Reduced mastication during growth inhibits cognitive function by affecting trigeminal ganglia and modulating Wnt signaling pathway and ARHGAP33 molecular transmission.

Binding of brain-derived neurotrophic factor (BDNF) to its receptor tyrosine kinase B (TrkB) is essential for the development of the hippocampus, which regulates memory and learning. Decreased masticatory stimulation during growth reportedly increases BDNF expression while decreasing TrkB expression in the hippocampus. Increased BDNF expression is associated with Wnt family member 3A (Wnt3a) expression and decreased expression of Rho GTPase Activating Protein 33 (ARHGAP33), which regulates intracellular transport of TrkB. TrkB expression may be decreased at the cell surface and affects the hippocampus via BDNF/TrkB signaling. Mastication affects cerebral blood flow and the neural cascade that occurs through the trigeminal nerve and hippocampus. In the current study, we hypothesized that decreased masticatory stimulation reduces memory/learning in mice due to altered Wnt3a and ARHGAP33 expression, which are related to memory/learning functions in the hippocampus. To test this hypothesis, we fed mice a powdered diet until 14 weeks of age and analyzed the BDNF and TrkB mRNA expression in the right hippocampus using real-time polymerase chain reaction and Wnt3a and ARHGAP33 levels in the left hippocampus using western blotting. Furthermore, we used staining to assess BDNF and TrkB expression in the hippocampus and the number of nerve cells, the average size of each single cell and the area of intercellular spaces of the trigeminal ganglion (TG). We found that decreased masticatory stimulation affected the expression of BDNF, Wnt3a, ARHGAP33, and TrkB proteins in the hippocampus, as well as memory/learning. The experimental group showed significantly decreased numbers of neurons and increased the area of intercellular spaces in the TG. Our findings suggest that reduced masticatory stimulation during growth induces a decline in memory/learning by modulating molecular transmission mechanisms in the hippocampus and TG.

Pre-Adolescent Diet Normalization Restores Cognitive Function in Young Mice.

Mastication is a fundamental function critical for human health. Controlled by the central nervous system (CNS), it influences CNS development and function. A poor masticatory performance causes cognitive dysfunction in both older adults and children. Improving mastication may prevent cognitive decline. However, no study has determined the period of masticatory dysfunction that impairs children's later acquisition of cognitive function. Herein, we developed an animal model wherein a soft diet was switched to a normal diet at early and late time points in young mice. We aimed to investigate the impact of restored mastication on learning and memory function. Behavioral studies were conducted to evaluate learning and memory. Micro-CT was used to evaluate orofacial structural differences, while histological and biochemical approaches were employed to assess differences in the hippocampal morphology and function. Correction to a hard-textured diet before adolescence restored mastication and cognitive function through the stimulation of neurogenesis, extracellular signal-regulated kinases, the cyclic adenosine monophosphate-response element-binding protein pathway, and the brain-derived neurotrophic factor, tyrosine receptor B. In contrast, post-adolescent diet normalization failed to rescue full mastication and led to impaired cognitive function, neuronal loss, and decreased hippocampal neurogenesis. These findings revealed a functional linkage between the masticatory and cognitive function in mice during the juvenile to adolescent period, highlighting the need for adequate food texture and early intervention for mastication-related cognitive impairment in children.

Effect of Obesity on Masticatory Muscle Activity and Rhythmic Jaw Movements Evoked by Electrical Stimulation of Different Cortical Masticatory Areas.

This study investigates rhythmic jaw movement (RJM) patterns and masticatory muscle activities during electrical stimulation in two cortical masticatory areas in obese male Zucker rats (OZRs), compared to their counterparts-lean male Zucker rats (LZRs) (seven each). At the age of 10 weeks, electromyographic (EMG) activity of the right anterior digastric muscle (RAD) and masseter muscles, and RJMs were recorded during repetitive intracortical micro-stimulation in the left anterior and posterior parts of the cortical masticatory area (A-area and P-area, respectively). Only P-area-elicited RJMs, which showed a more lateral shift and slower jaw-opening pattern than A-area-elicited RJMs, were affected by obesity. During P-area stimulation, the jaw-opening duration was significantly shorter (p < 0.01) in OZRs (24.3 ms) than LZRs (27.9 ms), the jaw-opening speed was significantly faster (p < 0.05) in OZRs (67.5 mm/s) than LZRs (50.8 mm/s), and the RAD EMG duration was significantly shorter (p < 0.01) in OZRs (5.2 ms) than LZR (6.9 ms). The two groups had no significant difference in the EMG peak-to-peak amplitude and EMG frequency parameters. This study shows that obesity affects the coordinated movement of masticatory components during cortical stimulation. While other factors may be involved, functional change in digastric muscle is partly involved in the mechanism.

Unilateral nasal obstruction affects development of cortical orofacial motor representation in the cortical masticatory area of growing rats.

The cortical masticatory area (CMA) regulates masticatory movements. However, there is limited information regarding the effect of respiratory disturbances on the functional development of the CMA. This study aimed to examine the effect of chronic unilateral nasal obstruction (UNO) on the CMA during the growth period. Forty-eight 8-day-old male Wistar albino rats were randomized into control (CONT, n = 24) and UNO (n = 24) groups. Arterial oxygen saturation (SpO2) and the number of positive intracortical microstimulation (ICMS) sites in the anterior digastric (AD) muscle were recorded at 5, 7, and 9 weeks of age. ICMS was performed under anesthesia. The CONT group exhibited significantly higher SpO2 values than the UNO group at each age. Furthermore, the number of positive ICMS sites in the AD muscle was significantly higher in the UNO group than in the CONT group at each age. The right AD was more strongly affected by UNO than the left AD. In addition, it was found that the P-area was more strongly affected by UNO than the A-area. These findings suggest that UNO during development induces changes in the motor representation in the CMA, which may affect respiratory and orofacial functions in rats. Therefore, we suggest that the development of respiratory dysfunction needs to be monitored and corrected promptly to avoid complications in physiological function.

Nasal obstruction during the growth period modulates the Wnt/ß-catenin pathway and brain-derived neurotrophic factor production in association with tyrosine kinase receptor B mRNA reduction in mouse hippocampus.

There is accumulating evidence that nasal obstruction induces high-level brain dysfunction, including memory and learning deficits. We previously demonstrated that unilateral nasal obstruction (UNO) during the growth period increases the expression of brain-derived neurotrophic factor (BDNF). The expression of BDNF is regulated by the Wnt/ß-Catenin pathway, which is linked to neuronal differentiation, proliferation, and maintenance. However, little is known about whether Wnt3a protein expression could be an index for modulations analyses in the Wnt/ß-Catenin pathway caused by UNO during the growth period. This study aimed to investigate the effects of UNO during the growth period on the Wnt/ß-Catenin pathway in the hippocampus using combined behavioural, biochemical, and histological approaches. Male BALB/C mice were randomly divided into the control (CONT; n = 6) and experimental (UNO; n = 6) groups. Blood oxygen saturation (SpO2 ) levels were measured, and a passive avoidance test was performed in mice aged 15 weeks. Brain tissues were subjected to immunohistochemistry, real-time reverse transcription-polymerase chain reaction, and western blot analysis. Compared with control mice, UNO mice had lower SpO2 levels and exhibited memory/learning impairments during behavioural testing. Moreover, Wnt3a protein, BDNF mRNA, and tyrosine kinase receptor B (TrkB) mRNA expression levels were significantly lower in the hippocampus in the UNO group than in the CONT group. Our findings suggested that UNO during the growth period appeared to modulate the hippocampal Wnt/ß-catenin pathway and BDNF production in association with TrkB mRNA reduction, thereby resulting in memory and learning impairments.

Effects of low occlusal loading on the neuromuscular behavioral development of cortically-elicited jaw movements in growing rats.

The effect of altered occlusal force on masticatory-related neuromuscular control, which projects from the anterior part of the cortical masticatory area (A-CMA), during growth remains unclear. This study sought to evaluate the effect of occlusal hypofunction on neuromuscular development of jaw muscle activities and cortically-induced rhythmic jaw movements (RJMs) in growing rats. Sixty-four 2-week-old male albino Wistar rats were divided into the control (fed normal diet) and experimental (fed soft diet) groups soon after weaning. Electromyographic activity was recorded at 5, 7, 9, and 11 weeks from the right masseter and anterior digastric along with RJMs. We found a significantly longer onset latency and smaller peak-to-peak amplitude in the experimental group than that in the control group. The RJMs showed an increase in gape size and lateral excursion until up to 9 weeks in both groups. However, both the average gape size and lateral excursion were significantly smaller in the experimental group than that in the control group after 9 weeks. The jaw movement pattern also showed a significant decrease at the maximum opening period in the experimental group. Our findings indicate that inadequate occlusal function during growth alters neuromuscular control of masticatory behaviors and impairs the pattern of RJMs.

Functional Analysis of Rhythmic Jaw Movements Evoked by Electrical Stimulation of the Cortical Masticatory Area During Low Occlusal Loading in Growing Rats.

The maturation of rhythmic jaw movements (RJMs) and related neuromuscular control has rarely been studied in animals, though this process is essential for regulating the development of stomatognathic functions. Previous studies have shown that occlusal hypofunction during growth alters masticatory performance. However, little is known about patterns of cortically-induced RJMs under conditions of soft-diet feeding during development. The aim of this study is to clarify the effect of low occlusal loading on the pattern of cortically induced RJMs and related neuromuscular responses in growing rats. Sixty-four 2-week-old male albino Wistar rats were randomly divided into two groups and fed on either a normal diet (control) or soft diet (experimental) soon after weaning. At 5, 7, 9, and 11 weeks of age, electromyographic (EMG) activity was recorded from the right masseter and anterior digastric muscles along with corresponding kinematic images in RJMs during repetitive intracortical microstimulation of the left cortical masticatory area (CMA). Rats in both groups showed an increase in gape size and lateral excursion until 9 weeks of age. The vertical jaw movement speed in both groups showed no significant difference between 5 and 7 weeks of age but increased with age from 9 to 11 weeks. Compared to the control group, the average gape size and vertical speed were significantly lower in the experimental group, and the pattern and rhythm of the jaw movement cycle were similar between both groups at each recording age. EMG recordings showed no age-related significant differences in onset latency, duration, and peak-to-peak amplitude. Moreover, we found significantly longer onset latency, smaller peak-to-peak amplitude, and greater drop-off mean and median frequencies in the experimental group than in the control group, while there was no significant difference in the duration between groups. These findings indicate that a lack of enough occlusal function in infancy impedes the development of patterns of RJMs and delays the neuromuscular response from specific stimulation of the CMA.