechanisms of type 2 inflammation in the skin and lung

Allergology International, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Type 2 inflammation has a major role in barrier tissues such as the skin and airways underlies common conditions including atopic dermatitis (AD) asthma. Cytokines interleukin 4 (IL-4), IL-5, IL-13 are key immune signatures of type targets multiple specific therapeutics for allergic diseases. Despite shared core mechanisms, distinct structures functions lead to unique therapeutic responses. It is increasingly recognized that nervous system sensing directing inflammatory processes. Indeed, crosstalk between activation somatosensory mediates tissue-specific itching skin. However, neuroimmune interactions shaped by neuronal landscapes, differ airways. In skin, dorsal root ganglia-derived neurons mediate pruritus via cytokines neurogenic mast cell or basophil activation. Conversely, vagal regulate airway responses releasing neuropeptides/neurotransmitters calcitonin gene-related peptides, neuromedin U, acetylcholine, noradrenaline. Sensory neuron-derived vasoactive intestinal peptide forms feedback loop with amplifying eosinophilic airways, mechanism absent These differences influence efficacy cytokine-targeted therapies. For instance, IL-4/IL-13-targeted therapies like dupilumab demonstrate AD diseases, whereas IL-5-targeted effective asthma but not AD. Understanding these underscores need tailored approaches address diseases where involved.

Язык: Английский

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Highly specific σ ₂ R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(52)

Опубликована: Дек. 20, 2023

The sigma 2 receptor (σ

Язык: Английский

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