{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:23:50Z","timestamp":1787649830594,"version":"build-2736575974"},"reference-count":116,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K06346"],"award-info":[{"award-number":["23K06346"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Neurodegenerative diseases such as Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD) develop over decades, yet their earliest pathogenic drivers remain poorly understood. Epidemiological and experimental animal studies suggest that disturbances in oral sensorimotor regulation, particularly within trigeminal proprioceptive pathways, may contribute to neural dysfunction long before clinical symptoms emerge. The mesencephalic trigeminal nucleus (MesV), the only primary sensory neuron population located entirely within the central nervous system (CNS), links oral proprioception with brainstem and forebrain networks. Chronic occlusal mismatch, impaired mastication, sleep bruxism, and sleep-disordered breathing may generate persistent sensorimotor prediction errors that destabilize MesV-centered circuits and subsequently recruit the locus coeruleus (LC), the brain\u2019s principal noradrenergic stress nucleus. This review proposes an oral\u2013brain axis model in which chronic MesV-related prediction error signaling engages LC-dependent stress systems, leading to neuroimmune activation, locus coeruleus\u2013asparagine endopeptidase (LC-AEP) pathway engagement, and downstream proteinopathic processes. Sustained LC activity may facilitate microglial priming, reactive astrocytosis, and neuroinflammatory signaling, creating conditions that favor LC-AEP pathway activation and downstream tau pathology. Epidemiological studies associate tooth loss, reduced occlusal support, and impaired mastication with increased dementia risk, while experimental models of prodromal PD demonstrate early trigeminal sensory-processing abnormalities preceding motor symptoms. Together, these findings support the hypothesis that chronic disturbances in oral sensorimotor homeostasis may increase neurodegenerative vulnerability. This framework identifies potential biomarkers and preventive targets, suggesting that modulation of oral function and neuroimmune pathways may help reduce neurodegenerative risk before irreversible neuronal loss occurs.<\/jats:p>","DOI":"10.3390\/ijms27177597","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:04:30Z","timestamp":1787648670000},"page":"7597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Oral\u2013Brain Axis: A Unified Framework Linking Trigeminal Sensorimotor Dysfunction, Chronic Stress, Neuroinflammation, and Neurodegeneration"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9907-7176","authenticated-orcid":false,"given":"Hiroki","family":"Toyoda","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Dentistry, Aichi Gakuin University, Nagoya 464-8650, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1002\/mds.26431","article-title":"MDS research criteria for prodromal Parkinson\u2019s disease","volume":"30","author":"Berg","year":"2015","journal-title":"Mov. Disord."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S1474-4422(12)70291-0","article-title":"Tracking pathophysiological processes in Alzheimer\u2019s disease: An updated hypothetical model of dynamic biomarkers","volume":"12","author":"Jack","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/nrneurol.2016.152","article-title":"Advances in markers of prodromal Parkinson disease","volume":"12","author":"Postuma","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","article-title":"Toward defining the preclinical stages of Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Sperling","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_5","first-page":"10","article-title":"Tooth Loss Increases the Risk of Diminished Cognitive Function: A Systematic Review and Meta-analysis","volume":"1","author":"Feine","year":"2016","journal-title":"JDR Clin. Trans. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1111\/ggi.12006","article-title":"Evaluation of chewing ability and its relationship with activities of daily living, depression, cognitive status and food intake in the community-dwelling elderly","volume":"13","author":"Kimura","year":"2013","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.neubiorev.2010.06.002","article-title":"Mastication for the mind\u2014The relationship between mastication and cognition in ageing and dementia","volume":"35","author":"Weijenberg","year":"2011","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1111\/jgs.14572","article-title":"Association Between Oral Health and Cognitive Status: A Systematic Review","volume":"64","author":"Wu","year":"2016","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e95","DOI":"10.1111\/jgs.14791","article-title":"Tooth Loss and Risk of Dementia in the Community: The Hisayama Study","volume":"65","author":"Takeuchi","year":"2017","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_10","first-page":"624","article-title":"Occlusion and brain function: Mastication as a prevention of cognitive dysfunction","volume":"37","author":"Ono","year":"2010","journal-title":"J. Oral. Rehabil."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.brainresrev.2007.08.009","article-title":"Neurobiology of orofacial proprioception","volume":"56","author":"Lazarov","year":"2007","journal-title":"Brain Res. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1007\/s12264-024-01211-4","article-title":"The Insular Cortex: An Interface Between Sensation, Emotion and Cognition","volume":"40","author":"Zhang","year":"2024","journal-title":"Neurosci. Bull."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.tics.2016.01.001","article-title":"The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain","volume":"20","author":"Mather","year":"2016","journal-title":"Trends Cogn. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/nrn2573","article-title":"The locus coeruleus and noradrenergic modulation of cognition","volume":"10","author":"Sara","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1177\/10454411910020010401","article-title":"Mastication and its control by the brain stem","volume":"2","author":"Lund","year":"1991","journal-title":"Crit. Rev. Oral. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"135","DOI":"10.2535\/ofaj.87.135","article-title":"Masticatory function and cognitive function","volume":"87","author":"Kubo","year":"2010","journal-title":"Okajimas Folia Anat. Jpn."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bourdiol, P., Hennequin, M., Peyron, M.A., and Woda, A. (2020). Masticatory Adaptation to Occlusal Changes. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00263"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev-neuro-060909-153135","article-title":"Error correction, sensory prediction, and adaptation in motor control","volume":"33","author":"Shadmehr","year":"2010","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1126\/science.7569931","article-title":"An internal model for sensorimotor integration","volume":"269","author":"Wolpert","year":"1995","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/nrn2787","article-title":"The free-energy principle: A unified brain theory?","volume":"11","author":"Friston","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Seki, S., Enomoto, A., and Tanaka, S. (2026). The mesencephalic trigeminal neuron: Electrophysiological insights into function and dysfunction. Front. Cell Neurosci., 20.","DOI":"10.3389\/fncel.2026.1752701"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.sleep.2021.11.008","article-title":"Associations between sleep bruxism and other sleep-related disorders in adults: A systematic review","volume":"89","author":"Kuang","year":"2022","journal-title":"Sleep. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3892\/br.2024.1747","article-title":"Neurobiology of bruxism: The impact of stress (Review)","volume":"20","author":"Pavlou","year":"2024","journal-title":"Biomed. Rep."},{"key":"ref_24","first-page":"e12257","article-title":"Locus coeruleus in the pathogenesis of Alzheimer\u2019s disease: A systematic review","volume":"8","author":"Chen","year":"2022","journal-title":"Alzheimers Dement"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/nan.12298","article-title":"Review: Sporadic Parkinson\u2019s disease: Development and distribution of alpha-synuclein pathology","volume":"42","author":"Braak","year":"2016","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1002\/acn3.50818","article-title":"Early alteration of the locus coeruleus in phenotypic variants of Alzheimer\u2019s disease","volume":"6","author":"Olivieri","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1038\/s12276-020-00494-7","article-title":"Delta-secretase cleavage of Tau mediates its pathology and propagation in Alzheimer\u2019s disease","volume":"52","author":"Kang","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.molcel.2017.07.018","article-title":"Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer\u2019s Disease","volume":"67","author":"Wang","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"RP106362","DOI":"10.7554\/eLife.106362","article-title":"Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity","volume":"14","author":"Toyoda","year":"2025","journal-title":"Elife"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e1929232024","DOI":"10.1523\/JNEUROSCI.1929-23.2024","article-title":"Norepinephrine Drives Sleep Fragmentation Activation of Asparagine Endopeptidase, Locus Ceruleus Degeneration, and Hippocampal Amyloid-\u03b242 Accumulation","volume":"44","author":"Zhang","year":"2024","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s40035-020-00221-2","article-title":"Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes","volume":"9","author":"Kwon","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"ref_33","first-page":"3599","article-title":"Astrocytes and microglia in the coordination of CNS development and homeostasis","volume":"168","author":"Eyo","year":"2024","journal-title":"J. Neurochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.tins.2020.01.003","article-title":"Astrocytes and Microglia: In Sickness and in Health","volume":"43","author":"Vainchtein","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.semcdb.2019.01.001","article-title":"Microglia: Neuroimmune-sensors of stress","volume":"94","author":"Frank","year":"2019","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.bbi.2020.05.063","article-title":"Acute stress induces chronic neuroinflammatory, microglial and behavioral priming: A role for potentiated NLRP3 inflammasome activation","volume":"89","author":"Frank","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Evans, A.K., Defensor, E., and Shamloo, M. (2022). Selective Vulnerability of the Locus Coeruleus Noradrenergic System and its Role in Modulation of Neuroinflammation, Cognition, and Neurodegeneration. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1030609"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0006-8993(01)02410-6","article-title":"Effects of soft-diet feeding on synaptic density in the hippocampus and parietal cortex of senescence-accelerated mice","volume":"902","author":"Yamamoto","year":"2001","journal-title":"Brain Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"114547","DOI":"10.1016\/j.bbr.2023.114547","article-title":"Increased vertical dimension of occlusion for varying periods differentially impairs learning and memory in guinea pigs","volume":"452","author":"Toyoda","year":"2023","journal-title":"Behav. Brain Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.neuroscience.2021.11.016","article-title":"Postnatal Maturation of Glutamatergic Inputs onto Rat Jaw-closing and Jaw-opening Motoneurons","volume":"480","author":"Nakamura","year":"2022","journal-title":"Neuroscience"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.archoralbio.2006.08.013","article-title":"The development of mastication in rodents: From neurons to behaviors","volume":"52","author":"Turman","year":"2007","journal-title":"Arch. Oral. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1006\/mcne.2001.1045","article-title":"Expression pattern in brain of TASK-1, TASK-3, and a tandem pore domain K+ channel subunit, TASK-5, associated with the central auditory nervous system","volume":"18","author":"Karschin","year":"2001","journal-title":"Mol. Cell Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5677","DOI":"10.1523\/JNEUROSCI.5407-09.2010","article-title":"Protein kinase G dynamically modulates TASK1-mediated leak K+ currents in cholinergic neurons of the basal forebrain","volume":"30","author":"Toyoda","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3412","DOI":"10.1523\/JNEUROSCI.5274-05.2006","article-title":"Participation of sodium currents in burst generation and control of membrane excitability in mesencephalic trigeminal neurons","volume":"26","author":"Enomoto","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"72","DOI":"10.32607\/20758251-2010-2-1-72-80","article-title":"Calcium signaling and neurodegeneration","volume":"2","author":"Bezprozvanny","year":"2010","journal-title":"Acta Naturae"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.bbrc.2016.09.053","article-title":"Dysregulation of neuronal calcium homeostasis in Alzheimer\u2019s disease\u2014A therapeutic opportunity?","volume":"483","author":"Popugaeva","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/nature02621","article-title":"Pathways towards and away from Alzheimer\u2019s disease","volume":"430","author":"Mattson","year":"2004","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1474-9726.2007.00275.x","article-title":"Calcium and neurodegeneration","volume":"6","author":"Mattson","year":"2007","journal-title":"Aging Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/nrn.2016.141","article-title":"Network abnormalities and interneuron dysfunction in Alzheimer disease","volume":"17","author":"Palop","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Toyoda, H., Won, J., Kim, W., Kim, H., Davy, O., Saito, M., Kim, D., Tanaka, T., Kang, Y., and Oh, S.B. (2022). The Nature of Noradrenergic Volume Transmission from Locus Coeruleus to Brainstem Mesencephalic Trigeminal Sensory Neurons. Front. Cell Neurosci., 16.","DOI":"10.3389\/fncel.2022.841239"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ide, M., Harris, M., Stevens, A., Sussams, R., Hopkins, V., Culliford, D., Fuller, J., Ibbett, P., Raybould, R., and Thomas, R. (2016). Periodontitis and Cognitive Decline in Alzheimer\u2019s Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151081"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.jalz.2007.08.004","article-title":"Inflammation and Alzheimer\u2019s disease: Possible role of periodontal diseases","volume":"4","author":"Kamer","year":"2008","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"eaau3333","DOI":"10.1126\/sciadv.aau3333","article-title":"Porphyromonas gingivalis in Alzheimer\u2019s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors","volume":"5","author":"Dominy","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nrneurol.2014.38","article-title":"Microglial priming in neurodegenerative disease","volume":"10","author":"Perry","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0003-9969(96)00081-7","article-title":"Effect of mastication on regional cerebral blood flow in humans examined by positron-emission tomography with 15O-labelled water and magnetic resonance imaging","volume":"42","author":"Momose","year":"1997","journal-title":"Arch. Oral. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1177\/0810743","article-title":"Mapping brain region activity during chewing: A functional magnetic resonance imaging study","volume":"81","author":"Onozuka","year":"2002","journal-title":"J. Dent. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1111\/joor.70149","article-title":"Dentition-Cognition Relationship in Aging Populations: A Meta-Analysis of Longitudinal Data","volume":"53","author":"Chen","year":"2026","journal-title":"J. Oral. Rehabil."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"106522","DOI":"10.1016\/j.archoralbio.2026.106522","article-title":"Experts\u2019 narrative review \u201cMastication, Hippocampal Structure Changes and Cognition\u201d","volume":"184","author":"Piancino","year":"2026","journal-title":"Arch. Oral. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"102370","DOI":"10.1016\/j.npep.2023.102370","article-title":"Reduced mastication during growth inhibits cognitive function by affecting trigeminal ganglia and modulating Wnt signaling pathway and ARHGAP33 molecular transmission","volume":"102","author":"Okihara","year":"2023","journal-title":"Neuropeptides"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e14750","DOI":"10.1111\/cns.14750","article-title":"Cognitive decline in Sprague-Dawley rats induced by neuroplasticity changes after occlusal support loss","volume":"30","author":"Wang","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nrneurol.2012.80","article-title":"Olfactory dysfunction in Parkinson disease","volume":"8","author":"Doty","year":"2012","journal-title":"Nat. Rev. Neurol."},{"key":"ref_62","first-page":"450939","article-title":"Olfactory loss in Parkinson\u2019s disease","volume":"2011","author":"Haehner","year":"2011","journal-title":"Park. Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.neurobiolaging.2003.12.015","article-title":"Alzheimer\u2019s disease: Intraneuronal alterations precede insoluble amyloid-beta formation","volume":"25","author":"Braak","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","article-title":"Staging of brain pathology related to sporadic Parkinson\u2019s disease","volume":"24","author":"Braak","year":"2003","journal-title":"Neurobiol. Aging"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s12640-011-9281-8","article-title":"Intranasal administration of neurotoxicants in animals: Support for the olfactory vector hypothesis of Parkinson\u2019s disease","volume":"21","author":"Prediger","year":"2012","journal-title":"Neurotox. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1084\/jem.20160368","article-title":"Widespread transneuronal propagation of alpha-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson\u2019s disease","volume":"213","author":"Rey","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.expneurol.2007.07.022","article-title":"Chronic inhalation of rotenone or paraquat does not induce Parkinson\u2019s disease symptoms in mice or rats","volume":"208","author":"Rojo","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Sato, H., Satoh, K., Nozaki, K., Yugawa, M., Kato, T., Toyoda, H., Katagiri, A., Suda, N., and Adachi, K. (2024). Reduced menthol sensitivity in a prodromal Parkinson\u2019s disease model induced by intranasal rotenone treatment. Front. Cell Neurosci., 18.","DOI":"10.3389\/fncel.2024.1345651"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/nature719","article-title":"Identification of a cold receptor reveals a general role for TRP channels in thermosensation","volume":"416","author":"McKemy","year":"2002","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/S0092-8674(02)00652-9","article-title":"A TRP channel that senses cold stimuli and menthol","volume":"108","author":"Peier","year":"2002","journal-title":"Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1007\/s00429-010-0262-0","article-title":"Saliency, switching, attention and control: A network model of insula function","volume":"214","author":"Menon","year":"2010","journal-title":"Brain Struct. Funct."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1017\/S1355617715000892","article-title":"Salience and Default Mode Network Coupling Predicts Cognition in Aging and Parkinson\u2019s Disease","volume":"22","author":"Putcha","year":"2016","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.clinph.2013.09.006","article-title":"Abnormal patterns of theta frequency oscillations during the temporal evolution of freezing of gait in Parkinson\u2019s disease","volume":"125","author":"Shine","year":"2014","journal-title":"Clin. Neurophysiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1176\/appi.ajp.2014.13121691","article-title":"Sensory processing dysfunction in the personal experience and neuronal machinery of schizophrenia","volume":"172","author":"Javitt","year":"2015","journal-title":"Am. J. Psychiatry"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nrn2555","article-title":"How do you feel--now? The anterior insula and human awareness","volume":"10","author":"Craig","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Toyoda, H., Katagiri, A., Kato, T., and Sato, H. (2020). Intranasal Administration of Rotenone Reduces GABAergic Inhibition in the Mouse Insular Cortex Leading to Impairment of LTD and Conditioned Taste Aversion Memory. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010259"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.pain.2011.11.014","article-title":"Menthol pain relief through cumulative inactivation of voltage-gated sodium channels","volume":"153","author":"Gaudioso","year":"2012","journal-title":"Pain"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1097\/00003643-200208000-00005","article-title":"Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol","volume":"19","author":"Haeseler","year":"2002","journal-title":"Eur. J. Anaesthesiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nrn2148","article-title":"The action potential in mammalian central neurons","volume":"8","author":"Bean","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1113\/jphysiol.2011.224204","article-title":"Voltage-gated sodium channels at 60: Structure, function and pathophysiology","volume":"590","author":"Catterall","year":"2012","journal-title":"J. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"16021","DOI":"10.1038\/s41598-021-95638-8","article-title":"Structural network topology and microstructural alterations of the anterior insula associate with cognitive and affective impairment in Parkinson\u2019s disease","volume":"11","author":"Jonkman","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Madetko-Alster, N., Otto-Slusarczyk, D., Migda, B., Chunowski, P., Struga, M., and Alster, P. (2026). Red blood cell-derived parameters as a potential tool in the differential diagnosis of parkinsonian syndromes. Sci. Rep.","DOI":"10.1038\/s41598-026-62325-5"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4050796","DOI":"10.1155\/2019\/4050796","article-title":"The Role of Mitochondrial Damage-Associated Molecular Patterns in Chronic Neuroinflammation","volume":"2019","author":"Bajwa","year":"2019","journal-title":"Mediat. Inflamm."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1038\/s41401-022-00879-6","article-title":"Mitochondrial-derived damage-associated molecular patterns amplify neuroinflammation in neurodegenerative diseases","volume":"43","author":"Lin","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.bbi.2015.10.003","article-title":"Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex","volume":"52","author":"Bollinger","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e200023","DOI":"10.1212\/NXI.0000000000200023","article-title":"Microglia as Central Protagonists in the Chronic Stress Response","volume":"9","author":"Schramm","year":"2022","journal-title":"Neurol. Neuroimmunol. Neuroinflamm"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6303","DOI":"10.1073\/pnas.1722613115","article-title":"Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning","volume":"115","author":"Gyorffy","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e1545","DOI":"10.1002\/wsbm.1545","article-title":"Complement and microglia dependent synapse elimination in brain development","volume":"14","author":"Soteros","year":"2022","journal-title":"WIREs Mech. Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.tins.2023.11.010","article-title":"Complement-mediated synapse loss in Alzheimer\u2019s disease: Mechanisms and involvement of risk factors","volume":"47","author":"Wen","year":"2024","journal-title":"Trends Neurosci."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Lima, M.N., Barbosa-Silva, M.C., and Maron-Gutierrez, T. (2022). Microglial Priming in Infections and Its Risk to Neurodegenerative Diseases. Front. Cell Neurosci., 16.","DOI":"10.3389\/fncel.2022.878987"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.neubiorev.2019.10.013","article-title":"Microglial memory of early life stress and inflammation: Susceptibility to neurodegeneration in adulthood","volume":"117","author":"Desplats","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1523\/JNEUROSCI.3561-14.2015","article-title":"Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: A priming stimulus of microglia and the NLRP3 inflammasome","volume":"35","author":"Weber","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Mayorquin, L.C., Rodriguez, A.V., Sutachan, J.J., and Albarracin, S.L. (2018). Connexin-Mediated Functional and Metabolic Coupling Between Astrocytes and Neurons. Front. Mol. Neurosci., 11.","DOI":"10.3389\/fnmol.2018.00118"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"109106","DOI":"10.1155\/2015\/109106","article-title":"Activity-Dependent Plasticity of Astroglial Potassium and Glutamate Clearance","volume":"2015","author":"Cheung","year":"2015","journal-title":"Neural Plast."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1016\/j.bpj.2013.09.012","article-title":"Potassium buffering in the neurovascular unit: Models and sensitivity analysis","volume":"105","author":"Witthoft","year":"2013","journal-title":"Biophys. J."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41573-022-00390-x","article-title":"Function and therapeutic value of astrocytes in neurological diseases","volume":"21","author":"Lee","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/jnc.15811","article-title":"Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission-The essential roles of astrocytes","volume":"166","author":"Andersen","year":"2023","journal-title":"J. Neurochem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","article-title":"A Unique Microglia Type Associated with Restricting Development of Alzheimer\u2019s Disease","volume":"169","author":"Spinrad","year":"2017","journal-title":"Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.cell.2018.05.003","article-title":"Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration","volume":"173","author":"Deczkowska","year":"2018","journal-title":"Cell"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1038\/s41590-018-0212-1","article-title":"The identity and function of microglia in neurodegeneration","volume":"19","author":"Song","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1038\/nm.3700","article-title":"Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer\u2019s disease","volume":"20","author":"Zhang","year":"2014","journal-title":"Nat. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"17495","DOI":"10.1074\/jbc.M112.446070","article-title":"Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease","volume":"288","author":"Tung","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e70111","DOI":"10.1111\/ejn.70111","article-title":"The Locus Coeruleus: Anatomy, Physiology, and Stress-Related Neuropsychiatric Disorders","volume":"61","author":"Reyes","year":"2025","journal-title":"Eur. J. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1007\/s10266-023-00887-w","article-title":"Long-lasting adverse effects of short-term stress during the suckling-mastication transition period on masticatory function and intraoral sensation in rats","volume":"112","author":"Katagiri","year":"2024","journal-title":"Odontology"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Hashimoto, A., Nozaki, A., Inoue, H., and Kuwano, T. (2023). High masticatory ability attenuates psychosocial stress: A cross-sectional study. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0279891"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Zhao, Y.J., Liu, Y., Wang, J., Li, Q., Zhang, Z.M., Tu, T., Lei, R., Zhang, M., and Chen, Y.J. (2022). Activation of the Mesencephalic Trigeminal Nucleus Contributes to Masseter Hyperactivity Induced by Chronic Restraint Stress. Front. Cell Neurosci., 16.","DOI":"10.3389\/fncel.2022.841133"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1177\/00220345010800101501","article-title":"Sleep bruxism: An oromotor activity secondary to micro-arousal","volume":"80","author":"Kato","year":"2001","journal-title":"J. Dent. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.job.2023.04.005","article-title":"Understanding the pathophysiology of sleep bruxism based on human and animal studies: A narrative review","volume":"65","author":"Kato","year":"2023","journal-title":"J. Oral. Biosci."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1113\/JP275001","article-title":"Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor-dependent sensory long-term facilitation in naive carotid bodies","volume":"596","author":"Roy","year":"2018","journal-title":"J. Physiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e12965","DOI":"10.1111\/nan.12965","article-title":"Changes in the locus coeruleus during the course of Alzheimer\u2019s disease and their relationship to cortical pathology","volume":"50","author":"Beardmore","year":"2024","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tins.2018.01.010","article-title":"Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease","volume":"41","author":"Weinshenker","year":"2018","journal-title":"Trends Neurosci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1007\/s00429-024-02797-1","article-title":"The degeneration of locus coeruleus occurring during Alzheimer\u2019s disease clinical progression: A neuroimaging follow-up investigation","volume":"229","author":"Galgani","year":"2024","journal-title":"Brain Struct. Funct."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/s41594-022-00745-3","article-title":"Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation","volume":"29","author":"Kang","year":"2022","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"e0138","DOI":"10.1523\/ENEURO.0138-16.2016","article-title":"The Possible Role of TASK Channels in Rank-Ordered Recruitment of Motoneurons in the Dorsolateral Part of the Trigeminal Motor Nucleus","volume":"3","author":"Okamoto","year":"2016","journal-title":"eNeuro"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Saito, M., Tanaka, C., Toyoda, H., and Kang, Y. (2022). Subcellular Localization of Homomeric TASK3 Channels and Its Presumed Functional Significances in Trigeminal Motoneurons. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010344"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7597\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:05:30Z","timestamp":1787648730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7597"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":116,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177597"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177597","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}