Hiroki Toyoda

Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s 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’s principal noradrenergic stress nucleus. This review proposes an oral–brain axis model in which chronic MesV-related prediction error signaling engages LC-dependent stress systems, leading to neuroimmune activation, locus coeruleus–asparagine 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.

Objective: This study evaluated the educational value and motivational impact of unit-based Key Terminology Tests, combined with a dedicated glossary, in a second-year dental physiology course designed to support preparation for computer-based testing (CBT) and the Japanese National Dentist Examination. Methods: Seventy-six second-year dental students completed periodic terminology tests aligned with lecture units (50 items per test, 25 min each). Bonus points were awarded for scores of ≥45/50. At the end of the semester, students completed an anonymous questionnaire assessing perceived test burden (scope, duration, and number of items), preparation time, clarity and use of the glossary, perceived contribution to lecture comprehension, and the motivational impact of bonus points. Quantitative data were summarized descriptively, and free-text responses were analyzed thematically. Results: Most students rated the test scope and number of questions as appropriate (50.0% and 67.1%, respectively), although 48.7% perceived the scope as somewhat excessive or excessive, and 35.6% felt the time limit was short or somewhat short. The glossary improved lecture comprehension for 68.4% of respondents, and bonus points enhanced learning motivation for 53.9%. In addition, 86.9% reported using the glossary at least occasionally during routine study. Conclusions: Students perceived the terminology test system as supportive of lecture comprehension, perceived learning support, and sustained learning motivation, suggesting that it may serve as a useful preparatory approach for CBT and the National Dentist Examination.

Mastication is a fundamental rhythmic motor behavior controlled by a brainstem central pattern generator (CPG) located within the pontine and medullary reticular formations. Coordinated activation of jaw-opening and jaw-closing muscles is generated by this network and continuously refined through sensory feedback from periodontal mechanoreceptors and muscle spindles, together with descending inputs from the cortical masticatory area (CMA), basal ganglia, and cerebellum. Thus, mastication is regulated by distributed neural circuits rather than a single central locus. At the cellular level, the rhythmic activity of the masticatory CPG depends on the coordinated action of voltage-gated and ligand-gated ion channels. Recent electrophysiological and computational studies have identified candidate conductances that are proposed to underlie rhythm generation. Persistent sodium currents are proposed to facilitate burst initiation, whereas T-type calcium channels are thought to promote burst activation through post-inhibitory rebound. HCN channels may contribute to rhythmic timing, while calcium-activated potassium channels are thought to participate in burst termination. This review summarizes the hierarchical neural control of mastication and the biophysical mechanisms by which ion channels shape CPG rhythmogenesis. It also discusses the impact of channelopathies and neurodegenerative disorders on masticatory function, highlighting potential ion-channel-targeted therapeutic approaches for temporomandibular disorders, bruxism, and impaired mastication.

Primary sensory neurons typically regulate voluntary isometric contraction, MTN neurons are also involved in malocclusion-induced anxiety and stress, likely due to their diverse synaptic inputs from higher brain regions. Notably, stress often manifests as bruxism, whereas normal mastication aids in coping with stress. Furthermore, chronic malocclusion-induced stress may progress to Alzheimer-type dementia, suggesting an involvement of MTN in its pathogenesis (Kang et al. 2024). It was demonstrated that MTN neurons display two distinct spike waveforms depending on two functional modes: one as primary sensory neurons faithfully relaying spindle impulses to jaw-closing motoneurons (JCMNs), and the other as premotor neurons driving JCMNs independently of spindle activity (Saito et al. 2006). The switching between the two modes is mediated by Nav1.6, GluRs together with mGluR1/5, HCN, and 2A-adrenergic receptors (Chung et al. 2015;Kawasaki et al. 2018;Toyoda et al. 2022). These two modes may provide insights into the intricate involvement of MTN in both malocclusion-induced stress and stress-induced bruxism, which are likely the result of the activation of these modes. This research topic aimed to integrate findings on ion channels, receptors, neuromodulators, and transcriptome/proteome data in MTN neurons, which are likely involved in transitioning between the two functional modes of MTN neurons.In regard to the mode of primary sensory neuron, the review by Lee and Oh provides a comprehensive molecular and developmental framework for MTN neurons, emphasizing their role in coordinated oral motor function and potential links to cognitive decline. They identified three unique features of MTN neurons that distinguish them from dorsal root ganglion (DRG) proprioceptors: 1) Origin and Location: Unlike neural crest-derived DRG neurons, MTN neurons originate from the dorsal midbrain and reside within the CNS, reflecting their specialized role in complex jaw movements. A key mediator in this process is the astrocyte-derived protein S100β, which modulates extracellular calcium to facilitate ectopic firing in NVmes neurons. Notably, S100β knockout mice did not exhibit these pain-related neuronal changes, identifying a specific molecular link between glial signaling and sensory dysfunction. The findings demonstrate a causal cascade where maladaptive neuron-astrocyte signaling in a primary proprioceptive nucleus activates downstream nociceptive brainstem circuits. By showing that proprioceptive afferents can actively drive pain signaling, this study challenges traditional sensory boundaries and highlights neuron-glia interactions within primary afferent structures as promising therapeutic targets for persistent muscle pain.

The insular cortex integrates interoceptive and exteroceptive signals to support sensory perception, affective processing, and motivated behaviors. Capsaicin and menthol, prototypical agonists of TRPV1 and TRPM8 thermosensitive transient receptor potential (TRP) channels, are widely used to probe peripheral somatosensory pathways. However, these amphiphilic compounds can also modulate neuronal excitability through mechanisms independent of canonical TRP signaling. This study investigated their effects on intrinsic excitability in layer 2/3 pyramidal neurons of the mouse insular cortex using whole-cell patch-clamp recordings in acute brain slices. Bath application of capsaicin or menthol strongly suppressed repetitive action potential firing evoked by depolarizing current injections and increased the current threshold required to elicit action potentials, with minimal effects on resting membrane potential, input resistance, or spike threshold. These suppressive effects persisted in the presence of selective TRPV1 and TRPM8 antagonists, indicating a TRP-independent mechanism. Voltage-clamp recordings showed no substantial change in the voltage dependence of Na⁺ channel activation. In contrast, both compounds induced a clear hyperpolarizing shift in steady-state inactivation of voltage-gated Na⁺ channels, thereby reducing channel availability at subthreshold potentials. Additionally, both compounds reduced burst firing frequency under hyperexcitable ionic conditions. These results demonstrate that capsaicin and menthol suppress cortical pyramidal neuron excitability primarily by stabilizing the inactivated state of voltage-gated Na⁺ channels, independent of canonical TRP signaling. The findings highlight direct actions on Na⁺ channels that should be considered when interpreting the effects of these compounds in central neurons beyond their established role as selective TRP agonists.

Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer’s disease (AD). Increases in cytosolic noradrenaline (NA) concentration and monoamine oxidase A (MAO-A) activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclusively in cytoplasmic vesicles from dopamine by dopamine-β-hydroxylase. Since reuptake of autocrine-released NA following spike activity is the major source of NA accumulation, we investigated whether and how chronic stress can increase the spike activity accompanied by NA autocrine. Overexcitation of LC neurons is normally prevented by the autoinhibition mediated by activation of α2A-adrenergic receptor (AR)-coupled inwardly rectifying potassium-current (GIRK-I) with autocrine-released NA. Patch-clamp study revealed that NA-induced GIRK-I in LC neurons was decreased in chronic restraint stress (RS) mice, while a similar decrease was gradually caused by repeated excitation. Chronic RS caused internalization of α2A-ARs expressed in cell membrane in LC neurons and decreased protein/mRNA levels of α2A-ARs/GIRKs in membrane fraction. Subsequently, chronic RS increased the protein levels of MAO-A, DOPEGAL-induced asparagine endopeptidase (AEP), and tau N368. These results suggest that chronic RS-induced overexcitation due to the internalization of α2A-ARs/GIRK is accompanied by [Ca ²⁺ ] _i increases, subsequently increasing Ca ²⁺ -dependent MAO-A activity and NA autocrine. Thus, it is likely that internalization of α2A-AR increased cytosolic NA, as reflected in AEP increases, by facilitating reuptake of autocrine-released NA. The suppression of α2A-AR internalization may have a translational potential for anxiety/AD treatment.

Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer’s disease (AD). Increases in cytosolic noradrenaline (NA) concentration and MAO-A activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl- glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclusively in cytoplasmic vesicles from dopamine by dopamine-β-hydroxylase. Since re-uptake of autocrine-released NA following spike activity is the major source of NA accumulation, we investigated whether and how chronic stress can increase the spike activity accompanied by NA-autocrine. Overexcitation of LC neurons is normally prevented by the autoinhibition mediated by activation of α2A-adrenergic receptor (AR)-coupled inwardly rectifying potassium-current (GIRK-I) with autocrine-released NA. Patch-clamp study revealed that NA-induced GIRK-I in LC neurons was decreased in chronic restraint stress (RS) mice while a similar decrease was gradually caused by repeated excitation. Chronic RS caused internalization of α2A-ARs expressed in cell membrane in LC neurons and decreased protein/mRNA levels of α2A-ARs/GIRKs in membrane fraction. Subsequently, chronic RS increased the protein levels of MAO-A, DOPEGAL-induced asparagine endopeptidase (AEP) and tau N368. These results suggest that chronic RS-induced overexcitation due to the internalization of α2A-ARs/GIRK is accompanied by [Ca2+]i increases, subsequently increasing Ca2+-dependent MAO-A activity and NA-autocrine. Thus, it is likely that internalization of α2A-AR increased cytosolic NA, as reflected in AEP increases, by facilitating re-uptake of autocrine-released NA. The suppression of α2A-AR internalization may have a translational potential for anxiety/AD treatment.

Brain degenerations in sporadic Alzheimer’s disease (AD) are observed earliest in the locus coeruleus (LC), a population of noradrenergic neurons, in which hyperphosphorylated tau protein expression and β-amyloid (Aβ) accumulation begin. Along with this, similar changes occur in the basal forebrain cholinergic neurons, such as the nucleus basalis of Meynert. Neuronal degeneration of the two neuronal nuclei leads to a decrease in neurotrophic factors such as brain-derived neurotrophic factor (BDNF) in the hippocampus and cerebral cortex, which results in the accumulation of Aβ and hyperphosphorylated tau protein and ultimately causes neuronal cell death in those cortices. On the other hand, a large number of epidemiological studies have shown that tooth loss or masticatory dysfunction is a risk factor for dementia including AD, and numerous studies using experimental animals have also shown that masticatory dysfunction causes brain degeneration in the basal forebrain, hippocampus, and cerebral cortex similar to those observed in human AD, and that learning and memory functions are impaired accordingly. However, it remains unclear how masticatory dysfunction can induce such brain degeneration similar to AD, and the neural mechanism linking the trigeminal nervous system responsible for mastication and the cognitive and memory brain system remains unknown. In this review paper, we provide clues to the search for such “missing link” by discussing the embryological, anatomical, and physiological relationship between LC and its laterally adjoining mesencephalic trigeminal nucleus which plays a central role in the masticatory functions.