{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:17:50Z","timestamp":1790785070464,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T00:00:00Z","timestamp":1758931200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"\n Abstract<\/jats:title>\n \n The evolution of oxygen sensing included a transition from a diffuse distribution of respiratory chemoreceptors in the gills of water\u2010breathing vertebrates to chemoreceptor clusters confined to the pulmonary epithelium and carotid body in air\u2010breathers. Since the excitatory neurotransmitters mediating oxygen sensing in anamniotes have never been confirmed, the origins of oxygen sensing in vertebrates have remained controversial. In gills isolated from Tg(\n elavl3<\/jats:italic>\n :GCaMP6s) zebrafish expressing a genetically encoded reporter of intracellular Ca\n 2+<\/jats:sup>\n concentration ([Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n ), we demonstrate that acetylcholine (ACh) and nicotine induced a dose\u2010dependent increase in [Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n in postsynaptic sensory neurons innervating oxygen\u2010chemoreceptive neuroepithelial cells (NECs). Hypoxic stimulation of NECs evoked a similar rise in neuronal [Ca\n 2+<\/jats:sup>\n ]\n i<\/jats:sub>\n that was abolished by the nicotinic antagonist hexamethonium. Using immunohistochemistry and RT\u2010qPCR, we identified a novel population of ACh\u2010containing NECs associated with sensory neurons expressing the \u03b12 subunit of nicotinic ACh receptors.\n In vivo<\/jats:italic>\n whole\u2010larva Ca\n 2+<\/jats:sup>\n imaging showed that cholinergic and hypoxic activation of the gills generated Ca\n 2+<\/jats:sup>\n activity in neurons of vagal sensory ganglia with time\u2010dependent characteristics of neurotransmission towards the hindbrain. We identified a second source of hypoxic activity in vagal sensory ganglia operating exclusively through 5\u2010HT\n 3<\/jats:sub>\n receptors and dependent upon vesicular monoamine transport (VMAT2) in the gill. We traced expression of 5\u2010HT\n 3<\/jats:sub>\n receptors to nerve terminals surrounding a separate population of serotonergic VMAT2\u2010positive NECs. Our investigation reveals independent cholinergic and serotonergic autonomic pathways of oxygen sensing in zebrafish and provides novel physiological evidence consistent with the idea that gill chemoreceptors are homologues of both pulmonary and carotid body chemoreceptors in mammals.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n The excitatory neurotransmitters mediating oxygen sensing in anamniotes have never been confirmed. Thus, the origins of oxygen sensing in vertebrates have remained controversial.<\/jats:p>\n <\/jats:list-item>\n \n \n In transgenic zebrafish expressing a genetically encoded reporter of intracellular Ca\n 2+<\/jats:sup>\n concentration, we identified two independent pathways of oxygen sensing in the gill: one involving acetylcholine and interneurons intrinsic to the gill, and the other via serotonin acting directly upon ganglionic neurons.\n <\/jats:p>\n <\/jats:list-item>\n \n Both pathways resulted in excitation of vagal sensory ganglia that receive hypoxic inputs from the gills and innervate the hindbrain.<\/jats:p>\n <\/jats:list-item>\n \n We argue that gill chemoreceptors are homologues of both pulmonary and carotid body chemoreceptors in mammals.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp289409","type":"journal-article","created":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T21:15:51Z","timestamp":1759007751000},"page":"7123-7144","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dual cholinergic and serotonergic excitatory pathways mediate oxygen sensing in the zebrafish gill"],"prefix":"10.1113","volume":"603","author":[{"given":"Maddison","family":"Reed","sequence":"first","affiliation":[{"name":"Department of Biology University of Ottawa Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthea A.","family":"Mavridis","sequence":"additional","affiliation":[{"name":"Department of Biology University of Ottawa Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan A.","family":"Mennigen","sequence":"additional","affiliation":[{"name":"Department of Biology University of Ottawa Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2111-1570","authenticated-orcid":false,"given":"Michael G.","family":"Jonz","sequence":"additional","affiliation":[{"name":"Department of Biology University of Ottawa Ottawa Ontario Canada"},{"name":"Brain and Mind Research Institute University of Ottawa Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,27]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1092330118"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(95)00029-D"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2012.09.003"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1092360109"},{"key":"e_1_2_5_6_1","first-page":"1063","article-title":"Oxygen sensing: Responses and adaptation to hypoxia","volume":"94","author":"Dinger B.","year":"2003","journal-title":"Journal of Applied Physiology"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmor.1051930107"},{"issue":"6","key":"e_1_2_5_8_1","first-page":"1342","article-title":"Neuroepithelial cells in fish gill primary lamellae","volume":"53","author":"Dunel\u2010Erb S.","year":"1982","journal-title":"Journal of Applied Physiology\u2010Respiratory, Environmental and Exercise Physiology"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12741"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00714.2004"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.21231"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00673.2001"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10680"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.01564"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.069294"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2014.09.002"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2005.04.004"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2012.tb00399.x"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00225"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00360-024-01553-5"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2007.02.007"},{"key":"e_1_2_5_23_1","first-page":"112","article-title":"Neurotransmitter and neuromodulatory mechanisms at peripheral arterial chemoreceptors","volume":"174","author":"Nurse C. 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