@article{f8111e686c6a47f789233b21da3e0bc9,
title = "DRG afferents that mediate physiologic and pathologic mechanosensation from the distal colon",
abstract = "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 (GI) 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 Aδ-HTMR population mediates behavioral over-reactivity to colon distension caused by inflammation in a model of inflammatory bowel disease. Thus, like cutaneous DRG mechanoreceptor populations, colon-innervating mechanoreceptors 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.",
keywords = "colon, dorsal root ganglia, inflammatory pain, mechanosensation, sensory physiology",
author = "Wolfson, {Rachel L.} and Amira Abdelaziz and Genelle Rankin and Sarah Kushner and Lijun Qi and Ofer Mazor and Seungwon Choi and Nikhil Sharma and Ginty, {David D.}",
note = "Funding Information: We thank P. Gorelik and M. DeLisle for technical assistance, J. Peng for input on human DRG ISH, and Ginty lab members for comments on the manuscript. We thank Caiying Guo and the Janelia Transgenic Core Facility for generating Bmpr1b CreER and R26 FSF-LSL-Caspase3 mouse lines. We thank X. Dong for PIRT Cre mice. This work was supported by the NIH grants T32-GM007753 and 1-R25-AI147393-01 (R.L.W.), DP2NS127278 (N.S.), and NS097344 and AT011447 (D.D.G.); an NEI P30 Core Grant for Vision Research EY012196 (O.M.); Klingenstein-Simons Foundation (N.S.); Whitehall Foundation (N.S.); The Tan-Yang Center for Autism Research (D.D.G.); and the Lefler Center for Neurodegenerative Disorders (D.D.G.). D.D.G. is an HHMI investigator. This article is subject to HHMI{\textquoteright}s Open Access to Publications policy. HHMI lab heads have previously granted a nonexclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles. Pursuant to those licenses, the author-accepted manuscript of this article can be made freely available under a CC BY 4.0 license immediately upon publication. Funding Information: We thank P. Gorelik and M. DeLisle for technical assistance, J. Peng for input on human DRG ISH, and Ginty lab members for comments on the manuscript. We thank Caiying Guo and the Janelia Transgenic Core Facility for generating Bmpr1bCreER and R26FSF-LSL-Caspase3 mouse lines. We thank X. Dong for PIRTCre mice. This work was supported by the NIH grants T32-GM007753 and 1-R25-AI147393-01 (R.L.W.), DP2NS127278 (N.S.), and NS097344 and AT011447 (D.D.G.); an NEI P30 Core Grant for Vision Research EY012196 (O.M.); Klingenstein-Simons Foundation (N.S.); Whitehall Foundation (N.S.); The Tan-Yang Center for Autism Research (D.D.G.); and the Lefler Center for Neurodegenerative Disorders (D.D.G.). D.D.G. is an HHMI investigator. This article is subject to HHMI's Open Access to Publications policy. HHMI lab heads have previously granted a nonexclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles. Pursuant to those licenses, the author-accepted manuscript of this article can be made freely available under a CC BY 4.0 license immediately upon publication. R.L.W. and D.D.G. conceived the study. R.L.W. A.A. and S.K. performed anatomical and behavior experiments. R.L.W. performed calcium imaging experiments, with input from L.Q. R.L.W. and G.R. performed in vivo DRG electrophysiological experiments. R.L.W. A.A. L.Q. and N.S. characterized mouse lines. R.L.W. analyzed data with assistance from L.Q. O.M. and S.C.; G.R. analyzed MEA data. R.L.W. and D.D.G. wrote the paper with input from all authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = aug,
day = "3",
doi = "10.1016/j.cell.2023.07.007",
language = "English (US)",
volume = "186",
pages = "3368--3385.e18",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "16",
}