{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:58:39Z","timestamp":1791928719902,"version":"4.3.4"},"reference-count":51,"publisher":"Association for Research in Vision and Ophthalmology (ARVO)","issue":"2","license":[{"start":{"date-parts":[[2019,2,8]],"date-time":"2019-02-08T00:00:00Z","timestamp":1549584000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Invest. Ophthalmol. Vis. Sci."],"published-print":{"date-parts":[[2019,2,8]]},"DOI":"10.1167\/iovs.18-26318","type":"journal-article","created":{"date-parts":[[2019,2,8]],"date-time":"2019-02-08T19:00:05Z","timestamp":1549652405000},"page":"615","source":"Crossref","is-referenced-by-count":34,"title":["Changes in Murine Subbasal Corneal Nerves After Scopolamine-Induced Dry Eye Stress Exposure"],"prefix":"10.1167","volume":"60","author":[{"given":"Cem","family":"Simsek","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kojima","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taeko","family":"Nagata","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"Dogru","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuo","family":"Tsubota","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"27","reference":[{"key":"i1552-5783-60-2-615-b01","doi-asserted-by":"crossref","unstructured":"Muller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res. 2003; 76: 521\u2013542.","DOI":"10.1016\/S0014-4835(03)00050-2"},{"key":"i1552-5783-60-2-615-b02","doi-asserted-by":"crossref","unstructured":"Marfurt CF, Cox J, Deek S, Dvorscak L. Anatomy of the human corneal innervation. Exp Eye Res. 2010; 90: 478\u2013492.","DOI":"10.1016\/j.exer.2009.12.010"},{"key":"i1552-5783-60-2-615-b03","doi-asserted-by":"crossref","unstructured":"Gonzalez-Gonzalez O, Bech F, Gallar J, Merayo-Lloves J, Belmonte C. Functional properties of sensory nerve terminals of the mouse cornea. Invest Ophthalmol Vis Sci. 2017; 58: 404\u2013415.","DOI":"10.1167\/iovs.16-20033"},{"key":"i1552-5783-60-2-615-b04","doi-asserted-by":"crossref","unstructured":"Guthoff RF, Wienss H, Hahnel C, Wree A. Epithelial innervation of human cornea: a three-dimensional study using confocal laser scanning fluorescence microscopy. Cornea. 2005; 24: 608\u2013613.","DOI":"10.1097\/01.ico.0000154384.05614.8f"},{"key":"i1552-5783-60-2-615-b05","unstructured":"Yang AY, Chow J, Liu J. Corneal innervation and sensation: the eye and beyond. Yale J Biol Med. 2018; 91: 13\u201321."},{"key":"i1552-5783-60-2-615-b06","doi-asserted-by":"crossref","unstructured":"Yamaguchi T, Turhan A, Harris DL, et al. Bilateral nerve alterations in a unilateral experimental neurotrophic keratopathy model: a lateral conjunctival approach for trigeminal axotomy. PLoS One. 2013; 8: e70908.","DOI":"10.1371\/journal.pone.0070908"},{"key":"i1552-5783-60-2-615-b07","doi-asserted-by":"crossref","unstructured":"Ferrari G, Ueno H, Bignami F, Rama P, Dana R. Trigeminal stereotactic electrolysis induces dry eye in mice. Acta Ophthalmol. 2013; 91: e162\u2013e163.","DOI":"10.1111\/j.1755-3768.2012.02529.x"},{"key":"i1552-5783-60-2-615-b08","doi-asserted-by":"crossref","unstructured":"Tsubota K, Yokoi N, Shimazaki J, et al. New perspectives on dry eye definition and diagnosis: a consensus report by the Asia Dry Eye Society. Ocul Surf 2017; 15: 65\u201376.","DOI":"10.1016\/j.jtos.2016.09.003"},{"key":"i1552-5783-60-2-615-b09","doi-asserted-by":"crossref","unstructured":"Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II report executive summary. Ocul Surf. 2017; 15: 802\u2013812.","DOI":"10.1016\/j.jtos.2017.08.003"},{"key":"i1552-5783-60-2-615-b10","doi-asserted-by":"crossref","unstructured":"Parissi M, Karanis G, Randjelovic S, et al. Standardized baseline human corneal subbasal nerve density for clinical investigations with laser-scanning in vivo confocal microscopy. Invest Ophthalmol Vis Sci. 2013; 54: 7091\u20137102.","DOI":"10.1167\/iovs.13-12999"},{"key":"i1552-5783-60-2-615-b11","doi-asserted-by":"crossref","unstructured":"Cruzat A, Pavan-Langston D, Hamrah P. In vivo confocal microscopy of corneal nerves: analysis and clinical correlation. Semin Ophthalmol. 2010; 25: 171\u2013177.","DOI":"10.3109\/08820538.2010.518133"},{"key":"i1552-5783-60-2-615-b12","doi-asserted-by":"crossref","unstructured":"Park YS, Gauna AE, Cha S. Mouse models of primary Sjogren's syndrome. Curr Pharm Des. 2015; 21: 2350\u20132364.","DOI":"10.2174\/1381612821666150316120024"},{"key":"i1552-5783-60-2-615-b13","doi-asserted-by":"crossref","unstructured":"Simsek C, Kojima T, Dogru M, Tsubota K. Alterations of murine subbasal corneal nerves after environmental dry eye stress. Invest Ophthalmol Vis Sci. 2018; 59: 1986\u20131995.","DOI":"10.1167\/iovs.17-23743"},{"key":"i1552-5783-60-2-615-b14","doi-asserted-by":"crossref","unstructured":"Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007; 39: 175\u2013191.","DOI":"10.3758\/BF03193146"},{"key":"i1552-5783-60-2-615-b15","doi-asserted-by":"crossref","unstructured":"Yamazaki R, Yamazoe K, Yoshida S, et al. The semaphorin 3A inhibitor SM-345431 preserves corneal nerve and epithelial integrity in a murine dry eye model. Sci Rep. 2017; 7: 15584.","DOI":"10.1038\/s41598-017-15682-1"},{"key":"i1552-5783-60-2-615-b16","doi-asserted-by":"crossref","unstructured":"Shimmura S, Ono M, Shinozaki K, et al. Sodium hyaluronate eyedrops in the treatment of dry eyes. Br J Ophthalmol 1995; 79: 1007\u20131011.","DOI":"10.1136\/bjo.79.11.1007"},{"key":"i1552-5783-60-2-615-b17","doi-asserted-by":"crossref","unstructured":"Oliveira-Soto L, Efron N. Morphology of corneal nerves using confocal microscopy. Cornea. 2001; 20: 374\u2013384.","DOI":"10.1097\/00003226-200105000-00008"},{"key":"i1552-5783-60-2-615-b18","doi-asserted-by":"crossref","unstructured":"Jiang MS, Yuan Y, Gu ZX, Zhuang SL. Corneal confocal microscopy for assessment of diabetic peripheral neuropathy: a meta-analysis. Br J Ophthalmol. 2016; 100: 9\u201314.","DOI":"10.1136\/bjophthalmol-2014-306038"},{"key":"i1552-5783-60-2-615-b19","doi-asserted-by":"crossref","unstructured":"Alhatem A, Cavalcanti B, Hamrah P. In vivo confocal microscopy in dry eye disease and related conditions. Semin Ophthalmol. 2012; 27: 138\u2013148.","DOI":"10.3109\/08820538.2012.711416"},{"key":"i1552-5783-60-2-615-b20","doi-asserted-by":"crossref","unstructured":"De Cilla S, Fogagnolo P, Sacchi M, et al. Corneal involvement in uneventful cataract surgery: an in vivo confocal microscopy study. Ophthalmologica. 2014; 231: 103\u2013110.","DOI":"10.1159\/000355490"},{"key":"i1552-5783-60-2-615-b21","doi-asserted-by":"crossref","unstructured":"Erie JC, McLaren JW, Hodge DO, Bourne WM. Recovery of corneal subbasal nerve density after PRK and LASIK. Am J Ophthalmol. 2005; 140: 1059\u20131064.","DOI":"10.1016\/j.ajo.2005.07.027"},{"key":"i1552-5783-60-2-615-b22","doi-asserted-by":"crossref","unstructured":"Erie JC, McLaren JW, Hodge DO, Bourne WM. The effect of age on the corneal subbasal nerve plexus. Cornea. 2005; 24: 705\u2013709.","DOI":"10.1097\/01.ico.0000154387.51355.39"},{"key":"i1552-5783-60-2-615-b23","doi-asserted-by":"crossref","unstructured":"Hamrah P, Cruzat A, Dastjerdi MH, et al. Unilateral herpes zoster ophthalmicus results in bilateral corneal nerve alteration: an in vivo confocal microscopy study. Ophthalmology. 2013; 120: 40\u201347.","DOI":"10.1016\/j.ophtha.2012.07.036"},{"key":"i1552-5783-60-2-615-b24","doi-asserted-by":"crossref","unstructured":"Misra S, Ahn HN, Craig JP, Pradhan M, Patel DV, McGhee CN. Effect of panretinal photocoagulation on corneal sensation and the corneal subbasal nerve plexus in diabetes mellitus. Invest Ophthalmol Vis Sci. 2013; 54: 4485\u20134490.","DOI":"10.1167\/iovs.12-10571"},{"key":"i1552-5783-60-2-615-b25","doi-asserted-by":"crossref","unstructured":"Neira-Zalentein W, Holopainen JM, Tervo TM, et al. Corneal sensitivity in diabetic patients subjected to retinal laser photocoagulation. Invest Ophthalmol Vis Sci. 2011; 52: 6043\u20136049.","DOI":"10.1167\/iovs.10-7054"},{"key":"i1552-5783-60-2-615-b26","doi-asserted-by":"crossref","unstructured":"Niederer RL, Perumal D, Sherwin T, McGhee CN. Corneal innervation and cellular changes after corneal transplantation: an in vivo confocal microscopy study. Invest Ophthalmol Vis Sci. 2007; 48: 621\u2013626.","DOI":"10.1167\/iovs.06-0538"},{"key":"i1552-5783-60-2-615-b27","doi-asserted-by":"crossref","unstructured":"Niederer RL, Perumal D, Sherwin T, McGhee CN. Age-related differences in the normal human cornea: a laser scanning in vivo confocal microscopy study. Br J Ophthalmol. 2007; 91: 1165\u20131169.","DOI":"10.1136\/bjo.2006.112656"},{"key":"i1552-5783-60-2-615-b28","doi-asserted-by":"crossref","unstructured":"Van Went C, Alalwani H, Brasnu E, et al. Corneal sensitivity in patients treated medically for glaucoma or ocular hypertension [in French]. J Fr Ophtalmol. 2011; 34: 684\u2013690.","DOI":"10.1016\/j.jfo.2011.07.011"},{"key":"i1552-5783-60-2-615-b29","doi-asserted-by":"crossref","unstructured":"Villani E, Baudouin C, Efron N, et al. In vivo confocal microscopy of the ocular surface: from bench to bedside. Curr Eye Res. 2014; 39: 213\u2013231.","DOI":"10.3109\/02713683.2013.842592"},{"key":"i1552-5783-60-2-615-b30","doi-asserted-by":"crossref","unstructured":"Benitez del Castillo JM, Wasfy MA, Fernandez C, Garcia-Sanchez J. An in vivo confocal masked study on corneal epithelium and subbasal nerves in patients with dry eye. Invest Ophthalmol Vis Sci. 2004; 45: 3030\u20133035.","DOI":"10.1167\/iovs.04-0251"},{"key":"i1552-5783-60-2-615-b31","doi-asserted-by":"crossref","unstructured":"Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017; 15: 438\u2013510.","DOI":"10.1016\/j.jtos.2017.05.011"},{"key":"i1552-5783-60-2-615-b32","doi-asserted-by":"crossref","unstructured":"Choi EY, Kang HG, Lee CH, et al. Langerhans cells prevent subbasal nerve damage and upregulate neurotrophic factors in dry eye disease. PLoS One. 2017; 12: e0176153.","DOI":"10.1371\/journal.pone.0176153"},{"key":"i1552-5783-60-2-615-b33","doi-asserted-by":"crossref","unstructured":"He J, Cortina MS, Kakazu A, Bazan HE. The PEDF neuroprotective domain plus DHA induces corneal nerve regeneration after experimental surgery. Invest Ophthalmol Vis Sci. 2015; 56: 3505\u20133513.","DOI":"10.1167\/iovs.15-16755"},{"key":"i1552-5783-60-2-615-b34","doi-asserted-by":"crossref","unstructured":"Stepp MA, Pal-Ghosh S, Tadvalkar G, Williams AR, Pflugfelder SC, de Paiva CS. Reduced corneal innervation in the CD25 null model of Sjogren syndrome. Int J Mol Sci. 2018; 19: E3821.","DOI":"10.3390\/ijms19123821"},{"key":"i1552-5783-60-2-615-b35","doi-asserted-by":"crossref","unstructured":"Stepp MA, Pal-Ghosh S, Tadvalkar G, Williams A, Pflugfelder SC, de Paiva CS. Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL\/6 mice. Exp Eye Res. 2018; 169: 91\u201398.","DOI":"10.1016\/j.exer.2018.01.024"},{"key":"i1552-5783-60-2-615-b36","doi-asserted-by":"crossref","unstructured":"De Paiva CS, Chotikavanich S, Pangelinan SB, et al. IL-17 disrupts corneal barrier following desiccating stress. Mucosal Immunol. 2009; 2: 243\u2013253.","DOI":"10.1038\/mi.2009.5"},{"key":"i1552-5783-60-2-615-b37","doi-asserted-by":"crossref","unstructured":"Hosal BM, Ornek N, Zilelioglu G, Elhan AH. Morphology of corneal nerves and corneal sensation in dry eye: a preliminary study. Eye (Lond). 2005; 19: 1276\u20131279.","DOI":"10.1038\/sj.eye.6701760"},{"key":"i1552-5783-60-2-615-b38","doi-asserted-by":"crossref","unstructured":"Villani E, Galimberti D, Viola F, Mapelli C, Ratiglia R. The cornea in Sjogren's syndrome: an in vivo confocal study. Invest Ophthalmol Vis Sci. 2007; 48: 2017\u20132022.","DOI":"10.1167\/iovs.06-1129"},{"key":"i1552-5783-60-2-615-b39","doi-asserted-by":"crossref","unstructured":"Villani E, Magnani F, Viola F, et al. In vivo confocal evaluation of the ocular surface morpho-functional unit in dry eye. Optom Vis Sci. 2013; 90: 576\u2013586.","DOI":"10.1097\/OPX.0b013e318294c184"},{"key":"i1552-5783-60-2-615-b40","doi-asserted-by":"crossref","unstructured":"Zhang M, Chen J, Luo L, Xiao Q, Sun M, Liu Z. Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy. Cornea. 2005; 24: 818\u2013824.","DOI":"10.1097\/01.ico.0000154402.01710.95"},{"key":"i1552-5783-60-2-615-b41","doi-asserted-by":"crossref","unstructured":"Villani E, Galimberti D, Viola F, Mapelli C, Del Papa N, Ratiglia R. Corneal involvement in rheumatoid arthritis: an in vivo confocal study. Invest Ophthalmol Vis Sci. 2008; 49: 560\u2013564.","DOI":"10.1167\/iovs.07-0893"},{"key":"i1552-5783-60-2-615-b42","doi-asserted-by":"crossref","unstructured":"Villani E, Garoli E, Termine V, Pichi F, Ratiglia R, Nucci P. Corneal confocal microscopy in dry eye treated with corticosteroids. Optom Vis Sci. 2015; 92: e290\u2013e295.","DOI":"10.1097\/OPX.0000000000000600"},{"key":"i1552-5783-60-2-615-b43","doi-asserted-by":"crossref","unstructured":"Wei Y, Asbell PA. The core mechanism of dry eye disease is inflammation. Eye Contact Lens. 2014; 40: 248\u2013256.","DOI":"10.1097\/ICL.0000000000000042"},{"key":"i1552-5783-60-2-615-b44","doi-asserted-by":"crossref","unstructured":"Yagci A, Gurdal C. The role and treatment of inflammation in dry eye disease. Int Ophthalmol. 2014; 34: 1291\u20131301.","DOI":"10.1007\/s10792-014-9969-x"},{"key":"i1552-5783-60-2-615-b45","doi-asserted-by":"crossref","unstructured":"Tepelus TC, Chiu GB, Huang J, et al. Correlation between corneal innervation and inflammation evaluated with confocal microscopy and symptomatology in patients with dry eye syndromes: a preliminary study. Graefes Arch Clin Exp Ophthalmol. 2017; 255: 1771\u20131778.","DOI":"10.1007\/s00417-017-3680-3"},{"key":"i1552-5783-60-2-615-b46","unstructured":"Rosenberg ME, Tervo TM, Immonen IJ, Muller LJ, Gronhagen-Riska C, Vesaluoma MH. Corneal structure and sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci. 2000; 41: 2915\u20132921."},{"key":"i1552-5783-60-2-615-b47","doi-asserted-by":"crossref","unstructured":"Malik RA, Kallinikos P, Abbott CA, et al. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia. 2003; 46: 683\u2013688.","DOI":"10.1007\/s00125-003-1086-8"},{"key":"i1552-5783-60-2-615-b48","doi-asserted-by":"crossref","unstructured":"Patel DV, McGhee CN. Mapping the corneal sub-basal nerve plexus in keratoconus by in vivo laser scanning confocal microscopy. Invest Ophthalmol Vis Sci. 2006; 47: 1348\u20131351.","DOI":"10.1167\/iovs.05-1217"},{"key":"i1552-5783-60-2-615-b49","doi-asserted-by":"crossref","unstructured":"Tuominen IS, Konttinen YT, Vesaluoma MH, Moilanen JA, Helinto M, Tervo TM. Corneal innervation and morphology in primary Sjogren's syndrome. Invest Ophthalmol Vis Sci. 2003; 44: 2545\u20132549.","DOI":"10.1167\/iovs.02-1260"},{"key":"i1552-5783-60-2-615-b50","doi-asserted-by":"crossref","unstructured":"Xu KP, Yagi Y, Tsubota K. Decrease in corneal sensitivity and change in tear function in dry eye. Cornea. 1996; 15: 235\u2013239.","DOI":"10.1097\/00003226-199605000-00002"},{"key":"i1552-5783-60-2-615-b51","doi-asserted-by":"crossref","unstructured":"Reichard M, Weiss H, Poletti E, et al. Age-related changes in murine corneal nerves. Curr Eye Res. 2016; 41: 1021\u20131028.","DOI":"10.3109\/02713683.2015.1088952"}],"container-title":["Investigative Opthalmology & Visual Science"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/iovs.arvojournals.org\/article.aspx?articleid=2724453","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:31:12Z","timestamp":1791927072000},"score":1,"resource":{"primary":{"URL":"http:\/\/iovs.arvojournals.org\/article.aspx?doi=10.1167\/iovs.18-26318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,8]]},"references-count":51,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,2,1]]}},"URL":"https:\/\/doi.org\/10.1167\/iovs.18-26318","relation":{},"ISSN":["1552-5783"],"issn-type":[{"value":"1552-5783","type":"print"}],"subject":[],"published":{"date-parts":[[2019,2,8]]}}}