Maternal Active Mastication during Prenatal Stress Ameliorates Prenatal Stress-Induced Lower Bone Mass in Adult Mouse Offspring.

Chronic psychological stress is a risk factor for osteoporosis. Maternal active mastication during prenatal stress attenuates stress response. The aim of this study is to test the hypothesis that maternal active mastication influences the effect of prenatal stress on bone mass and bone microstructure in adult offspring. Pregnant ddY mice were randomly divided into control, stress, and stress/chewing groups. Mice in the stress and stress/chewing groups were placed in a ventilated restraint tube for 45 minutes, 3 times a day, and was initiated on day 12 of gestation and continued until delivery. Mice in the stress/chewing group were allowed to chew a wooden stick during the restraint stress period. The bone response of 5-month-old male offspring was evaluated using quantitative micro-CT, bone histomorphometry, and biochemical markers. Prenatal stress resulted in significant decrease of trabecular bone mass in both vertebra and distal femur of the offspring. Maternal active mastication during prenatal stress attenuated the reduced bone formation and increased bone resorption, improved the lower trabecular bone volume and bone microstructural deterioration induced by prenatal stress in the offspring. These findings indicate that maternal active mastication during prenatal stress can ameliorate prenatal stress-induced lower bone mass of the vertebra and femur in adult offspring. Active mastication during prenatal stress in dams could be an effective coping strategy to prevent lower bone mass in their offspring.

Tooth loss early in life suppresses neurogenesis and synaptophysin expression in the hippocampus and impairs learning in mice.

OBJECTIVE: Tooth loss induced neurological alterations through activation of a stress hormone, corticosterone. Age-related hippocampal morphological and functional changes were accelerated by early tooth loss in senescence-accelerated mouse prone 8 (SAMP8). In order to explore the mechanism underlying the impaired hippocampal function resulting from early masticatory dysfunction due to tooth loss, we investigated the effects of early tooth loss on plasma corticosterone levels, learning ability, neurogenesis, and synaptophysin expression in the hippocampus later in life of SAMP8 mice. DESIGN: We examined the effects of tooth loss soon after tooth eruption (1 month of age) on plasma corticosterone levels, learning ability in the Morris water maze, newborn cell proliferation, survival and differentiation in the hippocampal dentate gyrus, and synaptophysin expression in the hippocampus of aged (8 months of age) SAMP8 mice. RESULTS: Aged mice with early tooth loss exhibited increased plasma corticosterone levels, hippocampus-dependent learning deficits in the Morris water maze, decreased cell proliferation, and cell survival in the dentate gyrus, and suppressed synaptophysin expression in the hippocampus. Newborn cell differentiation in the hippocampal dentate gyrus, however, was not affected by early tooth loss. CONCLUSION: These findings suggest that learning deficits in aged SAMP8 mice with tooth loss soon after tooth eruption are associated with suppressed neurogenesis and decreased synaptophysin expression resulting from increased plasma corticosterone levels, and that long-term tooth loss leads to impaired cognitive function in older age.

CXCL14-like Immunoreactivity Exists in Somatostatin-containing Endocrine Cells, and in the Lamina Propria and Submucosal Somatostatinergic Nervous System of Mouse Alimentary Tract.

In the present study, we investigated the distribution of CXCL14 immunoreactive endocrine cells and neurons in mouse alimentary tract by immunohistochemistry. CXCL14 immunoreactive endocrine cells were found as closed-type cells in the stomach and open-type cells in the small intestine. The immunostaining of these endocrine cells corresponded with that of the somatostatin-containing endocrine cells. Only a few CXCL14 immunoreactive endocrine cells were seen in the large intestine. CXCL14 immunoreactive fibers were observed in the muscular layer from the stomach to the rectum with most abundance in the rectum. Many CXCL14 immunoreactive fibers were observed in the lamina propria and submucosal layer from the duodenum to the rectum with most abundance in the rectum; these fibers corresponded to the somatostatin-containing nerve fibers. Some CXCL14 immunoreactive neuronal somata that were also immuno-positive for somatostatin, were noted in the submucosal layer of the rectum. However, the remaining parts of the alimentary tract presented with almost negligible immunoreactive somata. The co-localization of CXCL14 and somatostatin suggests that CXCL14 contributes to the function of somatostatin, which include the inhibition of other endocrine and exocrine cells and the enteric nervous systems.

Influence of restoration adjustments on prefrontal blood flow: A simplified NIRS preliminary study.

OBJECTIVE: The aim of this study was to examine, after setting several restorations, the influence of adjusted occlusal interference during gum chewing on blood flow in the prefrontal area as determined using near-infrared spectroscopy. MATERIAL AND METHODS: The physiological rate was assessed using a visual analog scale (VAS) questionnaire. We selected 16 patients who desired prosthetic restorative treatment on the lateral dentition, and eight healthy volunteers. Subjects were divided into three eight-person groups. One group received restorations on the premolar area (PA), another group received restorations on the molar area (MA), and the control group (CT) received no prosthetic restorations. The spectroscope was fastened to the frontal region of the head after placement of the final restoration, but before adjustment. RESULTS: Pre-adjustment (first gum chewing for CT) blood flow in the prefrontal cortex was measured during gum chewing. Blood flow was again measured during gum chewing after the restoration (second gum chewing for CT) had been adjusted in accordance with the subjective assessment of the patient while wearing the device. The VAS provided quantification of comfort during gum chewing before and after restoration adjustment. For the PA and MA groups, adjusting restorations decreased discomfort significantly during gum chewing. Moreover, in the MA group, prefrontal blood flow was significantly reduced, and blood flow correlated with discomfort. CONCLUSIONS: Activation of the prefrontal area may provide an objective criterion for judging the functionality of occlusion after prosthetic occlusal reconstruction and/or orthodontics.

Chewing prevents stress-induced hippocampal LTD formation and anxiety-related behaviors: a possible role of the dopaminergic system.

The present study examined the effects of chewing on stress-induced long-term depression (LTD) and anxiogenic behavior. Experiments were performed in adult male rats under three conditions: restraint stress condition, voluntary chewing condition during stress, and control condition without any treatments except handling. Chewing ameliorated LTD development in the hippocampal CA1 region. It also counteracted the stress-suppressed number of entries to the center region of the open field when they were tested immediately, 30 min, or 60 min after restraint. At the latter two poststress time periods, chewing during restraint significantly increased the number of times of open arm entries in the elevated plus maze, when compared with those without chewing. The in vivo microdialysis further revealed that extracellular dopamine concentration in the ventral hippocampus, which is involved in anxiety-related behavior, was significantly greater in chewing rats than in those without chewing from 30 to 105 min after stress exposure. Development of LTD and anxiolytic effects ameliorated by chewing were counteracted by administering the D1 dopamine receptor antagonist SCH23390, which suggested that chewing may activate the dopaminergic system in the ventral hippocampus to suppress stress-induced anxiogenic behavior.

Chewing and attention: a positive effect on sustained attention.

Chewing is crushing food not only to aid swallowing and digestion, but also to help stress relief and regulate cognitive function, especially in attention. It is well known that chewing gum is used for sleepiness prevention during work, learning, and driving, suggesting a link between chewing and sustained attention. We hypothesized that chewing elevates attention and/or alertness, leading to improvements in cognitive performance. We carried out a systematic review of the PubMed database. We inspected the attributes of effects on attention in studies investigating the effects of chewing on attention or alertness conducted with pre-post design in healthy subjects, except elderly. We identified 151 references, 22 of which were included: 14 (64%) showed positive attributes of effects on attention, 1 (5%) showed negative attributes of effects on attention, 5 (23%) showed both positive and negative attributes of effects on attention, and 2 (9%) showed no significant attributes of effects on attention. Thus, positive attributes of effects of chewing on attention, especially on sustained attention, were shown in over half of the reports. These effects also appeared with improvement in mood and stress relief and were influenced by time-on-task effect. Further studies are needed, but chewing could be useful for modifying cognitive function.

Chewing Maintains Hippocampus-Dependent Cognitive Function.

Mastication (chewing) is important not only for food intake, but also for preserving and promoting the general health. Recent studies have showed that mastication helps to maintain cognitive functions in the hippocampus, a central nervous system region vital for spatial memory and learning. The purpose of this paper is to review the recent progress of the association between mastication and the hippocampus-dependent cognitive function. There are multiple neural circuits connecting the masticatory organs and the hippocampus. Both animal and human studies indicated that cognitive functioning is influenced by mastication. Masticatory dysfunction is associated with the hippocampal morphological impairments and the hippocampus-dependent spatial memory deficits, especially in elderly. Mastication is an effective behavior for maintaining the hippocampus-dependent cognitive performance, which deteriorates with aging. Therefore, chewing may represent a useful approach in preserving and promoting the hippocampus-dependent cognitive function in older people. We also discussed several possible mechanisms involved in the interaction between mastication and the hippocampal neurogenesis and the future directions for this unique fascinating research.

Chewing suppresses the stress-induced increase in the number of pERK-immunoreactive cells in the periaqueductal grey.

We investigated the effects of chewing under immobilization stress on the periaqueductal gray (PAG) matter using phosphorylated extracellular signal-regulated kinase (pERK) as a marker of responding cells. Immobilization stress increased pERK-immunoreactive cells in the PAG. Among four subdivisions of the PAG, the increase of immunoreactive cells was remarkable in the dorsolateral and ventrolateral subdivisions. However, increase of pERK-immunoreactive cells by the immobilization stress was not so evident in the dorsomedial and lateral subdivisions. The chewing under immobilization stress prevented the stress-induced increase of pERK-immunoreactive cells in the dorsolateral and ventrolateral subdivisions with statistical significances (p<0.05). Again, chewing effects on pERK-immunoreactive cells were not visible in the dorsomedial and lateral subdivisions. These results suggest that the chewing alleviates the PAG (dorsolateral and ventrolateral subdivisions) responses to stress.

Loss of molars early in life develops behavioral lateralization and impairs hippocampus-dependent recognition memory.

BACKGROUND: Using senescence-accelerated mouse prone 8 (SAMP8), we examined whether reduced mastication from a young age affects hippocampal-dependent cognitive function. We anesthetized male SAMP8 mice at 8 weeks of age and extracted all maxillary molar teeth of half the animals. The other animals were treated similarly, except that molar teeth were not extracted. At 12 and 24 weeks of age, their general behavior and their ability to recognize novel objects were tested using the open-field test (OFT) and the object-recognition test (ORT), respectively. RESULTS: The body weight of molarless mice was reduced significantly compared to that of molar-intact mice after the extraction and did not recover to the weight of age-matched molar-intact mice throughout the experimental period. At 12 weeks of age, molarless mice showed significantly greater locomotor activity in the OFT than molar-intact mice. However, the ability of molarless mice to discriminate a novel object in the ORT was impaired compared to that of molar-intact mice. The ability of both molarless and molar-intact SAMP8 mice to recognize objects was impaired at 24 weeks of age. These results suggest that molarless SAMP8 mice develop a deficit of cognitive function earlier than molar-intact SAMP8 mice. Interestingly, both at 12 and 24 weeks of age, molarless mice showed a lateralized preference of object location in the encoding session of the ORT, in which two identical objects were presented. Their lateralized preference of object location was positively correlated with the rightward turning-direction preference, which reached statistical significance at 24 weeks of age. CONCLUSIONS: Loss of masticatory function in early life causes malnutrition and chronic stress and impairs the ability to recognize novel objects. Hyperactivation and lateralized rotational behavior are commonly observed with dysfunction of the dopaminergic system, therefore, reduced masticatory function may deplete the mesolimbic and mesocorticolimbic dopaminergic systems to impair the cognitive functions of selective attention and recognition memory in the prefrontal cortex and the hippocampus.

[Chewing and cognitive function].

Chewing does not only crush food to aid swallowing and digestion; it also helps to relieve stress and regulate cognitive functions, including alertness and executive function. It is well known that chewing gum is used for sleepiness prevention during work, learning, and driving. In addition, it has been shown in the elderly that a decrease in the number of residual teeth is related to dementia onset. These findings suggest a link between chewing and maintaining memory and attention. Recently, many studies regarding the effects of chewing on memory and attention were conducted using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). When a working memory task was used, the middle frontal gyrus in the dorsolateral prefrontal cortex showed greater activation in addition to producing higher alertness after chewing. Furthermore, using an attentional network test, reaction time shortened, and the anterior cingulate cortex and left frontal gyrus were both activated for the executive network. From these results, it is suggested that chewing elevates alertness, consequently leading to improvements in cognitive performance. In this review, we introduce findings concerning the effects of chewing on cognitive performance, and discuss the neuronal mechanisms underlying these effects.

Occlusal Disharmony Transiently Impairs Learning and Memory in the Mouse by Increasing Dynorphin A Levels in the Amygdala.

Occlusal disharmony sometimes causes not only stiffness of neck but also psychiatric depression, suggesting that the condition of oral cavity may affect the central nervous system. Dynorphin A is an endogenous opioid peptide that specifically binds the κ-opioid receptor and has a protective role against stress. Dynorphinergic nervous system is intensely distributed in the amygdala and hippocampus that are coping areas with stress. As a model of malocclusion, we placed dental resin on the molars to increase the occlusal vertical dimension (bite-raise). After various survival times, we analyzed the amygdala and hippocampus by immunohistochemistry and immunosorbent assay (ELISA). Furthermore, the effects on learning and memory were assessed by Morris water maze test. In the amygdala, the levels of dynorphin A were increased on the 1st day after increasing the vertical dimension as indicated by immunohistochemical and ELISA assessments. The levels of dynorphin A returned to control levels on the 5th day. In the hippocampus, there were no noticeable changes in dynorphin A levels. The water maze test indicated that increasing the vertical dimension caused longer escape latency times on the 3rd day compared to those of sham-operated group. However, the bite-raised mice treated with a dynorphin antagonist, nor-binaltorphimine, showed similar escape latency times to the times of sham-operated group, even on the 3rd day. These results suggest that occlusal disharmony causes stress resulting in a transient increase of dynorphin A levels at least in the amygdala and that the increased dynorphin A levels transiently impair learning and memory.

Age-related changes in trabecular and cortical bone microstructure.

The elderly population has substantially increased worldwide. Aging is a complex process, and the effects of aging are myriad and insidious, leading to progressive deterioration of various organs, including the skeleton. Age-related bone loss and resultant osteoporosis in the elderly population increase the risk for fractures and morbidity. Osteoporosis is one of the most common conditions associated with aging, and age is an independent risk factor for osteoporotic fractures. With the development of noninvasive imaging techniques such as computed tomography (CT), micro-CT, and high resolution peripheral quantitative CT (HR-pQCT), imaging of the bone architecture provides important information about age-related changes in bone microstructure and estimates of bone strength. In the past two decades, studies of human specimens using imaging techniques have revealed decreased bone strength in older adults compared with younger adults. The present paper addresses recently studied age-related changes in trabecular and cortical bone microstructure based primarily on HR-pQCT and micro-CT. We specifically focus on the three-dimensional microstructure of the vertebrae, femoral neck, and distal radius, which are common osteoporotic fracture sites.

Effects of chewing on cognitive processing speed.

In recent years, chewing has been discussed as producing effects of maintaining and sustaining cognitive performance. We have reported that chewing may improve or recover the process of working memory; however, the mechanisms underlying these phenomena are still to be elucidated. We investigated the effect of chewing on aspects of attention and cognitive processing speed, testing the hypothesis that this effect induces higher cognitive performance. Seventeen healthy adults (20-34 years old) were studied during attention task with blood oxygenation level-dependent functional (fMRI) at 3.0 T MRI. The attentional network test (ANT) within a single task fMRI containing two cue conditions (no cue and center cue) and two target conditions (congruent and incongruent) was conducted to examine the efficiency of alerting and executive control. Participants were instructed to press a button with the right or left thumb according to the direction of a centrally presented arrow. Each participant underwent two back-to-back ANT sessions with or without chewing gum, odorless and tasteless to remove any effect other than chewing. Behavioral results showed that mean reaction time was significantly decreased during chewing condition, regardless of speed-accuracy trade-off, although there were no significant changes in behavioral effects (both alerting and conflict effects). On the other hand, fMRI analysis revealed higher activations in the anterior cingulate cortex and left frontal gyrus for the executive network and motor-related regions for both attentional networks during chewing condition. These results suggested that chewing induced an increase in the arousal level and alertness in addition to an effect on motor control and, as a consequence, these effects could lead to improvements in cognitive performance.

WITHDRAWN: Chewing during chronic stress ameliorates stress-induced suppression of neurogenesis in the hippocampal dentate gyrus in aged SAMP8 mice.

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Activation of dorsolateral prefrontal cortex in a dual neuropsychological screening test: an fMRI approach.

BACKGROUND: The Kana Pick-out Test (KPT), which uses Kana or Japanese symbols that represent syllables, requires parallel processing of discrete (pick-out) and continuous (reading) dual tasks. As a dual task, the KPT is thought to test working memory and executive function, particularly in the prefrontal cortex (PFC), and is widely used in Japan as a clinical screen for dementia. Nevertheless, there has been little neurological investigation into PFC activity during this test. METHODS: We used functional magnetic resonance imaging (fMRI) to evaluate changes in the blood oxygenation level-dependent (BOLD) signal in young healthy adults during performance of a computerized KPT dual task (comprised of reading comprehension and picking out vowels) and compared it to its single task components (reading or vowel pick-out alone). RESULTS: Behavioral performance of the KPT degraded compared to its single task components. Performance of the KPT markedly increased BOLD signal intensity in the PFC, and also activated sensorimotor, parietal association, and visual cortex areas. In conjunction analyses, bilateral BOLD signal in the dorsolateral PFC (Brodmann's areas 45, 46) was present only in the KPT. CONCLUSIONS: Our results support the central bottleneck theory and suggest that the dorsolateral PFC is an important mediator of neural activity for both short-term storage and executive processes. Quantitative evaluation of the KPT with fMRI in healthy adults is the first step towards understanding the effects of aging or cognitive impairment on KPT performance.

Effect of bite-raised condition on the hippocampal cholinergic system of aged SAMP8 mice.

Occlusal disharmony induces chronic stress, which results in learning deficits in association with the morphologic changes in the hippocampus, e.g., neuronal degeneration and increased hypertrophied glial fibrillary acidic protein-positive cells. To investigate the mechanisms underlying impaired hippocampal function resulting from occlusal disharmony, we examined the effects of the bite-raised condition on the septohippocampal cholinergic system by assessing acetylcholine release in the hippocampus and choline acetyltransferase immunoreactivity in the medial septal nucleus in aged SAMP8 mice that underwent the bite raising procedure. Aged bite-raised mice showed decreased acetylcholine release in the hippocampus and a reduced number of choline acetyltransferase-immunopositive neurons in the medial septal nucleus compared to age-matched control mice. These findings suggest that the bite-raised condition in aged SAMP8 mice enhances the age-related decline in the septohippocampal cholinergic system, leading to impaired learning.

Chewing ameliorates stress-induced suppression of spatial memory by increasing glucocorticoid receptor expression in the hippocampus.

Chewing alters hypothalamic-pituitary-adrenal axis function and improves the ability to cope with stress in rodents. Given that stress negatively influences hippocampus-dependent learning and memory, we aimed to elucidate whether masticatory movements, namely chewing, improve the stress-induced impairment of spatial memory in conjunction with increased hippocampal glucocorticoid receptor expression. Male Sprague-Dawley rats were subjected to restraint stress by immobilization for 2h: the stress with chewing (SC) group were allowed to chew on a wooden stick during the latter half of the immobilization period, whereas the stress without chewing (ST) group were not allowed to do so. Performance in the Morris water maze test was significantly impaired in the ST group compared with the SC group. Further, the numbers of glucocorticoid receptor immunopositive neurons in the hippocampal cornu ammonis 1 region were significantly lower in the ST group than in the control and SC groups. The control and SC rats showed no significant differences in both the water maze performance and the numbers of glucocorticoid receptor-immunopositive neurons. The immunohistochemical finding correlated with the performance in the water maze test. These results suggest that chewing is a behavioral mechanism to cope with stress by increasing hippocampal glucocorticoid receptor expression.

Active coping with stress suppresses glucose metabolism in the rat hypothalamus.

We used 18F-fluorodeoxyglucose small-animal positron-emission tomography to determine whether different styles of coping with stress are associated with different patterns of neuronal activity in the hypothalamus. Adult rats were subjected to immobilization (IMO)-stress or to a non-immobilized condition for 30 min, in random order on separate days, each of which was followed by brain-scanning. Some rats in the immobilized condition were allowed to actively cope with the stress by chewing a wooden stick during IMO, while the other immobilized rats were given nothing to chew on. Voxel-based statistical analysis of the brain imaging data shows that chewing counteracted the stress-induced increased glucose uptake in the hypothalamus to the level of the non-immobilized condition. Region-of-interest analysis of the glucose uptake values further showed that chewing significantly suppressed stress-induced increased glucose uptake in the paraventricular hypothalamic nucleus and the anterior hypothalamic area but not in the lateral hypothalamus. Together with the finding that the mean plasma corticosterone concentration at the termination of the IMO was also significantly suppressed when rats had an opportunity to chew a wooden stick, our results showed that active coping by chewing inhibited the activation of the hypothalamic-pituitary-adrenal axis to reduce the endocrine stress response.

Soft-food diet induces oxidative stress in the rat brain.

Decreased dopamine (DA) release in the hippocampus may be caused by dysfunctional mastication, although the mechanisms involved remain unclear. The present study examined the effects of soft- and hard-food diets on oxidative stress in the brain, and the relationship between these effects and hippocampal DA levels. The present study showed that DA release in the hippocampus was decreased in rats fed a soft-food diet. Electron spin resonance studies using the nitroxyl spin probe 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl directly demonstrated a high level of oxidative stress in the rat brain due to soft-food diet feeding. In addition, we confirmed that DA directly react with reactive oxygen species such as hydroxyl radical and superoxide. These observations suggest that soft-food diet feeding enhances oxidative stress, which leads to oxidation and a decrease in the release of DA in the hippocampus of rats.

Chewing reduces sympathetic nervous response to stress and prevents poststress arrhythmias in rats.

Reducing stress is important in preventing sudden death in patients with cardiovascular disease, as stressful events may cause autonomic imbalance and trigger fatal arrhythmias. Since chewing has been shown to inhibit stress-induced neuronal responses in the hypothalamus, we hypothesized that chewing could ameliorate stress-induced autonomic imbalance and prevent arrhythmias. To test this hypothesis, we analyzed changes in radiotelemetered electrocardiograms in rats that were allowed to chew a wooden stick during a 1-h period of immobilization stress. Chewing significantly reduced the occurrence of ventricular premature beats (VPBs) and complex ventricular ectopy after immobilization and prevented stress-induced prolongation of the QT interval of VPBs throughout the 10-h experimental period. It also prevented prolongation of the QRS complex and fluctuations in the QT interval in normal sinus rhythm beats preceding VPBs during both immobilization and in the poststress period. Fast Fourier transform-based spectral analysis of heart-rate variability further showed that chewing significantly inhibited the stress-induced increase in the power ratio of low-to-high frequency activity (LF/HF: a marker of sympathetic activity) during immobilization and in addition was associated with blunting of the stress-induced increase in plasma noradrenaline observed at the termination of immobilization. Similar suppressive effects on the occurrence of VPBs and the LF/HF were observed in rats that were administered the ß-adrenergic blocker propranolol before immobilization. These results indicate that chewing can ameliorate sympathetic hyperactivity during stress and prevent poststress arrhythmias and suggest that chewing may provide a nonpharmacological and cost-effective treatment option for patients with a high risk of stress-induced fatal arrhythmia.