TY - JOUR
T1 - Sympathetic Input to Multiple Cell Types in Mouse and Human Colon Produces Region-Specific Responses
AU - Smith-Edwards, Kristen M.
AU - Edwards, Brian S.
AU - Wright, Christina M.
AU - Schneider, Sabine
AU - Meerschaert, Kimberly A.
AU - Ejoh, Lindsay L.
AU - Najjar, Sarah A.
AU - Howard, Marthe J.
AU - Albers, Kathryn M.
AU - Heuckeroth, Robert O.
AU - Davis, Brian M.
N1 - Funding Information:
Funding Supported by National Institutes of Health grants: OT2-OD023859 (Marthe J. Howard), T32DK063922-GI, T32NS073548-PCPR, R01AR069951 (Kathryn M. Albers, Brian M. Davis), R01DK122798 (Brian M. Davis), R01DK124955 (Brian M. Davis), F32 DK120115 (Kristen M. Smith-Edwards). Irma and Norman Braman Endowment (Robert O. Heuckeroth), the Suzi and Scott Lustgarten Center Endowment (Robert O. Heuckeroth), The Children's Hospital of Philadelphia Research Institute (Robert O. Heuckeroth), and REACHirschsprung's Foundation (Kristen M. Smith-Edwards).
Funding Information:
Funding Supported by National Institutes of Health grants: OT2-OD023859 (Marthe J. Howard), T32DK063922-GI, T32NS073548-PCPR, R01AR069951 (Kathryn M. Albers, Brian M. Davis), R01DK122798 (Brian M. Davis), R01DK124955 (Brian M. Davis), F32 DK120115 (Kristen M. Smith-Edwards). Irma and Norman Braman Endowment (Robert O. Heuckeroth), the Suzi and Scott Lustgarten Center Endowment (Robert O. Heuckeroth), The Children’s Hospital of Philadelphia Research Institute (Robert O. Heuckeroth), and REACHirschsprung’s Foundation (Kristen M. Smith-Edwards).
Publisher Copyright:
© 2021 AGA Institute
PY - 2021/3
Y1 - 2021/3
N2 - Background & Aims: The colon is innervated by intrinsic and extrinsic neurons that coordinate functions necessary for digestive health. Sympathetic input suppresses colon motility by acting on intrinsic myenteric neurons, but the extent of sympathetic-induced changes on large-scale network activity in myenteric circuits has not been determined. Compounding the complexity of sympathetic function, there is evidence that sympathetic transmitters can regulate activity in non-neuronal cells (such as enteric glia and innate immune cells). Methods: We performed anatomical tracing, immunohistochemistry, optogenetic (GCaMP calcium imaging, channelrhodopsin), and colon motility studies in mice and single-cell RNA sequencing in human colon to investigate how sympathetic postganglionic neurons modulate colon function. Results: Individual neurons in each sympathetic prevertebral ganglion innervated the proximal or distal colon, with processes closely opposed to multiple cell types. Calcium imaging in semi-intact mouse colon preparations revealed changes in spontaneous and evoked neural activity, as well as activation of non-neuronal cells, induced by sympathetic nerve stimulation. The overall pattern of response to sympathetic stimulation was unique to the proximal or distal colon. Region-specific changes in cellular activity correlated with motility patterns produced by electrical and optogenetic stimulation of sympathetic pathways. Pharmacology experiments (mouse) and RNA sequencing (human) indicated that appropriate receptors were expressed on different cell types to account for the responses to sympathetic stimulation. Regional differences in expression of α-1 adrenoceptors in human colon emphasize the translational relevance of our mouse findings. Conclusions: Sympathetic neurons differentially regulate activity of neurons and non-neuronal cells in proximal and distal colon to promote distinct changes in motility patterns, likely reflecting the distinct roles played by these 2 regions.
AB - Background & Aims: The colon is innervated by intrinsic and extrinsic neurons that coordinate functions necessary for digestive health. Sympathetic input suppresses colon motility by acting on intrinsic myenteric neurons, but the extent of sympathetic-induced changes on large-scale network activity in myenteric circuits has not been determined. Compounding the complexity of sympathetic function, there is evidence that sympathetic transmitters can regulate activity in non-neuronal cells (such as enteric glia and innate immune cells). Methods: We performed anatomical tracing, immunohistochemistry, optogenetic (GCaMP calcium imaging, channelrhodopsin), and colon motility studies in mice and single-cell RNA sequencing in human colon to investigate how sympathetic postganglionic neurons modulate colon function. Results: Individual neurons in each sympathetic prevertebral ganglion innervated the proximal or distal colon, with processes closely opposed to multiple cell types. Calcium imaging in semi-intact mouse colon preparations revealed changes in spontaneous and evoked neural activity, as well as activation of non-neuronal cells, induced by sympathetic nerve stimulation. The overall pattern of response to sympathetic stimulation was unique to the proximal or distal colon. Region-specific changes in cellular activity correlated with motility patterns produced by electrical and optogenetic stimulation of sympathetic pathways. Pharmacology experiments (mouse) and RNA sequencing (human) indicated that appropriate receptors were expressed on different cell types to account for the responses to sympathetic stimulation. Regional differences in expression of α-1 adrenoceptors in human colon emphasize the translational relevance of our mouse findings. Conclusions: Sympathetic neurons differentially regulate activity of neurons and non-neuronal cells in proximal and distal colon to promote distinct changes in motility patterns, likely reflecting the distinct roles played by these 2 regions.
KW - GCaMP
KW - Gastrointestinal
KW - Interstitial Cells of Cajal
KW - Platelet-Derived Growth Factor Receptor–α
UR - http://www.scopus.com/inward/record.url?scp=85102101904&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102101904&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2020.09.030
DO - 10.1053/j.gastro.2020.09.030
M3 - Article
C2 - 32980343
AN - SCOPUS:85102101904
SN - 0016-5085
VL - 160
SP - 1208-1223.e4
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -