{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:41:46Z","timestamp":1791906106149,"version":"4.3.4"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Vestibular hair cells (HCs) are mechanoreceptors that sense head motions by modulating the firing rate of vestibular ganglion neurons (VGNs), whose central processes project to vestibular nucleus neurons (VNNs) and cerebellar neurons. We explored vestibular function after HC destruction in adult <jats:italic>Pou4f3<jats:sup>+\/DTR<\/jats:sup> (DTR)<\/jats:italic> mice, in which injections of high-dose (50\u2009ng\/g) diphtheria toxin (DT) destroyed most vestibular HCs within 2\u2009weeks. At that time, <jats:italic>DTR<\/jats:italic> mice had lost the horizontal vestibulo-ocular reflex (aVOR<jats:sub>H<\/jats:sub>), and their VNNs failed to upregulate nuclear cFos expression in response to a vestibular stimulus (centrifugation). Five months later, 21 and 14% of HCs were regenerated in utricles and horizontal ampullae, respectively. The vast majority of HCs present were type II. This degree of HC regeneration did not restore the aVOR<jats:sub>H<\/jats:sub> or centrifugation-evoked cFos expression in VNNs. The failure to regain vestibular pathway function was not due to degeneration of VGNs or VNNs because normal neuron numbers were maintained after HC destruction. Furthermore, sinusoidal galvanic stimulation at the mastoid process evoked cFos protein expression in VNNs, indicating that VGNs were able to regulate VNN activity after HC loss. aVOR<jats:sub>H<\/jats:sub> and cFos responses in VNNs were robust after low-dose (25\u2009ng\/g) DT, which compared to high-dose DT resulted in a similar degree of type II HC death and regeneration but spared more type I HCs in both organs. These findings demonstrate that having more type I HCs is correlated with stronger responses to vestibular stimulation and suggest that regenerating type I HCs may improve vestibular function after HC loss.<\/jats:p>","DOI":"10.3389\/fneur.2024.1322647","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T04:44:40Z","timestamp":1709873080000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Sensorineural correlates of failed functional recovery after natural regeneration of vestibular hair cells in adult mice"],"prefix":"10.3389","volume":"15","author":[{"given":"Emmanuel J.","family":"J\u00e1uregui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelli L.","family":"Scheinman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid K.","family":"Bibriesca Mejia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Pruett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Zaini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor","family":"Finkbeiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay A.","family":"Gantz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tot Bui","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James O.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer S.","family":"Stone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,3,8]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2068","DOI":"10.1016\/j.neurobiolaging.2015.02.013","article-title":"Characterizing human vestibular sensory epithelia for experimental studies: new hair bundles on old tissue and implications for therapeutic interventions in ageing","volume":"36","author":"Taylor","year":"2015","journal-title":"Neurobiol Aging"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1111\/j.1749-6632.2001.tb03748.x","article-title":"Decreasing hair cell counts in aging humans","volume":"942","author":"Rauch","year":"2001","journal-title":"Ann N Y Acad Sci"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1002\/ar.22578","article-title":"Cisplatin and aminoglycoside antibiotics: hearing loss and its prevention","volume":"295","author":"Schacht","year":"2012","journal-title":"Anat Rec"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1001\/archinternmed.2009.66","article-title":"Disorders of balance and vestibular function in US adults","volume":"169","author":"Agrawal","year":"2009","journal-title":"Arch Intern Med"},{"key":"ref5","year":"2018"},{"key":"ref6","year":"2023"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e34817","DOI":"10.7554\/eLife.34817","article-title":"Regenerating hair cells in vestibular sensory epithelia from humans","volume":"7","author":"Taylor","year":"2018","journal-title":"Elife"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1126\/science.8456284","article-title":"Ultrastructural evidence for hair cell regeneration in the mammalian inner ear","volume":"259","author":"Forge","year":"1993","journal-title":"Science"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1002\/(SICI)1096-9861(19980720)397:1<69::AID-CNE6>3.0.CO;2-G","article-title":"Hair cell recovery in the vestibular sensory epithelia of mature Guinea pigs","volume":"397","author":"Forge","year":"1998","journal-title":"J Comp Neurol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.heares.2008.08.010","article-title":"Spontaneous hair cell regeneration in the mouse utricle following gentamicin ototoxicity","volume":"247","author":"Kawamoto","year":"2009","journal-title":"Hear Res"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"15093","DOI":"10.1523\/JNEUROSCI.1709-12.2012","article-title":"Hair cell replacement in adult mouse utricles after targeted ablation of hair cells with diphtheria toxin","volume":"32","author":"Golub","year":"2012","journal-title":"J Neurosci"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"15329","DOI":"10.1523\/JNEUROSCI.2057-11.2011","article-title":"Inhibition of notch activity promotes nonmitotic regeneration of hair cells in adult mouse utricles","volume":"31","author":"Lin","year":"2011","journal-title":"J Neurosci"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1007\/s10162-013-0414-z","article-title":"Hair cell generation by notch inhibition in the adult mammalian cristae","volume":"14","author":"Slowik","year":"2013","journal-title":"J Assoc Res Otolaryngol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1006\/frne.1993.1006","article-title":"C-fos and related immediate early gene products as markers of activity in neuroendocrine systems","volume":"14","author":"Hoffman","year":"1993","journal-title":"Front Neuroendocrinol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1111\/j.1365-2826.2008.01734.x","article-title":"Measurement of immediate-early gene activation- c-fos and beyond","volume":"20","author":"Kov\u00e1cs","year":"2008","journal-title":"J Neuroendocrinol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S0301-0082(96)00021-4","article-title":"Activation of c-fos in the brain","volume":"50","author":"Herrera","year":"1996","journal-title":"Prog Neurobiol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.brainres.2010.05.087","article-title":"Otolith stimulation induces c-Fos expression in vestibular and precerebellar nuclei in cats and squirrel monkeys","volume":"1351","author":"Baizer","year":"2010","journal-title":"Brain Res"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1002\/cne.11048","article-title":"Fos expression in otolith-related brainstem neurons of postnatal rats following off-vertical axis rotation","volume":"470","author":"Lai","year":"2004","journal-title":"J Comp Neurol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.1111\/j.1460-9568.2006.04762.x","article-title":"Maturation of otolith-related brainstem neurons in the detection of vertical linear acceleration in rats","volume":"23","author":"Lai","year":"2006","journal-title":"Eur J Neurosci"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/0006-8993(91)90637-B","article-title":"Activation of a specific vestibulo-olivary pathway by centripetal acceleration in rat","volume":"562","author":"Kaufman","year":"1991","journal-title":"Brain Res"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"4489","DOI":"10.1523\/JNEUROSCI.12-11-04489.1992","article-title":"Fos-defined activity in rat brainstem following centripetal acceleration","volume":"12","author":"Kaufman","year":"1992","journal-title":"J Neurosci"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.brainresrev.2005.06.001","article-title":"Fos expression in the vestibular brainstem: what one marker can tell us about the network","volume":"50","author":"Kaufman","year":"2005","journal-title":"Brain Res Rev"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"7878","DOI":"10.1523\/JNEUROSCI.2179-14.2015","article-title":"Selective deletion of cochlear hair cells causes rapid age-dependent changes in spiral ganglion and cochlear nucleus neurons","volume":"35","author":"Tong","year":"2015","journal-title":"J Neurosci"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/S0165-0270(00)00218-1","article-title":"A comparison of video and magnetic search coil recordings of mouse eye movements","volume":"99","author":"Stahl","year":"2000","journal-title":"J Neurosci Methods"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"3419","DOI":"10.1016\/j.visres.2004.09.006","article-title":"Comparison of plasticity and development of mouse optokinetic and vestibulo-ocular reflexes suggests differential gain control mechanisms","volume":"44","author":"Faulstich","year":"2004","journal-title":"Vis Res"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.jneumeth.2010.08.023","article-title":"A preformed ccleral search coil for measuring mouse eye movements","volume":"193","author":"Kaneko","year":"2010","journal-title":"J Neurosci Methods"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"4","DOI":"10.3389\/fneur.2012.00004","article-title":"Fos expression in neurons of the rat vestibulo-autonomic pathway activated by sinusoidal galvanic vestibular stimulation","volume":"3","author":"Holstein","year":"2012","journal-title":"Front Neurol"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s00221-011-2604-4","article-title":"Sinusoidal galvanic vestibular stimulation (sGVS) induces a vasovagal response in the rat","volume":"210","author":"Cohen","year":"2011","journal-title":"Exp Brain Res"},{"key":"ref29","volume-title":"The mouse brain in stereotaxic coordinates","author":"Paxinos","year":"2001"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.18128","article-title":"Supporting cells remove and replace sensory receptor hair cells in a balance organ of adult mice","volume":"6","author":"Bucks","year":"2017","journal-title":"Elife"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"3141","DOI":"10.1002\/cne.23625","article-title":"Large basolateral processes on type II hair cells are novel processing units in mammalian vestibular organs","volume":"522","author":"Pujol","year":"2014","journal-title":"J Comp Neurol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"9445","DOI":"10.1073\/pnas.94.17.9445","article-title":"Essential role of POU-domain factor Brn-3c in auditory and vestibular hair cell development","volume":"94","author":"Xiang","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/381603a0","article-title":"Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development","volume":"381","author":"Erkman","year":"1996","journal-title":"Nature"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"107838","DOI":"10.1016\/j.heares.2019.107838","article-title":"Atoh1 is required in supporting cells for regeneration of vestibular hair cells in adult mice","volume":"385","author":"Hicks","year":"2020","journal-title":"Hear Res"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"108642","DOI":"10.1016\/j.heares.2022.108642","article-title":"Sox2 is required in supporting cells for normal levels of vestibular hair cell regeneration in adult mice","volume":"426","author":"Ciani Berlingeri","year":"2022","journal-title":"Hear Res"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"7779","DOI":"10.1523\/JNEUROSCI.3127-20.2021","article-title":"The differentiation status of hair cells that regenerate naturally in the vestibular inner ear of the adult mouse","volume":"41","author":"Gonz\u00e1lez-Garrido","year":"2021","journal-title":"J Neurosci"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1023\/A:1025080314925","article-title":"Functional organization of brain pathways subserving the baroreceptor reflex: studies in conscious animals using immediate early gene expression","volume":"23","author":"Dampney","year":"2003","journal-title":"Cell Mol Neurobiol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/0006-8993(82)90990-8","article-title":"Responses of vestibular-nerve afferents in the squirrel monkey to externally applied galvanic currents","volume":"252","author":"Goldberg","year":"1982","journal-title":"Brain Res"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1152\/jn.1984.51.6.1236","article-title":"Relation between discharge regularity and responses to externally applied galvanic currents in vestibular nerve afferents of the squirrel monkey","volume":"51","author":"Goldberg","year":"1984","journal-title":"J Neurophysiol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1097\/01.mao.0000169766.08421.ef","article-title":"Patient and normal three-dimensional eye-movement responses to maintained (DC) surface galvanic vestibular stimulation","volume":"26","author":"MacDougall","year":"2005","journal-title":"Otol Neurotol"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1007\/s002210050533","article-title":"Maintained ocular torsion produced by bilateral and unilateral galvanic (DC) vestibular stimulation in humans","volume":"122","author":"Watson","year":"1998","journal-title":"Exp Brain Res"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/0165-0173(92)90006-8","article-title":"Vestibular influences on the sympathetic nervous system","volume":"17","author":"Yates","year":"1992","journal-title":"Brain Res Rev"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"83","DOI":"10.3389\/fneur.2017.00083","article-title":"Vestibular activation habituates the vasovagal response in the rat","volume":"8","author":"Cohen","year":"2017","journal-title":"Front Neurol"},{"key":"ref44","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2011.00090","article-title":"What does galvanic vestibular stimulation actually activate?","volume":"2","author":"Cohen","year":"2012","journal-title":"Front Neurol"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"117","DOI":"10.3389\/fneur.2012.00117","article-title":"What galvanic vestibular stimulation actually activates","volume":"3","author":"Curthoys","year":"2012","journal-title":"Front Neurol"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/S0165-0173(98)00018-6","article-title":"Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB\/ATF proteins","volume":"28","author":"Herdegen","year":"1998","journal-title":"Brain Res Rev"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1097\/00001756-199210000-00002","article-title":"Brainstem Fos expression following acute unilateral labyrinthectomy in the rat","volume":"3","author":"Kaufman","year":"1992","journal-title":"Neuroreport"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/0006-8993(95)00950-U","article-title":"Effects of MK801 on Fos expression in the rat brainstem after unilateral labyrinthectomy","volume":"700","author":"Kitahara","year":"1995","journal-title":"Brain Res"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1080\/03655230601065175","article-title":"C-Fos expression in the mouse brainstem after unilateral labyrinthectomy","volume":"127","author":"Tsuji","year":"2007","journal-title":"Acta Otolaryngol"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/S0197-0186(98)00023-0","article-title":"C-Fos as a transcription factor: a stressful re-view from a functional map","volume":"33","author":"Kov\u00e1cs","year":"1998","journal-title":"Neurochem Int"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/0306-4522(94)00355-9","article-title":"Pattern and time course of immediate early gene expression in rat brain following acute stress","volume":"64","author":"Cullinan","year":"1995","journal-title":"Neuroscience"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1159\/000357587","article-title":"Does vestibular end-organ function recover after gentamicin-induced trauma in Guinea pigs?","volume":"19","author":"Bremer","year":"2014","journal-title":"Audiol Neurotol"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.celrep.2019.06.028","article-title":"Atoh1 directs regeneration and functional recovery of the mature mouse vestibular system","volume":"28","author":"Sayyid","year":"2019","journal-title":"Cell Rep"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1152\/jn.00160.2004","article-title":"Effects of intratympanic gentamicin on vestibular afferents and hair cells in the chinchilla","volume":"93","author":"Hirvonen","year":"2005","journal-title":"J Neurophysiol"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"R181","DOI":"10.1152\/ajpregu.00317.2022","article-title":"Behavioral and neural responses to high strength magnetic fields are reduced in otolith mutant mice","volume":"325","author":"Cote","year":"2023","journal-title":"Am J Phys Regul Integr Comp Phys"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1146\/annurev-neuro-061010-113710","article-title":"Vestibular hair cells and afferents: two channels for head motion signals","volume":"34","author":"Eatock","year":"2011","journal-title":"Annu Rev Neurosci"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/S0378-5955(99)00046-5","article-title":"Distribution and time course of hair cell regeneration in the pigeon utricle","volume":"133","author":"Dye","year":"1999","journal-title":"Hear Res"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/cne.903310106","article-title":"Hair cell regeneration after streptomycin toxicity in the avian vestibular epithelium","volume":"331","author":"Weisleder","year":"1993","journal-title":"J Comp Neurol"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/0378-5955(94)00169-Q","article-title":"Hair cell replacement in avian vestibular epithelium: supporting cell to type I hair cell","volume":"82","author":"Weisleder","year":"1995","journal-title":"Hear Res"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"2881","DOI":"10.1523\/JNEUROSCI.3903-05.2006","article-title":"Regeneration of vestibular otolith afferents after ototoxic damage","volume":"26","author":"Zakir","year":"2006","journal-title":"J Neurosci"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"3301","DOI":"10.1152\/jn.1996.76.5.3301","article-title":"Hair cell regeneration and recovery of the vestibuloocular reflex in the avian vestibular system","volume":"76","author":"Carey","year":"1996","journal-title":"J Neurophysiol"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1152\/jn.1999.81.3.1025","article-title":"Recovery of the vestibulocolic reflex after aminoglycoside ototoxicity in domestic chickens","volume":"81","author":"Goode","year":"1999","journal-title":"J Neurophysiol"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1152\/jn.01038.2007","article-title":"Recovery of gaze stability during vestibular regeneration","volume":"99","author":"Haque","year":"2008","journal-title":"J Neurophysiol"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"6111","DOI":"10.1523\/JNEUROSCI.23-14-06111.2003","article-title":"Caspase inhibitors promote vestibular hair cell survival and function after aminoglycoside treatment in vivo","volume":"23","author":"Matsui","year":"2003","journal-title":"J Neurosci"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2024.1322647\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T04:44:43Z","timestamp":1709873083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2024.1322647\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,8]]},"references-count":64,"alternative-id":["10.3389\/fneur.2024.1322647"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2024.1322647","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,8]]},"article-number":"1322647"}}