DRG afferents that mediate physiologic and pathologic mechanosensation from the distal colon

The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology and gastrointestinal disease. Here, we report genetically defined subsets of colon innervating DRG neurons with diverse morphologic and physiologic properties. Four colon innervating DRG neuron populations are mechanosensitive and exhibit distinct force thresholds to colon distension. The highest threshold population, selectively labeled using Bmpr1b genetic tools, is necessary and sufficient for behavioral responses to high colon distension, which is partly mediated by the mechanosensory ion channel Piezo2. This HTMR population mediates behavioral over-reactivity to colon distension caused by inflammation in a model of inflammatory bowel disease. Thus, like cutaneous mechanoreceptor populations, colon innervating DRG afferents exhibit distinct anatomical and physiological properties and tile force threshold space, and genetically defined colon innervating HTMRs mediate pathophysiological responses to colon distension revealing a target population for therapeutic intervention.

[1]  C. Harvey,et al.  Mechanoreceptor signal convergence and transformation in the dorsal horn flexibly shape a diversity of outputs to the brain , 2022, Cell.

[2]  Sung-Yon Kim,et al.  Neural signalling of gut mechanosensation in ingestive and digestive processes , 2022, Nature Reviews Neuroscience.

[3]  C. Harvey,et al.  Cortical Responses to Touch Reflect Subcortical Integration of LTMR Signals , 2021, Nature.

[4]  P. Dinning,et al.  Understanding the physiology of human defaecation and disorders of continence and evacuation , 2021, Nature Reviews Gastroenterology & Hepatology.

[5]  D. Ginty,et al.  The mechanosensory neurons of touch and their mechanisms of activation , 2021, Nature Reviews Neuroscience.

[6]  Shaoqiu He,et al.  Calcium imaging in population of dorsal root ganglion neurons unravels novel mechanisms of visceral pain sensitization and referred somatic hypersensitivity. , 2020, Pain.

[7]  Shiaoching Gong,et al.  Parallel ascending spinal pathways for affective touch and pain , 2020, Nature.

[8]  Nicole L. Neubarth,et al.  Meissner corpuscles and their spatially intermingled afferents underlie gentle touch perception , 2020, Science.

[9]  H. Koerber,et al.  Unique Molecular Characteristics of Visceral Afferents Arising from Different Levels of the Neuraxis: Location of Afferent Somata Predicts Function and Stimulus Detection Modalities , 2020, The Journal of Neuroscience.

[10]  B. Aronow,et al.  Identification of a Sacral, Visceral Sensory Transcriptome in Embryonic and Adult Mice , 2020, eNeuro.

[11]  Allon M. Klein,et al.  The emergence of transcriptional identity in somatosensory neurons , 2020, Nature.

[12]  G. Zheng,et al.  Optical recording reveals topological distribution of functionally classified colorectal afferent neurons in intact lumbosacral DRG , 2019, Physiological reports.

[13]  Xinzhong Dong,et al.  Sphingosine‐1‐phosphate activates mouse vagal airway afferent C‐fibres via S1PR3 receptors , 2019, The Journal of physiology.

[14]  N. Spencer,et al.  Spinal Afferent Innervation of the Colon and Rectum , 2018, Front. Cell. Neurosci..

[15]  Kara L. Marshall,et al.  The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice , 2018, Science Translational Medicine.

[16]  Lars E. Borm,et al.  Molecular Architecture of the Mouse Nervous System , 2018, Cell.

[17]  Alex Gutteridge,et al.  Single-cell RNAseq reveals seven classes of colonic sensory neuron , 2018, Gut.

[18]  M. Krashes,et al.  Specialized Mechanosensory Nociceptors Mediating Rapid Responses to Hair Pull , 2017, Neuron.

[19]  Lauren L. Orefice,et al.  The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn , 2017, Cell.

[20]  K. Bielefeldt,et al.  Physiology of Visceral Pain. , 2016, Comprehensive Physiology.

[21]  S. Brookes,et al.  Identification of different functional types of spinal afferent neurons innervating the mouse large intestine using a novel CGRPα transgenic reporter mouse. , 2016, American journal of physiology. Gastrointestinal and liver physiology.

[22]  Paul E. Miller,et al.  α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors , 2016, Gut.

[23]  Rafael Yuste,et al.  moco: Fast Motion Correction for Calcium Imaging , 2015, Front. Neuroinform..

[24]  Nicole L. Neubarth,et al.  Genetic Identification of an Expansive Mechanoreceptor Sensitive to Skin Stroking , 2015, Cell.

[25]  Nayoung Kim,et al.  Adequate Dextran Sodium Sulfate-induced Colitis Model in Mice and Effective Outcome Measurement Method , 2015, Journal of cancer prevention.

[26]  M. Camilleri,et al.  Yamada's textbook of gastroenterology / , 2015 .

[27]  S. Brookes,et al.  Activation of intestinal spinal afferent endings by changes in intra‐mesenteric arterial pressure , 2015, The Journal of physiology.

[28]  M. Unno,et al.  Intracolonic Administration of the TRPA1 Agonist Allyl Isothiocyanate Stimulates Colonic Motility and Defecation in Conscious Dogs , 2015, Journal of Gastrointestinal Surgery.

[29]  S. Linnarsson,et al.  Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing , 2014, Nature Neuroscience.

[30]  Valérie Bégay,et al.  Piezo2 is the major transducer of mechanical forces for touch sensation in mice , 2014, Nature.

[31]  N. Spencer,et al.  Identification of Different Types of Spinal Afferent Nerve Endings That Encode Noxious and Innocuous Stimuli in the Large Intestine Using a Novel Anterograde Tracing Technique , 2014, PloS one.

[32]  Gonçalo Lopes,et al.  Bonsai: an event-based framework for processing and controlling data streams , 2014, bioRxiv.

[33]  C. Goridis,et al.  A Phox2b::FLPo transgenic mouse line suitable for intersectional genetics , 2013, Genesis.

[34]  C. N. Honda,et al.  Visualization of spinal afferent innervation in the mouse colon by AAV8‐mediated GFP expression , 2013, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[35]  Yiyuan Cui,et al.  A subpopulation of nociceptors specifically linked to itch , 2012, Nature Neuroscience.

[36]  David J. Anderson,et al.  Genetic identification of C-fibers that detect massage-like stroking of hairy skin in vivo , 2012, Nature.

[37]  D. Ginty,et al.  Sexually Dimorphic BDNF Signaling Directs Sensory Innervation of the Mammary Gland , 2012, Science.

[38]  P. Chuang,et al.  Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis , 2012, Proceedings of the National Academy of Sciences.

[39]  E. Schwartz,et al.  Altered colorectal afferent function associated with TNBS-induced visceral hypersensitivity in mice. , 2012, American journal of physiology. Gastrointestinal and liver physiology.

[40]  M. Zylka,et al.  CGRPα-Expressing Sensory Neurons Respond to Stimuli that Evoke Sensations of Pain and Itch , 2012, PloS one.

[41]  Wenqin Luo,et al.  The Functional Organization of Cutaneous Low-Threshold Mechanosensory Neurons , 2011, Cell.

[42]  Fan Wang,et al.  Temporal control of gene deletion in sensory ganglia using a tamoxifen-inducible Advillin-Cre-ERT2 recombinase mouse , 2011, Molecular pain.

[43]  G. Gebhart,et al.  Characterization of silent afferents in the pelvic and splanchnic innervations of the mouse colorectum. , 2011, American journal of physiology. Gastrointestinal and liver physiology.

[44]  You-Wen He,et al.  Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway , 2010, Proceedings of the National Academy of Sciences.

[45]  D. Ginty,et al.  Molecular Identification of Rapidly Adapting Mechanoreceptors and Their Developmental Dependence on Ret Signaling , 2009, Neuron.

[46]  David Julius,et al.  Cellular and Molecular Mechanisms of Pain , 2009, Cell.

[47]  S. Brookes,et al.  Identification of medium/high-threshold extrinsic mechanosensitive afferent nerves to the gastrointestinal tract. , 2009, Gastroenterology.

[48]  David J Anderson,et al.  Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli , 2009, Proceedings of the National Academy of Sciences.

[49]  D. R. Linden,et al.  Post-inflammatory colonic afferent sensitisation: different subtypes, different pathways and different time courses , 2009, Gut.

[50]  S. Brookes,et al.  Identification of functional intramuscular rectal mechanoreceptors in aganglionic rectal smooth muscle from piebald lethal mice. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[51]  D. Anderson,et al.  Cutaneous sensory neurons expressing the Mrgprd receptor sense extracellular ATP and are putative nociceptors. , 2008, Journal of neurophysiology.

[52]  Kathleen R. Cho,et al.  Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. , 2007, Cancer research.

[53]  J. Christianson,et al.  Assessment of colon sensitivity by luminal distension in mice , 2007, Nature Protocols.

[54]  L. Blackshaw,et al.  Activation of splanchnic and pelvic colonic afferents by bradykinin in mice , 2005, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[55]  David J. Anderson,et al.  Topographically Distinct Epidermal Nociceptive Circuits Revealed by Axonal Tracers Targeted to Mrgprd , 2005, Neuron.

[56]  T. Brennan,et al.  The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function. , 2004, Gastroenterology.

[57]  S. Brierley,et al.  Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice. , 2004, Gastroenterology.

[58]  S. Brookes,et al.  Rectal intraganglionic laminar endings are transduction sites of extrinsic mechanoreceptors in the guinea pig rectum. , 2003, Gastroenterology.

[59]  E. Perl,et al.  Calcitonin gene‐related peptide immunoreactivity and afferent receptive properties of dorsal root ganglion neurones in guinea‐pigs , 2002, The Journal of physiology.

[60]  E. García-Nicas,et al.  A new model of visceral pain and referred hyperalgesia in the mouse , 2001, PAIN®.

[61]  E. Perl,et al.  Sensory fibers of the pelvic nerve innervating the Rat's urinary bladder. , 2000, Journal of neurophysiology.

[62]  L. Blackshaw,et al.  In vitro recordings of afferent fibres with receptive fields in the serosa, muscle and mucosa of rat colon , 1999, The Journal of physiology.

[63]  G. Gebhart,et al.  Characterization of mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat. , 1994, Journal of neurophysiology.

[64]  P. Vera,et al.  Neurons labelled after the application of tracer to the distal stump of the transected hypogastric nerve in the rat. , 1991, Journal of the autonomic nervous system.

[65]  S. McMahon,et al.  Physiological properties of primary sensory neurons appropriately and inappropriately innervating skeletal muscle in adult rats. , 1991, Journal of neurophysiology.

[66]  S. Lawson,et al.  Cell type and conduction velocity of rat primary sensory neurons with calcitonin gene-related peptide-like immunoreactivity , 1990, Neuroscience.

[67]  E. Perl,et al.  Myelinated afferent fibres innervating the primate skin and their response to noxious stimuli , 1968, The Journal of physiology.