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| 1.
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Yuhi, Teruko ; Kyuta, Hiroaki ; Mori, Hisa-aki ; Murakami, Chihiro ; Furuhara, Kazumi ; Okuno, Mari ; Takahashi, Masaki ; Fuji, Daikei ; Higashida, Haruhiro ; 由比, 光子 ; 東田, 陽博
概要:
金沢大学子どものこころの発達研究センター<br />Many emotionally-disturbed children who have been maltreated and are legally separated from th
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eir parents or primary caregivers live in group homes and receive compulsory education. Such institutions provide various special intervention programs. Taiko-ensou, a Japanese style of group drumming, is one such program because playing drums in a group may improve children’s emotional well-being. However, evidence for its efficacy has not been well established at the biological level. In this study, we measured salivary levels of oxytocin (OT), a neuropeptide associated with social memory and communication, in three conditions (recital, practice, and free sessions) in four classes of school-aged children. Following the sessions, OT concentrations showed changes in various degrees and directions (no change, increases, or decreases). The mean OT concentration changes after each session increased, ranging from 112% to 165%. Plasma OT concentrations were equally sensitive to drum playing in school-aged boys and girls. However, the difference between practice and free play sessions was only significant among elementary school boys aged 8–12 years. The results suggest that younger boys are most responsive to this type of educational music intervention.
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| 2.
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2. Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice
Yamamoto, Yasuhiko ; Liang, Mingkun ; Munesue, Seiichi ; Deguchi, Kisaburo ; Harashima, Ai ; Furuhara, Kazumi ; Yuhi, Teruko ; Zhong, Jing ; Akther, Shirin ; Goto, Hisanori ; Eguchi, Yuya ; Kitao, Yasuko ; Hori, Osamu ; Shiraishi, Yoshitake ; Ozaki, Noriyuki ; Shimizu, Yu ; Kamide, Tomoya ; Yoshikawa, Akifumi ; Hayashi, Yasuhiko ; Nakada, Mitsutoshi ; Lopatina, Olga ; Gerasimenko, Maria ; Komleva, Yulia ; Malinovskaya, Natalia ; Salmina, Alla B. ; Asano, Masahide ; Nishimori, Katsuhiko ; Shoelson, Steven E. ; Yamamoto, Hiroshi ; Higashida, Haruhiro ; 山本, 靖彦 ; 棟居, 聖一 ; 古原, 和美 ; 堀, 修 ; 白石, 昌武 ; 尾﨑, 紀之 ; 吉川, 陽文 ; 中田, 光俊 ; 東田, 陽博
概要:
金沢大学医薬保健研究域医学系<br />Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bo
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nding behaviours. Mice lacking secreted oxcytocin (Oxt -/-, Cd38 -/-) or its receptor (Oxtr -/-) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt -/- and Cd38 -/-, but not Oxtr -/- mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager -/- male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager -/- mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.<br />30820471
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Higashida, Haruhiro ; Kamimura, Shin-ya ; Inoue, Takeshi ; Hori, Osamu ; Islam, Mohammad Saharul ; Lopatina, Olga ; Tsuji, Chiharu ; 東田, 陽博 ; 堀, 修 ; 辻, 知陽
概要:
The role of cyclic ADP-ribose (cADPR) as a second messenger and modulator of the mTOR pathway downstream of dopamine (DA
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) receptors and/or CD38 was re-examined in the mouse. ADP-ribosyl activity was low in the membranes of neonates, but DA stimulated it via both D1- and D2-like receptors. ADP-ribosyl cyclase activity increased significantly during development in association with increased expression of CD38. The cADPR binding proteins, FKBP12 and FKBP12.6, were expressed in the adult mouse striatum. The ratio of phosphorylated to non-phosphorylated S6 kinase (S6K) in whole mouse striatum homogenates decreased after incubation of adult mouse striatum with extracellular cADPR for 5 min. This effect of cADPR was much weaker in MPTP-treated Parkinson’s disease model mice. The inhibitory effects of cADPR and rapamycin were identical. These data suggest that cADPR is an endogenous inhibitor of the mTOR signaling pathway downstream of DA receptors in the mouse striatum and that cADPR plays a certain role in the brain in psychiatric and neurodegenerative diseases. © 2016 Springer-Verlag Wien<br />Embargo Period 12 months
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Higashida, Haruhiro ; Salmina, Alla ; Hashii, Minako ; Yokoyama, Shigeru ; Zhang, Jia-Sheng ; Noda, Mami ; Zhong, Zen-Guo
概要:
金沢大学大学院医学系研究科脳細胞分子学<br />ADP-ribosyl cyclase activity in the crude membrane fraction of neuroblastoma × glioma NGPM1-27
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hybrid cells was measured by monitoring [3H] cyclic ADP-ribose (cADPR) formation from [3H] NAD+. Bradykinin (BK) at 100 nM increased ADP-ribosyl cyclase activity by about 2.5-fold. Application of 300 nM BK to living NGPM1-27 cells decreased NAD+ to 78% of the prestimulation level at 30 s. In contrast, intracellular cADPR concentrations were increased by 2-3-fold during the period from 30 to 120 s after the same treatment. Our results suggest that cADPR is one of the second messengers downstream of B2 BK receptors. © 2006 Federation of European Biochemical Societies.
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Higashida, Haruhiro ; Salmina, Alla B. ; Olovyannikova, Raissa Ya ; Hashii, Minako ; Yokoyama, Shigeru ; Koizumi, Keita ; Jin, Duo ; Liu, Hong-Xiang ; Lopatina, Olga ; Amina, Sarwat ; Mohammad, Saharul Islam ; Huang, Jian-Jun ; Noda, Mami
概要:
金沢大学大学院医学系研究科脳細胞分子学<br />β-NAD+ is as abundant as ATP in neuronal cells. β-NAD+ functions not only as a coenzyme but als
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o as a substrate. β-NAD+-utilizing enzymes are involved in signal transduction. We focus on ADP-ribosyl cyclase/CD38 which synthesizes cyclic ADP-ribose (cADPR), a universal Ca2+ mobilizer from intracellular stores, from β-NAD+. cADPR acts through activation/modulation of ryanodine receptor Ca2+ releasing Ca2+ channels. cADPR synthesis in neuronal cells is stimulated or modulated via different pathways and various factors. Subtype-specific coupling of various neurotransmitter receptors with ADP-ribosyl cyclase confirms the involvement of the enzyme in signal transduction in neurons and glial cells. Moreover, cADPR/CD38 is critical in oxytocin release from the hypothalamic cell dendrites and nerve terminals in the posterior pituitary. Therefore, it is possible that pharmacological manipulation of intracellular cADPR levels through ADP-ribosyl cyclase activity or synthetic cADPR analogues may provide new therapeutic opportunities for treatment of neurodevelopmental disorders. © 2007.
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| 6.
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Kasai, Satoka ; Yoshihara, Toru ; Lopatina, Olga ; Ishihara, Katsuhiko ; Higashida, Haruhiro
概要:
Parkinson’s disease (PD), a neurodegenerative disorder, is accompanied by various non-motor symptoms including depressio
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n and anxiety, which may precede the onset of motor symptoms. Selegiline is an irreversible monoamine oxidase-B (MAO-B) inhibitor, and is widely used in the treatment of PD and major depression. However, there are few reports about the effects of selegiline on non-motor symptoms in PD. The aim of this study was to explore the antidepressant and anxiolytic effects of selegiline, using CD157/BST1 knockout (CD157 KO) mouse, a PD-related genetic model displaying depression and anxiety, compared with other antiparkinsonian drugs and an antidepressant, and was to investigate the effects of selegiline on biochemical parameters in emotion-related brain regions. A single administration of selegiline (1–10 mg/kg) dose-dependently reduced immobility time in the forced swimming test (FST) in CD157 KO mice, but not C57BL/6N wild-type (WT) mice. At 10 mg/kg, but not 3 mg/kg, selegiline significantly increased climbing time in CD157 KO mice. A single administration of the antiparkinsonian drugs pramipexole (a dopamine (DA) D2/D3 receptor agonist) or rasagiline (another MAO-B inhibitor), and repeated injections of a noradrenergic and specific serotonergic antidepressant (NaSSA), mirtazapine, also decreased immobility time, but did not increase climbing time, in CD157 KO mice. The antidepressant-like effects of 10 mg/kg selegiline were comparable to those of 10 mg/kg rasagiline, and tended to be stronger than those of 1 mg/kg rasagiline. After the FST, CD157 KO mice showed decreases in striatal and hippocampal serotonin (5-HT) content, cortical norepinephrine (NE) content, and plasma corticosterone concentration. A single administration of selegiline at 10 mg/kg returned striatal 5-HT, cortical NE, and plasma corticosterone levels to those observed in WT mice. In the open field test (OFT), repeated administration of mirtazapine had anxiolytic effects, and selegiline nonsignificantly ameliorated anxiety-like behaviors in CD157 KO mice. In the social interaction and preference tests, repeated mirtazapine ameliorated the high anxiety and low sociability of CD157 KO mice, whereas selegiline did not. These results indicate that selegiline has antidepressant and mild anxiolytic effects in CD157 KO mice, and suggest that it is an effective antiparkinsonian drug for depressive and anxiety symptoms in PD patients with a CD157 single nucleotide polymorphism (SNP). © 2017 Kasai, Yoshihara, Lopatina, Ishihara and Higashida.
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| 7.
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Higashida, Haruhiro ; Liang, Mingkun ; Yoshihara, Toru ; Akther, Shirin ; Fakhrul, Azam ; Stanislav, Cherepanov ; Nam, Tae-Sik ; Kim, Uh-Hyun ; Kasai, Satoka ; Nishimura, Tomoko ; Al Mahmuda, Naila ; Yokoyama, Shigeru ; Ishihara, Katsuhiko ; Gerasimenko, Maria ; Salmina, Alla ; Zhong, Jing ; Tsuji, Takahiro ; Tsuji, Chiharu ; Lopatina, Olga
概要:
Background: Recent rodent and human studies provide evidence in support of the fact that CD157, well known as bone marro
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w stromal cell antigen-1 (BST-1) and a risk factor in Parkinson's disease, also meaningfully acts in the brain as a neuroregulator and affects social behaviors. It has been shown that social behaviors are impaired in CD157 knockout mice without severe motor dysfunction and that CD157/BST1 gene single nucleotide polymorphisms are associated with autism spectrum disorder in humans. However, it is still necessary to determine how this molecule contributes to the brain's physiological and pathophysiological functions. Methods: To gain fresh insights about the relationship between the presence of CD157 in the brain and its enzymatic activity, and aberrant social behavior, CD157 knockout mice of various ages were tested. Results: CD157 immunoreactivity colocalized with nestin-positive cells and elements in the ventricular zones in E17 embryos. Brain CD157 mRNA levels were high in neonates but low in adults. Weak but distinct immunoreactivity was detected in several areas in the adult brain, including the amygdala. CD157 has little or no base exchange activity, but some ADP-ribosyl cyclase activity, indicating that CD157 formed cyclic ADP-ribose but much less nicotinic acid adenine dinucleotide phosphate, with both mobilizing Ca2+ from intracellular Ca2+ pools. Social avoidance in CD157 knockout mice was rescued by a single intraperitoneal injection of oxytocin. Conclusions: CD157 may play a role in the embryonic and adult nervous systems. The functional features of CD157 can be explained in part through the production of cyclic ADP-ribose rather than nicotinic acid adenine dinucleotide phosphate. Further experiments are required to elucidate how the embryonic expression of CD157 in neural stem cells contributes to behaviors in adults or to psychiatric symptoms. © 2017 The Author(s).
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| 8.
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Higashida, Haruhiro ; Yokoyama, Shigeru ; Tsuji, Chiharu ; Muramatsu, Shin-ichi
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We overview the 16-kDa proteolipid mediatophore, the transmembrane c-subunit of the V0 sector of the vacuolar proton ATP
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ase (ATP6V0C) that was shown to mediate the secretion of acetylcholine. Acetylcholine, serotonin, and dopamine (DA) are released from cell soma and/or dendrites if ATP6V0C is expressed in cultured cells. Adeno-associated viral vector-mediated gene transfer of ATP6V0C into the caudate putamen enhanced the depolarization-induced overflow of endogenous DA in Parkinson-model mice. Motor impairment was ameliorated in hemiparkinsonian model mice when ATP6V0C was expressed with DA-synthesizing enzymes. The review discusses application in the future as a potential tool for gene therapy, cell transplantation therapy, and inducible pluripotent stem cell therapy in neurological diseases, from the view point of recent findings regarding vacuolar ATPase. © 2016, The Physiological Society of Japan and Springer Japan.
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| 9.
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Zhong, Jing ; Amina, Sarwat ; Liang, Mingkun ; Akther, Shirin ; Yuhi, Teruko ; Nishimura, Tomoko ; Tsuji, Chiharu ; Tsuji, Takahiro ; Liu, Hong-Xiang ; Hashii, Minako ; Furuhara, Kazumi ; Yokoyama, Shigeru ; Yamamoto, Yasuhiko ; Okamoto, Hiroshi ; Zhao, Yong Juan ; Lee, Hon Cheung ; Tominaga, Makoto ; Lopatina, Olga ; Higashida, Haruhiro
概要:
Hypothalamic oxytocin (OT) is released into the brain by cyclic ADP-ribose (cADPR) with or without depolarizing stimulat
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ion. Previously, we showed that the intracellular free calcium concentration ([Ca2+]i) that seems to trigger OT release can be elevated by β-NAD+, cADPR, and ADP in mouse oxytocinergic neurons. As these β-NAD+ metabolites activate warm-sensitive TRPM2 cation channels, when the incubation temperature is increased, the [Ca2+]i in hypothalamic neurons is elevated. However, it has not been determined whether OT release is facilitated by heat in vitro or hyperthermia in vivo in combination with cADPR. Furthermore, it has not been examined whether CD38 and TRPM2 exert their functions on OT release during stress or stress-induced hyperthermia in relation to the anxiolytic roles and social behaviors of OT under stress conditions. Here, we report that OT release from the isolated hypothalami of male mice in culture was enhanced by extracellular application of cADPR or increasing the incubation temperature from 35°C to 38.5°C, and simultaneous stimulation showed a greater effect. This release was inhibited by a cADPR-dependent ryanodine receptor inhibitor and a nonspecific TRPM2 inhibitor. The facilitated release by heat and cADPR was suppressed in the hypothalamus isolated from CD38 knockout mice and CD38-or TRPM2-knockdown mice. In the course of these experiments, we noted that OT release differed markedly between individual mice under stress with group housing. That is, when male mice received cage-switch stress and eliminated due to their social subclass, significantly higher levels of OT release were found in subordinates compared with ordinates. In mice exposed to anxiety stress in an open field, the cerebrospinal fluid (CSF) OT level increased transiently at 5 min after exposure, and the rectal temperature also increased from 36.6°C to 37.8°C. OT levels in the CSF of mice with lipopolysaccharide-induced fever (+0.8°C) were higher than those of control mice. The TRPM2 mRNA levels and immunoreactivities increased in the subordinate group with cage-switch stress. These results showed that cADPR/CD38 and heat/TRPM2 are co-regulators of OT secretion and suggested that CD38 and TRPM2 are potential therapeutic targets for OT release in psychiatric diseases caused by social stress. © 2016 Zhong, Amina, Liang, Akther, Yuhi, Nishimura, Tsuji, Tsuji, Liu, Hashii, Furuhara, Yokoyama, Yamamoto, Okamoto, Zhao, Lee, Tominaga, Lopatina and Higashida.
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| 10.
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Kikuchi, Mitsuru ; Yoshimura, Yuko ; Shitamichi, Kiyomi ; Ueno, Sanae ; Hirosawa, Tetsu ; Munesue, Toshio ; Ono, Yasuki ; Tsubokawa, Tsunehisa ; Haruta, Yasuhiro ; Oi, Manabu ; Niida, Yo ; Remijn, Gerard B. ; Takahashi, Tsutomu ; Suzuki, Michio ; Higashida, Haruhiro ; Mianabe, Yoshio
概要:
A subset of individuals with autism spectrum disorder (ASD) performs more proficiently on certain visual tasks than may be predicted by their general cognitive performances. However, in younger children with ASD (aged 5 to 7),
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preserved ability in these tasks and the neurophysiological correlates of their ability are not well documented. In the present study, we used a custom child-sized magnetoencephalography system and demonstrated that preserved ability in the visual reasoning task was associated with rightward lateralisation of the neurophysiological connectivity between the parietal and temporal regions in children with ASD. In addition, we demonstrated that higher reading/decoding ability was also associated with the same lateralisation in children with ASD. These neurophysiological correlates of visual tasks are considerably different from those that are observed in typically developing children. These findings indicate that children with ASD have inherently different neural pathways that contribute to their relatively preserved ability in visual tasks.
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