Kagaku Azuma

Chronic Psychological Stress as a Risk Factor of Osteoporosis

Osteoporosis, the most common metabolic skeletal disease, is characterized by decreased bone mass and deteriorated bone quality, leading to increased fracture risk. With the aging of the population, osteoporotic fracture is an important public health issue. Organisms are constantly exposed to various stressful stimuli that affect physiological processes. Recent studies showed that chronic psychological stress is a risk factor for osteoporosis by various signaling pathways. The purpose of this article is to review the recent progress of the association between chronic psychological stress and osteoporosis. Increasing evidence confirms the physiological importance of the central nervous system, especially the hypothalamus, in the regulation of bone metabolism. Both animal and human studies indicate that chronic psychological stress induces a decrease of bone mass and deterioration of bone quality by influencing the hypothalamic-pituitary-adrenocortical (HPA) axis, sympathetic nervous system, and other endocrine, immune factors. Active mastication, proven to be an effective stress-coping behavior, can attenuate stress-induced neuroendocrine responses and ameliorate stress-induced bone loss. Therefore, active mastication may represent a useful approach in preventing and/or treating chronic stress-associated osteoporosis. We also discuss several potential mechanisms involved in the interaction between chronic stress, mastication and osteoporosis. Chronic stress activates the HPA axis and sympathetic nervous system, suppresses the secretion of gonadal hormone and growth hormone, and increases inflammatory cytokines, eventually leading to bone loss by inhibiting bone formation and stimulating bone resorption.

Hippocampus-dependent spatial memory impairment due to molar tooth loss is ameliorated by an enriched environment

BACKGROUND AND OBJECTIVE Teeth are crucial, not only for mastication, but for overall nutrition and general health, including cognitive function. Aged mice with chronic stress due to tooth loss exhibit impaired hippocampus-dependent learning and memory. Exposure to an enriched environment restores the reduced hippocampal function. Here, we explored the effects of an enriched environment on learning deficits and hippocampal morphologic changes in aged senescence-accelerated mouse strain P8 (SAMP8) mice with tooth loss. DESIGN Eight-month-old male aged SAMP8 mice with molar intact or with molars removed were housed in either a standard environment or enriched environment for 3 weeks. The Morris water maze was performed for spatial memory test. The newborn cell proliferation, survival, and differentiation in the hippocampus were analyzed using 5-Bromodeoxyuridine (BrdU) immunohistochemical method. The hippocampal brain-derived neurotrophic factor (BDNF) levels were also measured. RESULTS Mice with upper molars removed (molarless) exhibited a significant decline in the proliferation and survival of newborn cells in the dentate gyrus (DG) as well as in hippocampal BDNF levels. In addition, neuronal differentiation of newly generated cells was suppressed and hippocampus-dependent spatial memory was impaired. Exposure of molarless mice to an enriched environment attenuated the reductions in the hippocampal BDNF levels and neuronal differentiation, and partially improved the proliferation and survival of newborn cells, as well as the spatial memory ability. CONCLUSION These findings indicated that an enriched environment could ameliorate the hippocampus-dependent spatial memory impairment induced by molar tooth loss.

Effects of Active Mastication on Chronic Stress-Induced Bone Loss in Mice

Chronic psychologic stress increases corticosterone levels, which decreases bone density. Active mastication or chewing attenuates stress-induced increases in corticosterone. We evaluated whether active mastication attenuates chronic stress-induced bone loss in mice. Male C57BL/6 (B6) mice were randomly divided into control, stress, and stress/chewing groups. Stress was induced by placing mice in a ventilated restraint tube (60 min, 2x/day, 4 weeks). The stress/chewing group was given a wooden stick to chew during the experimental period. Quantitative micro-computed tomography, histologic analysis, and biochemical markers were used to evaluate the bone response. The stress/chewing group exhibited significantly attenuated stress-induced increases in serum corticosterone levels, suppressed bone formation, enhanced bone resorption, and decreased trabecular bone mass in the vertebrae and distal femurs, compared with mice in the stress group. Active mastication during exposure to chronic stress alleviated chronic stress-induced bone density loss in B6 mice. Active mastication during chronic psychologic stress may thus be an effective strategy to prevent and/or treat chronic stress-related osteopenia.

Association between Mastication, the Hippocampus, and the HPA Axis: A Comprehensive Review

Mastication is mainly involved in food intake and nutrient digestion with the aid of teeth. Mastication is also important for preserving and promoting general health, including hippocampus-dependent cognition. Both animal and human studies indicate that mastication influences hippocampal functions through the end product of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoid (GC). Epidemiologic studies suggest that masticatory dysfunction in aged individuals, such as that resulting from tooth loss and periodontitis, acting as a source of chronic stress, activates the HPA axis, leading to increases in circulating GCs and eventually inducing various physical and psychological diseases, such as cognitive impairment, cardiovascular disorders, and osteoporosis. Recent studies demonstrated that masticatory stimulation or chewing during stressful conditions suppresses the hyperactivity of the HPA axis via GCs and GC receptors within the hippocampus, and ameliorates chronic stress-induced hippocampus-dependent cognitive deficits. Here, we provide a comprehensive overview of current research regarding the association between mastication, the hippocampus, and HPA axis activity. We also discuss several potential molecular mechanisms involved in the interactions between mastication, hippocampal function, and HPA axis activity.

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.

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.

Novel stress increases hypothalamic-pituitary-adrenal activity in mice with a raised bite

BACKGROUND AND OBJECTIVE In humans, occlusal disharmony may cause various physical complaints, including head and neck ache, stiffness in the shoulder and neck, and arthrosis of the temporomandibular joints. Occlusal disharmony induced by raising the bite in rodents, increases plasma corticosterone levels, which leads to morphologic changes in the hippocampus and altered hippocampus-related behavior. The paraventricular nucleus (PVN) of the hypothalamus regulates the hypothalamic-pituitary-adrenal system. Chronically stressed animals exposed to a novel stress exhibit higher adrenocorticotropic hormone levels than naive control animals. We hypothesized that there would be different response of the corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) to a novel acute stress with occlusal disharmony. DESIGN In order to investigate how exposure of mice with occlusal disharmony to a novel acute stress (restraint stress) affects the PVN, we induced occlusal disharmony by raising the vertical dimension of the bite (bite-raised condition) and examined the expression of corticotrophin releasing hormone (CRH) mRNA and arginine vasopressin (AVP) mRNA in mouse PVN. RESULTS CRH mRNA expression was increased in the PVN of the bite-raised group 90min after the bite-raising procedure, but the expression was recovered to the control level at 14days. AVP mRNA expression in the PVN was normal at 90min, and increased significantly 14days after the bite-raising procedure. Exposure to restraint stress in the bite-raised mice induced a significant increase in CRH mRNA expression in the PVN. CONCLUSIONS The bite-raising procedure induced a rapid CRH mRNA response and a slower AVP mRNA response in the parvocellular PVN of the hypothalamus. Exposure to a novel stress following the bite-raising procedure further reinforced the CRH stress response. Thus, occlusal disharmony, such as that induced by raising the bite, may be a risk factor for hypersensitivity to a novel stress.

Chewing during prenatal stress prevents prenatal stress-induced suppression of neurogenesis, anxiety-like behavior and learning deficits in mouse offspring

Prenatal stress (PS) induces learning deficits and anxiety-like behavior in mouse pups by increasing corticosterone levels in the dam. We examined the effects of maternal chewing during PS on arginine vasopressin (AVP) mRNA expression in the dams and on neurogenesis, brain-derived neurotrophic factor (BDNF) mRNA expression, learning deficits and anxiety-like behavior in the offspring. Mice were divided into control, stress and stress/chewing groups. Pregnant mice were exposed to restraint stress beginning on day 12 of pregnancy and continuing until delivery. Mice in the stress/chewing group were given a wooden stick to chew during restraint stress. PS significantly increased AVP mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus in the dams. PS also impaired learning ability, suppressed neurogenesis and BDNF mRNA expression in the hippocampus, and induced anxiety-like behavior in the offspring. Chewing during PS prevented the PS-induced increase in AVP mRNA expression of the PVN in the dams. Chewing during PS significantly attenuated the PS-induced learning deficits, anxiety-like behavior, and suppression of neurogenesis and BDNF mRNA expression in the hippocampus of the offspring. Chewing during PS prevented the increase in plasma corticosterone in the dam by inhibiting the hypothalamic-pituitary-adrenal axis activity, and attenuated the attenuated the PS-induced suppression of neurogenesis and BDNF expression in the hippocampus of the pups, thereby ameliorating the PS-induced learning deficits and anxiety-like behavior. Chewing during PS is an effective stress-coping method for the dam to prevent PS-induced deficits in learning ability and anxiety-like behavior in the offspring.

Morphological and molecular characterization of the senile osteoporosis in senescence-accelerated mouse prone 6 (SAMP6)

Although the understanding of the complex pathogenesis for osteoporosis is appreciable, the underlying mechanism is not yet fully elucidated. There is a great need to further characterize the available animal models in osteoporosis research. The senescence-accelerated mouse prone 6 (SAMP6) mice have been developed as the spontaneous experimental model for senile osteoporosis. Here, we provide a comprehensive overview of current research regarding the bone morphological and molecular alterations and the possible mechanisms involved in these changes. There were significant decrease in trabecular bone mass at the axial and appendicular skeletal sites, with no marked alterations of cortical bone. Decreased bone formation on the endosteal surface and trabecular bone, and increased bone marrow adiposity were observed in SAMP6 mice. The elevated expression level of proliferator activator gamma (PPARγ) in the bone marrow suggest that PPARγ might regulate osteoblastic bone formation negatively in SAMP6 mice. The expression level of secreted frizzled-related protein 4 (Sfrp4) was found to be higher in SAMP6 mice. Sfrp4 is considered to suppress osteoblastic proliferation mediated by inhibition of Wnt signaling pathway. These findings may help us to gain more insight into the potential mechanism of senile osteoporosis.

Yokukansan Ameliorates Hippocampus-Dependent Learning Impairment in Senescence-Accelerated Mouse

Yokukansan (YKS) is a traditional Japanese herbal medicine. It has been currently applied for treating behavioral and psychological symptoms of dementia in Japan. We investigated the effect of YKS on learning ability, hippocampal cell proliferation, and neural ultrastructural features in senescence-accelerated mouse prone 8 (SAMP8), a proposed animal model of Alzheimers disease. Five-month-old male SAMP8 mice were randomly assigned to control and experimental groups. The control group had drug-free water ad libitum. The experimental mice were given 0.15% aqueous solution of YKS orally for eight weeks. Learning ability was assessed in Morris water maze test. Hippocampal cell proliferation was investigated using bromodeoxyuridine immunohistochemical method. The neural ultrastructural features, including myelin sheath and synapse, were investigated electron microscopy. Administration with YKS improved the hippocampal cell proliferation in dentate gyrus, and ameliorated learning impairment in SAMP8 mice. Numerous lipofuscin inclusions were presented in hippocampal neurons of the control mice. However, little were found after treatment with YKS. Myelin sheath was thicker and postsynaptic density length was longer after treatment with YKS. Administration with YKS ameliorated learning impairment in SAMP8 mice, mediated at least partially via delaying neuronal aging process, neurogenesis, myelin sheath and synaptic plasticity in the hippocampus. These results suggest that YKS might be effective for preventing hippocampus-dependent cognitive deficits with age.