担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Neuroscience  

Introduction: Occlusal disharmony induced by deteriorating oral health conditions, such as tooth loss and decreased masticatory muscle due to sarcopenia, is one of the causes of cognitive impairment. Chewing is an essential oral function for maintaining cognitive function not only in the elderly but also in young people. Malocclusion is an occlusal disharmony that commonly occurs in children. The connection between a decline in cognitive function and malocclusion in children has been shown with chronic mouth breathing, obstructive sleep apnea syndrome, and thumb/digit sucking habits. However, the mechanism of malocclusion-induced cognitive decline is not fully understood. We recently reported an association between feeding-related neuropeptides and cognitive decline in adolescent mice with activity-based anorexia. The aim of the present study was to assess the effects of malocclusion on cognitive behavior and clarify the connection between cognitive decline and hypothalamic feeding-related neuropeptides in adolescent mice with malocclusion. Methods: Four-week-old mice were randomly assigned to the sham-operated solid diet-fed (Sham/solid), sham-operated powder diet-fed (Sham/powder), or malocclusion-operated powder diet-fed (Malocclusion/powder) group. We applied composite resin to the mandibular anterior teeth to simulate malocclusion. We evaluated cognitive behavior using a novel object recognition (NOR) test, measured hypothalamic feeding-related neuropeptide mRNA expression levels, and enumerated c-Fos-positive cells in the hypothalamus 1 month after surgery. We also evaluated the effects of central antibody administration on cognitive behavior impairment in the NOR test. Results: The NOR indices were lower and the agouti-related peptide (AgRP) mRNA levels and number of c-Fos-positive cells were higher in the malocclusion/powder group than in the other groups. The c-Fos-positive cells were also AgRP-positive. We observed that the central administration of anti-AgRP antibody significantly increased the NOR indices. Discussion: The present study suggests that elevated cerebral AgRP signaling contributes to malocclusion-induced cognitive decline in adolescents, and the suppression of AgRP signaling can be a new therapeutic target against cognitive decline in occlusal disharmony.

DOI： 10.3389/fnins.2023.1156523

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biochemical and Biophysical Research Communications  

Cranial radiation therapy (CRT) is an effective treatment for brain tumors; however, it also causes brain injuries. The pediatric brain is considered especially vulnerable compared to the adult brain; thus, brain injuries caused by CRT may severely affect their quality of life. In this study, we determined the neuroprotective effects of nasal oxytocin administration following cranial radiation in mice. We investigated the cognitive behavior of mice (novel object recognition test and novel object location test), phosphorylated histone H2AX (γ-H2AX) and K+-Cl− transporter (KCC2) by immunohistochemical analysis of the hippocampal sections, and neuronal cells by immunocytochemistry after radiation and oxytocin administration. We found that the number of γ-H2AX foci was increased, and the surface signal intensity of KCC2 immunofluorescence was decreased in cells that were irradiated with X-rays (1.5 Gy, for three consecutive days) compared with cells that were not. Furthermore, using MQAE, we found that the intracellular chloride ion concentration was downregulated in oxytocin-treated cells by increasing surface KCC2 expression. These results indicate that nasal oxytocin administration after cranial irradiation attenuates cognitive dysfunction in mice and exerts multifaceted neuroprotective effects on DNA damage and maintains chloride ion concentration in neuronal cells.

DOI： 10.1016/j.bbrc.2022.04.099

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Aging Neuroscience  

The rapid aging of the population makes the detection and prevention of frailty increasingly important. Oral frailty has been proposed as a novel frailty phenotype and is defined as a decrease in oral function coexisting with a decline in cognitive and physical functions. Oral frailty has received particular attention in relation to Alzheimer's disease (AD). However, the pathomechanisms of oral frailty related to AD remain unknown. It is assumed that the mesencephalic trigeminal nucleus (Vmes), which controls mastication, is affected by AD pathology, and as a result, masticatory function may be impaired. To investigate this possibility, we included male 3 × Tg-AD mice and their non-transgenic counterpart (NonTg) of 3–4 months of age in the present study. Immunohistochemistry revealed amyloid-β deposition and excessive tau phosphorylation in the Vmes of 3 × Tg-AD mice. Furthermore, vesicular glutamate transporter 1-immunopositive axon varicosities, which are derived from Vmes neurons, were significantly reduced in the trigeminal motor nucleus of 3 × Tg-AD mice. To investigate whether the AD pathology observed in the Vmes affects masticatory function, we analyzed electromyography of the masseter muscle during feeding. The 3 × Tg-AD mice showed a significant delay in masticatory rhythm compared to NonTg mice. Furthermore, we developed a system to simultaneously record bite force and electromyography of masseter, and devised a new method to estimate bite force during food chewing in mice. Since the muscle activity of the masseter showed a high correlation with bite force, it could be accurately estimated from the muscle activity. The estimated bite force of 3 × Tg-AD mice eating sunflower seeds was predominantly smaller than that of NonTg mice. However, there was no difference in masseter weight or muscle fiber cross-sectional area between the two groups, suggesting that the decreased bite force and delayed mastication rhythm observed in 3 × Tg-AD mice were not due to abnormality of the masseter. In conclusion, the decreased masticatory function observed in 3 × Tg-AD mice was most likely caused by AD pathology in the Vmes. Thus, novel quantitative analyses of masticatory function using the mouse model of AD enabled a comprehensive understanding of oral frailty pathogenesis.

DOI： 10.3389/fnagi.2022.935033

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Neuroinflammation  

Background: Macrophages in the peripheral nervous system are key players in the repair of nerve tissue and the development of neuropathic pain due to peripheral nerve injury. However, there is a lack of information on the origin and morphological features of macrophages in sensory ganglia after peripheral nerve injury, unlike those in the brain and spinal cord. We analyzed the origin and morphological features of sensory ganglionic macrophages after nerve ligation or transection using wild-type mice and mice with bone-marrow cell transplants. Methods: After protecting the head of C57BL/6J mice with lead caps, they were irradiated and transplanted with bone-marrow-derived cells from GFP transgenic mice. The infraorbital nerve of a branch of the trigeminal nerve of wild-type mice was ligated or the infraorbital nerve of GFP-positive bone-marrow-cell-transplanted mice was transected. After immunostaining the trigeminal ganglion, the structures of the ganglionic macrophages, neurons, and satellite glial cells were analyzed using two-dimensional or three-dimensional images. Results: The number of damaged neurons in the trigeminal ganglion increased from day 1 after infraorbital nerve ligation. Ganglionic macrophages proliferated from days 3 to 5. Furthermore, the numbers of macrophages increased from days 3 to 15. Bone-marrow-derived macrophages increased on day 7 after the infraorbital nerve was transected in the trigeminal ganglion of GFP-positive bone-marrow-cell-transplanted mice but most of the ganglionic macrophages were composed of tissue-resident cells. On day 7 after infraorbital nerve ligation, ganglionic macrophages increased in volume, extended their processes between the neurons and satellite glial cells, and contacted these neurons. Most of the ganglionic macrophages showed an M2 phenotype when contact was observed, and little neuronal cell death occurred. Conclusion: Most of the macrophages that appear after a nerve injury are tissue-resident, and these make direct contact with damaged neurons that act in a tissue-protective manner in the M2 phenotype. These results imply that tissue-resident macrophages signal to neurons directly through physical contact.

DOI： 10.1186/s12974-021-02283-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Brain Research  

Kamishoyosan (KSS), a Japanese traditional herbal formula, is used to treat symptoms related to the autonomic nervous system in men and women; it is especially known for improving the symptoms of irritability (e.g., bad temper and persistent anger). Although clinical and ethological studies of KSS have been conducted, its efficacy in reducing irritability remains to be validated. In the present study, male and female ddY-strain mice were isolation-reared for 8 weeks (from the third postnatal week) to induce pathologically aggressive biting behavior (ABB), which was used as an indicator of irritability. The ABB of mice toward metal rods was measured using the Aggressive Response Meter. An intraperitoneal administration of KSS (100 mg/kg) effectively reduced ABB in male and female mice at 2 h after the administration; however, this effect was canceled by prior administration of WAY-100635 [a 5-hydroxytryptoamine (5-HT)-1A receptor antagonist; 0.5 mg/kg] and bicuculline (a type-A gamma-aminobutyric acid receptor antagonist; 1.0 mg/kg). Additionally, tamoxifen, ICI-182780, and G-15 (all estrogen receptor antagonists) inhibited the action of KSS in a dose-dependent manner. Furthermore, gene expression of tryptophan hydroxylase (Tph) 1 and Tph2 were increased and 5-HT immunofluorescence was slightly increased in the dorsal raphe nucleus (DRN) of isolation-reared mice administered with KSS. Collectively, these results indicate that KSS effectively reduces ABB in isolation-reared male and female mice through stimulation of 5-HT production in the DRN. Our findings also suggest that gene expression of estrogen receptor (Esr) 2 increased in the DRN might be associated with the reduction of ABB.

DOI： 10.1016/j.brainres.2021.147580

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総ページ数：185  

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記述言語：日本語 著書種別：学術書

記述言語：日本語 著書種別：学術書

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）  

開催年月日： 2018年12月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2018年9月

記述言語：英語   会議種別：口頭発表（一般）  

開催年月日： 2017年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2017年9月

記述言語：英語   会議種別：口頭発表（一般）  

開催年月日： 2017年3月

記述言語：日本語   会議種別：口頭発表（一般）  

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