{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:27:02Z","timestamp":1790436422726,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,3,21]],"date-time":"2020-03-21T00:00:00Z","timestamp":1584748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 106-2314-B-038-038-MY2"],"award-info":[{"award-number":["MOST 106-2314-B-038-038-MY2"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB1 in the chronic phase of CCH remains unclear. We developed a novel animal model of CCH with a modified bilateral common carotid artery occlusion (BCCAO) in C57BL\/6 mice. Cerebral blood flow (CBF) reduction, the expression of HMGB1 and its proinflammatory cytokines (tumor necrosis factor-alpha [TNF-\u03b1], interleukin [IL]-1\u03b2, and IL-6), and brain pathology were assessed. Furthermore, we evaluated the effect of HMGB1 suppression through bilateral intrahippocampus injection with the CRISPR\/Cas9 knockout plasmid. Three months after CCH induction, CBF decreased to 30\u201350% with significant cognitive decline in BCCAO mice. The 7T-aMRI showed hippocampal atrophy, but amyloid positron imaging tomography showed nonsignificant amyloid-beta accumulation. Increased levels of HMGB1, TNF-\u03b1, IL-1\u03b2, and IL-6 were observed 3 months after BCCAO. HMGB1 suppression with CRISPR\/Cas9 knockout plasmid restored TNF-\u03b1, IL-1\u03b2, and IL-6 and attenuated hippocampal atrophy and cognitive decline. We believe that HMGB1 plays a pivotal role in CCH-induced VCI pathophysiology and can be a potential therapeutic target of VCI.<\/jats:p>","DOI":"10.3390\/ijms21062176","type":"journal-article","created":{"date-parts":[[2020,3,23]],"date-time":"2020-03-23T04:03:01Z","timestamp":1584936181000},"page":"2176","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2741-2983","authenticated-orcid":false,"given":"Amelia Nur","family":"Vidyanti","sequence":"first","affiliation":[{"name":"International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Neurology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Yu","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Neurology, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1933-4564","authenticated-orcid":false,"given":"Kun-Ju","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Molecular Imaging Center, Linkou Chang Gung Memorial Hospital, Taoyuan City, 33302, Taiwan"},{"name":"Healthy Aging Research Center and Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao-Ching","family":"Fang","sequence":"additional","affiliation":[{"name":"Taipei Neuroscience Institute, Taipei 23561, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail","family":"Setyopranoto","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaur-Jong","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neurology, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Taipei Neuroscience Institute, Taipei 23561, Taiwan"},{"name":"Department of Neurology and Dementia Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"The PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1161\/CIRCRESAHA.116.308426","article-title":"Vascular Cognitive Impairment","volume":"120","author":"Dichgans","year":"2017","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1161\/CIRCRESAHA.116.308427","article-title":"Cerebral vascular disease and neurovascular injury in ischemic stroke","volume":"120","author":"Hu","year":"2017","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1042\/CS20160727","article-title":"Chronic cerebral hypoperfusion: A key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia","volume":"131","author":"Duncombe","year":"2017","journal-title":"Clin. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fnagi.2014.00010","article-title":"Chronic cerebral hypoperfusion causes decrease of O-GlcNAcylation, hyperphosphorylation of tau and behavioral deficits in mice","volume":"6","author":"Zhao","year":"2014","journal-title":"Front. Aging Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1161\/01.STR.0000143725.19053.60","article-title":"White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion","volume":"35","author":"Shibata","year":"2004","journal-title":"Stroke"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.brainresrev.2007.01.003","article-title":"Permanent, bilateral common carotid artery occlusion in the rat: A model for chronic cerebral hypoperfusion-related neurodegenerative diseases","volume":"54","author":"Farkas","year":"2007","journal-title":"Brain Res. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1177\/0271678X15606717","article-title":"Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory","volume":"36","author":"Kitamura","year":"2016","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.brainres.2006.02.134","article-title":"The effect of pre-and posttreatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat","volume":"1087","author":"Farkas","year":"2006","journal-title":"Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ejphar.2007.07.019","article-title":"Effects of cyclooxygenase (COX) inhibition on memory impairment and hippocampal damage in the early period of cerebral hypoperfusion in rats","volume":"574","author":"Institoris","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Washida, K., Hattori, Y., and Ihara, M. (2019). Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246176"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"32179","DOI":"10.1038\/srep32179","article-title":"Substantial reduction of parenchymal cerebral blood flow in mice with bilateral common carotid artery stenosis","volume":"6","author":"Hattori","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e002757","DOI":"10.1161\/JAHA.115.002757","article-title":"Gradual carotid artery stenosis in mice closely replicates hypoperfusive vascular dementia in humans","volume":"5","author":"Hattori","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_13","first-page":"220","article-title":"Neuronal damage of the dorsal hippocampus induced by long-term right common carotid artery occlusion in rats","volume":"17","author":"Tilokskulchai","year":"2014","journal-title":"Iran. J. Basic Med Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0143-4160(03)00141-6","article-title":"Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity","volume":"34","author":"Arundine","year":"2003","journal-title":"Cell Calcium"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0361-9230(98)00024-0","article-title":"Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis","volume":"46","author":"Martin","year":"1998","journal-title":"Brain Res. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1161\/HYPERTENSIONAHA.111.173534","article-title":"Attenuation of brain damage and cognitive impairment by direct renin inhibition in mice with chronic cerebral hypoperfusion","volume":"58","author":"Dong","year":"2011","journal-title":"Hypertension"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1089\/ars.2010.3356","article-title":"High-mobility group box 1, oxidative stress, and disease","volume":"14","author":"Tang","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nri1594","article-title":"High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal","volume":"5","author":"Lotze","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/j.autrev.2012.03.007","article-title":"HMGB1 in vascular diseases: Its role in vascular inflammation and atherosclerosis","volume":"11","author":"Westra","year":"2012","journal-title":"Autoimmun. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"31895","DOI":"10.1038\/srep31895","article-title":"HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer\u2019s disease","volume":"6","author":"Fujita","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/s12974-016-0670-z","article-title":"HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer\u2019s disease","volume":"13","author":"Festoff","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.neuroscience.2018.05.010","article-title":"HMGB1 neutralization attenuates hippocampal neuronal death and cognitive impairment in rats with chronic cerebral hypoperfusion via suppressing inflammatory responses and oxidative stress","volume":"383","author":"Hei","year":"2018","journal-title":"Neuroscience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1101\/lm.1484509","article-title":"A cognitive map for object memory in the hippocampus","volume":"16","author":"Manns","year":"2009","journal-title":"Learn. Mem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1093\/cercor\/bhg081","article-title":"The aging hippocampus: Cognitive, biochemical and structural findings","volume":"13","author":"Driscoll","year":"2003","journal-title":"Cereb. Cortex"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s10339-011-0430-z","article-title":"The novel object recognition memory: Neurobiology, test procedure, and its modifications","volume":"13","author":"Antunes","year":"2012","journal-title":"Cogn. Process."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Denninger, J.K., Smith, B.M., and Kirby, E.D. (2018). Novel Object Recognition and Object Location Behavioral Testing in Mice on a Budget. J. Vis. Exp., e58593.","DOI":"10.3791\/58593-v"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1002\/hbm.20934","article-title":"Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer\u2019s disease","volume":"31","author":"Mueller","year":"2010","journal-title":"Hum. Brain Mapp."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.neures.2018.06.002","article-title":"Acceleration of NLRP3 inflammasome by chronic cerebral hypoperfusion in Alzheimer\u2019s disease model mouse","volume":"143","author":"Shang","year":"2019","journal-title":"Neurosci. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"978761","DOI":"10.4061\/2011\/978761","article-title":"Lessons from a mouse model characterizing features of vascular cognitive impairment with white matter changes","volume":"2011","author":"Ihara","year":"2011","journal-title":"J. Aging Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.expneurol.2016.07.006","article-title":"Chronic cerebral hypoperfusion induces memory deficits and facilitates A\u03b2 generation in C57BL\/6J mice","volume":"283","author":"Wang","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.nbd.2016.07.013","article-title":"Chronic cerebral hypoperfusion-induced impairment of A\u03b2 clearance requires HB-EGF-dependent sequential activation of HIF1\u03b1 and MMP9","volume":"95","author":"Ashok","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1042\/CS20170962","article-title":"Chronic cerebral hypoperfusion alters amyloid-\u03b2 peptide pools leading to cerebral amyloid angiopathy, microinfarcts and haemorrhages in Tg-SwDI mice","volume":"131","author":"Salvadores","year":"2017","journal-title":"Clin. Sci."},{"key":"ref_33","first-page":"P693","article-title":"Chronic cerebral hypoperfusion increases amyloid plaques by accelerating amyloid beta aggregation in app\/ps1 transgenic mice","volume":"14","author":"Bannai","year":"2018","journal-title":"Alzheimer\u2019s Dement. J. Alzheimer\u2019s Assoc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3670","DOI":"10.1007\/s12035-016-9915-1","article-title":"Molecular mechanisms of vascular dementia: What can be learned from animal models of chronic cerebral hypoperfusion?","volume":"54","author":"Du","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.bbr.2004.12.016","article-title":"Permanent, 3-stage, 4-vessel occlusion as a model of chronic and progressive brain hypoperfusion in rats: A neurohistological and behavioral analysis","volume":"160","author":"Neto","year":"2005","journal-title":"Behav. Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.brainres.2009.07.078","article-title":"Chronic cerebral hypoperfusion accelerates amyloid \u03b2 deposition in APPSwInd transgenic mice","volume":"1294","author":"Kitaguchi","year":"2009","journal-title":"Brain Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.expneurol.2007.12.005","article-title":"Chronic cerebral hypoperfusion induced by right unilateral common carotid artery occlusion causes delayed white matter lesions and cognitive impairment in adult mice","volume":"210","author":"Yoshizaki","year":"2008","journal-title":"Exp. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/j.cub.2013.07.002","article-title":"The rodent hippocampus is essential for nonspatial object memory","volume":"23","author":"Cohen","year":"2013","journal-title":"Curr. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1002\/hipo.22615","article-title":"Detecting and discriminating novel objects: The impact of perirhinal cortex disconnection on hippocampal activity patterns","volume":"26","author":"Kinnavane","year":"2016","journal-title":"Hippocampus"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0006-8993(96)01453-9","article-title":"C57BL\/6 strain is most susceptible to cerebral ischemia following bilateral common carotid occlusion among seven mouse strains: Selective neuronal death in the murine transient forebrain ischemia","volume":"752","author":"Yang","year":"1997","journal-title":"Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jchemneu.2018.04.006","article-title":"Transient global cerebral ischemia differentially affects cortex, striatum and hippocampus in Bilateral Common Carotid Arterial occlusion (BCCAo) mouse model","volume":"92","author":"Wahul","year":"2018","journal-title":"J. Chem. Neuroanat."},{"key":"ref_42","first-page":"233","article-title":"Neurological Changes in Vulnerable Brain Areas of Chronic Cerebral Hypoperfusion Mice","volume":"24","author":"Somredngan","year":"2017","journal-title":"Ann. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s10571-015-0286-3","article-title":"Animal models of vascular cognitive impairment and dementia (VCID)","volume":"36","author":"Gooch","year":"2016","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.3233\/JAD-171094","article-title":"The effect of chronic cerebral hypoperfusion on amyloid-\u03b2 metabolism in a transgenic mouse model of Alzheimer\u2019s disease (PS1V97L)","volume":"62","author":"Yang","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1212\/WNL.54.2.362","article-title":"Hypoxia, hyperoxia, ischemia, and brain necrosis","volume":"54","author":"Miyamoto","year":"2000","journal-title":"Neurology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.smim.2018.02.011","article-title":"High-mobility group box 1 protein (HMGB1) operates as an alarmin outside as well as inside cells","volume":"38","author":"Andersson","year":"2018","journal-title":"Semin. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1097\/00001756-199801050-00033","article-title":"Chronic cerebral hypoperfusion elicits neuronal apoptosis and behavioral impairment","volume":"9","author":"Bennett","year":"1998","journal-title":"Neuroreport"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6413","DOI":"10.1523\/JNEUROSCI.3815-05.2006","article-title":"HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain","volume":"26","author":"Kim","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1161\/STROKEAHA.107.495820","article-title":"Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1\u2013inhibiting mechanism","volume":"39","author":"Hayakawa","year":"2008","journal-title":"Stroke"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"12023","DOI":"10.1523\/JNEUROSCI.2435-08.2008","article-title":"The HMGB1 receptor RAGE mediates ischemic brain damage","volume":"28","author":"Muhammad","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1002\/glia.23174","article-title":"Astrocyte-derived lipocalin-2 mediates hippocampal damage and cognitive deficits in experimental models of vascular dementia","volume":"65","author":"Kim","year":"2017","journal-title":"Glia"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1007\/s11064-016-2153-0","article-title":"HMGB1-TLR4 axis plays a regulatory role in the pathogenesis of mesial temporal lobe epilepsy in immature rat model and children via the p38MAPK signaling pathway","volume":"42","author":"Yang","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Speetzen, L.J., Endres, M., and Kunz, A. (2013). Bilateral common carotid artery occlusion as an adequate preconditioning stimulus to induce early ischemic tolerance to focal cerebral ischemia. JoVE (J. Vis. Exp.).","DOI":"10.3791\/4387-v"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e12366","DOI":"10.1111\/micc.12366","article-title":"Astrocyte activation and capillary remodeling in modified bilateral common carotid artery occlusion mice","volume":"24","author":"Song","year":"2017","journal-title":"Microcirculation"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.expneurol.2015.05.006","article-title":"Models and mechanisms of vascular dementia","volume":"272","author":"Venkat","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1111\/j.1471-4159.2010.06958.x","article-title":"Experimental models of vascular dementia and vascular cognitive impairment: A systematic review","volume":"115","author":"Jiwa","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"17948","DOI":"10.1523\/JNEUROSCI.1860-12.2012","article-title":"Cognitive deficits and delayed neuronal loss in a mouse model of multiple microinfarcts","volume":"32","author":"Wang","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Luong, T.N., Carlisle, H.J., Southwell, A., and Patterson, P.H. (2011). Assessment of motor balance and coordination in mice using the balance beam. JoVE (J. Vis. Exp.).","DOI":"10.3791\/2376"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Tung, V.W., Burton, T.J., Dababneh, E., Quail, S.L., and Camp, A.J. (2014). Behavioral assessment of the aging mouse vestibular system. JoVE (J. Vis. Exp.).","DOI":"10.3791\/51605-v"},{"key":"ref_60","unstructured":"Franklin, K.B., and Paxinos, G. (2008). The Mouse Brain in Stereotaxic Coordinates, Academic Press."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/6\/2176\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:10:28Z","timestamp":1760173828000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/6\/2176"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,21]]},"references-count":60,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["ijms21062176"],"URL":"https:\/\/doi.org\/10.3390\/ijms21062176","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,21]]}}}