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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PIEZO2 in somatosensory neurons controls gastrointestinal transit

Cell, Journal Year: 2023, Volume and Issue: 186(16), P. 3386 - 3399.e15

Published: Aug. 1, 2023

The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence food and help digestion mechanically breaking down propelling gut content. Mechanical sensing thought to be essential for regulating motility; however, identity neuronal populations, molecules involved, functional consequences this sensation unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel motility. Piezo2 mouse dorsal root, but not nodose ganglia required sense content, activity slows transit rates stomach, small intestine, colon. Indeed, directly detect colon distension vivo. Our study unveils mechanosensory mechanisms regulate luminal contents throughout gut, which critical process ensure proper digestion, nutrient absorption, waste removal.

Language: Английский

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Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia

Science Advances, Journal Year: 2024, Volume and Issue: 10(25)

Published: June 21, 2024

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal (TG) are specialized to detect transduce diverse environmental stimuli central nervous system. Single-cell RNA sequencing has provided insights into diversity of sensory ganglia cell types rodents, nonhuman primates, humans, but it remains difficult compare across studies species. We thus constructed harmonized atlases DRG TG that describe facilitate comparison 18 neuronal 11 non-neuronal six species 31 datasets. then performed single-cell/nucleus from both human highly regenerative axolotl found atlas also improves type annotation, particularly sparse subtypes. observed transcriptomes neuron subtypes broadly similar vertebrates, expression functionally important neuropeptides channels can vary notably. The resources presented here guide future comparative transcriptomics, simplify cell-type nomenclature differences studies, help prioritize targets for analgesic development.

Language: Английский

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A review of dorsal root ganglia and primary sensory neuron plasticity mediating inflammatory and chronic neuropathic pain

Neurobiology of Pain, Journal Year: 2024, Volume and Issue: 15, P. 100151 - 100151

Published: Jan. 1, 2024

Pain is a sensory state resulting from complex integration of peripheral nociceptive inputs and central processing. consists adaptive pain that acute beneficial for healing maladaptive often persistent pathological. indeed heterogeneous, can be expressed as nociceptive, inflammatory, or neuropathic in nature. Neuropathic an example occurs after spinal cord injury (SCI), which triggers wide range neural plasticity. The processing underlies hypersensitivity well-studied the cord. However, recent investigations show plasticity leads to pain, including SCI, also exists at sites, such dorsal root ganglia (DRG), contains cell bodies neurons. This review discusses important role DRGs play inflammatory pain. Specifically, it highlights nociceptor hyperexcitability critical increased states. Furthermore, reviews prior literature on glutamate receptors, voltage-gated sodium channels (VGSC), brain-derived neurotrophic factor (BDNF) signaling DRG contributors We previously reviewed BDNF's bidirectional neuromodulator Here, we shift focus periphery discuss BDNF-TrkB expression nociceptors, non-nociceptor neurons, non-neuronal cells potential contributor induction persistence SCI. Overall, this presents comprehensive evaluation large work individually DRG, BDNF, understand their interaction

Language: Английский

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Neuroimmune Interactions in the Intestine

Annual Review of Immunology, Journal Year: 2024, Volume and Issue: 42(1), P. 489 - 519

Published: June 28, 2024

Recent advances have contributed to a mechanistic understanding of neuroimmune interactions in the intestine and revealed an essential role this cross talk for gut homeostasis modulation inflammatory infectious intestinal diseases. In review, we describe innervation by intrinsic extrinsic neurons then focus on bidirectional communication between immune cells. First, highlight contribution neuronal subtypes development colitis discuss different epithelial cell types that are regulated via release neuropeptides neurotransmitters. Next, review inflammation visceral hypersensitivity summarize how mediators induce peripheral central sensitization gut-innervating sensory neurons. Finally, outline importance cells microbiota survival function populations at during bacterial helminth infection.

Language: Английский

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How Do Sensory Neurons Sense Danger Signals?

Trends in Neurosciences, Journal Year: 2020, Volume and Issue: 43(10), P. 822 - 838

Published: Aug. 21, 2020

Language: Английский

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The Form and Function of PIEZO2

Annual Review of Biochemistry, Journal Year: 2021, Volume and Issue: 90(1), P. 507 - 534

Published: June 20, 2021

Mechanosensation is the ability to detect dynamic mechanical stimuli (e.g., pressure, stretch, and shear stress) essential for a wide variety of processes, including our sense touch on skin. How detected transduced at molecular level has proved be one great mysteries sensory biology. A major breakthrough occurred in 2010 with discovery family mechanically gated ion channels that were coined PIEZOs. The last 10 years investigation have provided wealth information about functional roles mechanisms these molecules. Here we focus PIEZO2, two PIEZO proteins found humans other mammals. We review how work molecular, cellular, systems levels over past decade transformed understanding led unexpected insights into types mechanosensation beyond

Language: Английский

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The cellular and molecular basis of somatosensory neuron development

Neuron, Journal Year: 2021, Volume and Issue: 109(23), P. 3736 - 3757

Published: Sept. 29, 2021

Language: Английский

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The Genetics of Neuropathic Pain from Model Organisms to Clinical Application

Neuron, Journal Year: 2019, Volume and Issue: 104(4), P. 637 - 653

Published: Nov. 1, 2019

Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common disabling, rendering an urgent need for non-addictive, effective new therapies. Given high evolutionary conservation pain, investigative approaches from Drosophila mutagenesis human Mendelian genetics have aided our understanding maladaptive plasticity underlying NeuP. Successes include identification ion channel variants causing hyper-excitability importance neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models patients, brain imaging, electrophysiology-based biomarkers, collection large well-phenotyped population cohorts, neurons derived patient stem cells, high-precision CRISPR generated genetic editing. We will discuss how harness these resources understand pathophysiological drivers NeuP, define its relationship with comorbidities such as anxiety, depression, sleep disorders, explore apply findings prediction, diagnosis, treatment NeuP clinic. a consequence lesion or disease (Jensen et al., 2011Jensen T.S. Baron R. Haanpää M. Kalso E. Loeser J.D. Rice A.S.C. Treede R.-D. A definition neuropathic pain.Pain. 2011; 152: 2204-2205Abstract Full Text PDF PubMed Scopus (553) Google Scholar). It common, affecting 7%–10% general population, prevalence projected increase aging diabetes epidemic, cancer survival (van Hecke 2014van O. Austin S.K. Khan R.A. Smith B.H. Torrance N. population: systematic review epidemiological studies.Pain. 2014; 155: 654-662Abstract (349) Unfortunately, current drug treatments are inadequate poor efficacy tolerability (Finnerup 2015Finnerup N.B. Attal Haroutounian S. McNicol Dworkin R.H. Gilron I. Hansson P. Jensen al.Pharmacotherapy adults: meta-analysis.Lancet Neurol. 2015; 14: 162-173Abstract (1020) also associated level disability socio-economic cost: global burden survey showed that chronic third most important cause disability-adjusted life-years worldwide (GBD 2017 Disease Injury Incidence Prevalence Collaborators, 2018GBD CollaboratorsGlobal, regional, national incidence, prevalence, years lived 354 diseases injuries 195 countries territories, 1990–2017: analysis Global Burden Study 2017.Lancet. 2018; 392: 1789-1858Abstract (188) Scholar, 2016Rice A.S. Blyth F.M. Pain disease.Pain. 2016; 157: 791-796Crossref (58) The opioid epidemic exemplifies problems long term alternative non-addictive therapeutics (Jones 2018Jones M.R. Viswanath Peck J. Kaye A.D. Gill J.S. Simopoulos T.T. Brief History Opioid Epidemic Strategies Medicine.Pain Ther. 7: 13-21Crossref do not yet full extent which they depend on specific etiology. For example, factors precipitate traumatic nerve post-herpetic neuralgia same? Nor we explanation why, following same insult, some patients develop others not. Why instance only 30%–50% diabetic polyneuropathy (Feldman 2017Feldman E.L. Nave K.A. Bennett D.L.H. New Horizons Diabetic Neuropathy: Mechanisms, Bioenergetics, Pain.Neuron. 2017; 93: 1296-1313Abstract (98) Scholar)? Differences here likely complex interaction between environmental alter vulnerability resilience system. better architecture therefore provide fundamental insights into pathophysiology, help us inter-individual variation reveal targets. Despite great efforts, development has proved difficult, number promising pharmacological targets identified preclinical studies failing achieve clinical (Percie du Sert Rice, 2014Percie Improving translation analgesic drugs clinic: pain.Br. Pharmacol. 171: 2951-2963Crossref (52) reasons this complex, spanning whole process but broadly falling two categories: sensitivity trials therapies subjectivity reporting, placebo effect case mix 2018Finnerup Haanpaa Kamerman P.R. Moore A. al.Neuropathic trials: decreases estimated efficacy.Pain. 159: 2339-2346Crossref (10) Scholar) ability predict There been major advances gene sequencing technology informatics required deal data volumes. These now being applied at scale health services, instance, 100,000 genomes by National Health Service (NHS) UK (Samuel Farsides, 2017Samuel G.N. Farsides B. UK's Genomes Project: manifesting policymakers' expectations.New Genet. Soc. 36: 336-353Crossref (4) become more precise can be combined research cohorts UK-Biobank 500,000 people (Sudlow 2015Sudlow C. Gallacher Allen Beral V. Burton Danesh Downey Elliott Green Landray al.UK biobank: open access resource identifying causes wide range middle old age.PLoS Med. 12: e1001779Crossref (803) HEAL initiative USA (https://heal.nih.gov) collecting outcome measures (Volkow Koroshetz, 2019Volkow N.D. Koroshetz W.J. role neurologists tackling epidemic.Nat. Rev. 2019; 15: 301-305Crossref (0) providing opportunities create large-scale international consortia (Pascal 2019Pascal M.M.V. Themistocleous A.C. Binder Bouhassira D. Crombez G. Finnerup Gierthmühlen Granovsky Y. Groop L. al.DOLORisk: study protocol multi-centre observational risk determinants pain.Wellcome Open Res. 3: 63Crossref (1) Complementary mouse precision basic discovery mechanisms. speed manipulate genome model organisms fruit fly mouse, even means rapidly interrogate function once genes interest identified. multi-disciplinary expertise needed make use resources, organized joint satellite meeting Genetics Special Interest Groups (SIGs) International Association (IASP) Jackson Laboratory, Bar Harbor, ME (September 10 11, 2018), inspired many ideas presented review. past decade seen improvements techniques used profile (Figure 1). questionnaires assess quality, psychophysical tools perception, alteration experimental through conditioned modulation (CPM). e.g., NPSI, DN4, painDETECT, LANSS (Bennett 2007Bennett M.I. Backonja M.M. Freynhagen Scholz Tölle T.R. Wittchen H.U. Using screening identify 2007; 127: 199-203Abstract (358) incorporate descriptors symptoms generate score helps whether not, characterize distinct dimensions Psychophysical test benefited standardization quantitative testing (QST) protocols. This consistency reporting enables generation different centers, so enhancing statistical power (Rolke 2006Rolke Magerl W. Campbell Schalber Caspari Birklein F. R.D. Quantitative testing: comprehensive trials.Eur. Pain. 2006; 10: 77-88Crossref (660) Conditioned dynamic protocols aim individual's descending modulatory system, although complexity variability size stability response remains challenge (Kennedy 2016Kennedy D.L. Kemp H.I. Ridout Yarnitsky Reliability modulation: review.Pain. 2410-2419Crossref (77) Deployment combination above stratification according profile, much richer dataset than simply classifying etiology (e.g., versus neuralgia) enabling selection phenotypes empower (Attal 2018Attal Diagnosis assessment questionnaires.Lancet 17: 456-466Abstract significant biomarkers neurobiological processes dependent report, neurophysiology (microneurography evoked potentials) neuro-imaging (Tracey 2019Tracey Woolf C.J. Andrews N.A. Composite Biomarker Signatures Objective Assessment Effective Treatment.Neuron. 101: 783-800Abstract When objective indicators adequate specificity aid diagnosis prognosis Combining should added value pathophysiology relevance terms prognosis, choice. Their cohort studied. level, while QST feasible attending specialized services. However, enabled increased size. methods particular aspects phenotype, paradoxical heat sensation (the perception warmth/heat skin cooled) (Binder 2011Binder May Maier Berthele Faltraco Flor H. al.Transient receptor potential polymorphisms patients.PLoS ONE. 6: e17387Crossref Brain imaging level; plans image predominantly healthy genome-sequenced individuals, who then followed longitudinally. An initial already shown structural functional heritable (Elliott 2018Elliott L.T. Sharp K. Alfaro-Almagro Shi Miller K.L. Douaud Marchini S.M. Genome-wide association Biobank.Nature. 562: 210-216Crossref (32) Scholar), over 100 genomic regions showing associations phenotypes. Although undertaken using model, collected, begin insight basis structure/connectivity. inform brain's hypothesis circuitry confers (Denk 2014Denk McMahon S.B. Tracey vulnerability: perspective.Nat. Neurosci. 192-200Crossref (154) Genetic epidemiology—the play determining health-related states events population—is useful tool it (Manolio, 2010Manolio T.A. Genomewide disease.N. Engl. 2010; 363: 166-176Crossref (937) epidemiology challenges 2). first sample In order detect associations, particularly those small size, must sufficient power. genome-wide (GWASs) other conditions, well-powered usually exceed ten thousand participants. recent example type 2 where one 74,124 cases 824,006 controls combining 32 studies. authors 243 loci reached significance (p < 5 × 10−8) accounted approximately 18% variance around half overall heritability (Mahajan 2018Mahajan Taliun Thurner Robertson N.R. Torres J.M. Rayner N.W. Payne A.J. Steinthorsdottir Scott Grarup al.Fine-mapping single-variant resolution high-density imputation islet-specific epigenome maps.Nat. 50: 1505-1513Crossref To date, typically analyzed fewer cases, resulted suggestive (Hébert 2017Hébert H.L. Veluchamy Risk mellitus.Pain. 158: 560-568Crossref (2) One reason lack sizes costs recruiting, adequately phenotyping, genotyping cohort. solution problem lies cross-institution collaboration meta-analyses conducted boost requires harmonization them, brings onto next challenge. 29 studies, no (Veluchamy 2018Veluchamy Hébert Meng Palmer C.N.A. Systematic meta-analysis 825-848Crossref made difficult compare their estimates across combine conduct (Evangelou Ioannidis, 2013Evangelou Ioannidis J.P.A. Meta-analysis beyond.Nat. 2013; 379-389Crossref (258) robust phenotypic needed, all researchers adhere to, accurately controls. consensus led harmony assessment, necessarily amenable populations 2016Finnerup Cruccu Freeman Nurmikko T. pain: updated grading practice.Pain. 1599-1606Crossref (200) setting, good classification subgroups valid (identifying without NeuP), (in time, ethics, cost), accurate (having specificity), and, all, reproducible. address issue, SIG published set recommendations 2015van Bjornsdottir Diatchenko (NeuroPPIC) studies: NeuPSIG review, Delphi survey, expert panel recommendations.Pain. 156: 2337-2353Crossref (23) Phenotyping Consensus guidelines entry-level criteria participants including validated tool, anatomical distribution body chart checklist, history (including intensity, duration, etiology, demographics). preliminary feasibility NeuroPPIC suggests may currently overly stringent, meaning larger available would produce (unpublished data). demonstrates trade-off validity criteria. further complication fact standard always agree. agreement Self-report Leeds Symptoms Signs (S-LANSS) 2005Bennett Potter S-LANSS origin: validation postal research.J. 2005; 149-158Abstract (347) Douleur Neuropathique 4 Questions (DN4) (Bouhassira 2005Bouhassira Alchaar Boureau Brochet Bruxelle Cunin Fermanian Ginies Grun-Overdyking al.Comparison syndromes somatic lesions diagnostic questionnaire (DN4).Pain. 114: 29-36Abstract (1144) 45 low back related leg revealed moderate correlation, albeit statistically (Walsh 2012Walsh Rabey Hall T.M. Agreement correlation self-report leeds signs subjects back-related pain.J. Manipulative Physiol. 2012; 35: 196-202Abstract shortcomings, molecular, candidate-gene, humans comprehensively summarized Investigations eligible inclusion were examined compared 28 show study-wide presence Together, clues biological mechanisms involved onset persistence 3). COMT, OPRM1, SCN9A, SLC6A4, CACNG2 involvement neurotransmission. Major histocompatibility cytokine HLA-A, HLA-B, HLA-DQB1, HLA-DRB1, B2M, IL6, IL1R2, IL10, TNF-a represent immune pathway, interesting note neuropathy etiologies. Finally iron metabolism ACO1, BMP6, FXN, TF, CP, TFRC, SLC11A2, GCH1 illustrates metabolic pathways dysfunction. Of candidate gene-studies, HLA genes, TNF-a, found While SCN9A intensity (Reimann 2010Reimann Cox J.J. Belfer Zaykin D.V. McHale D.P. Drenth J.P. Dai Wheeler Sanders al.Pain altered nucleotide polymorphism SCN9A.Proc. Natl. Acad. Sci. USA. 107: 5148-5153Crossref (193) (A, B, DRB1) replicated consistently absence (post herpetic (Sato-Takeda 2004Sato-Takeda Ihn Ohashi Tsuchiya Satake Arita Tamaki Hanaoka Tokunaga Yabe leukocyte antigen (HLA) haplotype postherpetic after herpes zoster.Pain. 2004; 110: 329-336Abstract Ozawa 1999Ozawa Sasao Iwashita Miyahara Sugai Iizuka Kawakubo Ohkido Naruse Anzai al.HLA-A33 -B44 susceptibility (PHN).Tissue Antigens. 1999; 53: 263-268Crossref Sumiyama 2008Sumiyama Kikkawa E.F. Kita Y.F. Shinagawa Mabuchi Inoko alleles zoster.Tokai Exp. Clin. 2008; 33: 150-153PubMed addition, originally persistent lumbar root (Tegeder 2006Tegeder Costigan Griffin R.S. Abele Schmidt Ehnert Nejim Marian al.GTP cyclohydrolase tetrahydrobiopterin regulate persistence.Nat. 1269-1277Crossref (406) etiologies (HIV-induced postsurgical pain) suggesting recently discovered energy potentially lie key intersection (Cronin 2018Cronin S.J.F. Seehus Weidinger Talbot Reissig Seifert Pierson McNeill Longhi M.S. Turnes B.L. al.The metabolite BH4 T cell proliferation autoimmunity cancer.Nature. 563: 564-568Crossref (12) Furthermore, three GWASs date. Two prescription-based phenotype (572 961 cases) (Meng 2015aMeng Deshmukh H.A. Donnelly L.A. Colhoun H.M. C.N. Wellcome Trust Case Control Consortium (WTCCC2)Surrogate markers Micro- Macro-vascular hard endpoints Innovative Tools (SUMMIT) groupA provides evidence sex-specific chr1p35.1 (ZSCAN20-TLR12P) chr8p23.1 (HMGB1P46) pain.EBioMedicine. 2: 1386-1393Abstract 2015bMeng van Zuydam Liu Zhou Morris Markers Macro-Vascular Hard Endpoints Diabetes GroupA Chr8p21.3 (GFRA2) pain.Eur. 19: 392-399Crossref another knee screened painDETECT (331 (Warner 2017Warner S.C. Meurs J.B.J. Schiphof Bierma-Zeinstra Hofman Uitterlinden A.G. Richardson Jenkins Doherty Valdes A.M. scan post total replacement highlights variant protein-kinase C gene.Eur. Hum. 25: 446-451Crossref none (GFRA2, ZSCAN20-TLR12P, HMGB1P46, PRKCA) significance, again highlighting harmonization. Such addressed DOLORisk (http://dolorisk.eu/) European consortium aims study, core group developed, based guidelines. Scottish covering 33,000 individuals. consenting Biobank re-phenotyped DN4 (originally ∼500,000). still completed, expected responses received 175,000 Assuming 7% lower end estimations, predicted 12,000, novel variants. Requiring stringent p threshold multiple protect against I error (false association) tension greater chance II (overlooked genes). Pathway enrichment combines statistics co-involved defined signaling way issue. informative aggregate SNPs individually reach nominal 10−8 (Lötsch 2013Lötsch Doehring Mogil Arndt Geisslinger Ultsch Functional genomics therapy.Pharmacol. 139: 60-70Crossref Parisien 2019Parisien Samoshkin Tansley S.N. Piltonen M.H. Martin L.J. El-Hachem Dagostino

Language: Английский

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Distinct subtypes of proprioceptive dorsal root ganglion neurons regulate adaptive proprioception in mice

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Feb. 15, 2021

Abstract Proprioceptive neurons (PNs) are essential for the proper execution of all our movements by providing muscle sensory feedback to central motor network. Here, using deep single cell RNAseq adult PNs coupled with virus and genetic tracings, we molecularly identify three main types (Ia, Ib II) find that they segregate into eight distinct subgroups. Our data unveil a highly sophisticated organization discrete input channels spatial distribution, innervation patterns molecular profiles. Altogether, these features contribute finely regulate proprioception during complex behavior. Moreover, while Ib- II-PN subtypes specified around birth, Ia-PN diversify later in life along increased activity. We also show Ia-PNs plasticity following exercise training, suggesting important players adaptive proprioceptive function mice.

Language: Английский

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