Publications by authors named "Masatoshi Nagano"

25 Publications

  • Page 1 of 1

Cesarean section delivery is a risk factor of autism-related behaviors in mice.

Sci Rep 2021 Apr 26;11(1):8883. Epub 2021 Apr 26.

Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan.

Cesarean section (C/S) is one way of delivering babies, and is chosen when mothers or babies are facing problems or life-threatening conditions during pregnancy. Many meta-analyses have suggested an etiological relationship between C/S delivery and autism spectrum disorders (ASDs). However, as a risk factor for ASDs, C/S delivery has not yet been well studied. Because C/S deliveries have been increasing, it is very important to investigate the causal association between C/S and ASDs. Here, using three approaches, we showed experimentally that C/S delivery induced ASD-like traits in offspring mice, and that some of these changes were ameliorated by one-time oxytocin (OXT) treatment. Treatment with OXT receptor antagonists before natural delivery also induced ASD-related behaviors. Moreover, wild-type mice born to OXT-KO dams showed similar changes. Thus, insufficient OXT exposure from dams to offspring during delivery may be a trigger for ASD-related behaviors.
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http://dx.doi.org/10.1038/s41598-021-88437-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076189PMC
April 2021

HVGH: Unsupervised Segmentation for High-Dimensional Time Series Using Deep Neural Compression and Statistical Generative Model.

Front Robot AI 2019 20;6:115. Epub 2019 Nov 20.

Center for Mathematical Modeling and Data Science, Osaka University, Osaka, Japan.

Humans perceive continuous high-dimensional information by dividing it into meaningful segments, such as words and units of motion. We believe that such unsupervised segmentation is also important for robots to learn topics such as language and motion. To this end, we previously proposed a hierarchical Dirichlet process-Gaussian process-hidden semi-Markov model (HDP-GP-HSMM). However, an important drawback of this model is that it cannot divide high-dimensional time-series data. Furthermore, low-dimensional features must be extracted in advance. Segmentation largely depends on the design of features, and it is difficult to design effective features, especially in the case of high-dimensional data. To overcome this problem, this study proposes a hierarchical Dirichlet process-variational autoencoder-Gaussian process-hidden semi-Markov model (HVGH). The parameters of the proposed HVGH are estimated through a mutual learning loop of the variational autoencoder and our previously proposed HDP-GP-HSMM. Hence, HVGH can extract features from high-dimensional time-series data while simultaneously dividing it into segments in an unsupervised manner. In an experiment, we used various motion-capture data to demonstrate that our proposed model estimates the correct number of classes and more accurate segments than baseline methods. Moreover, we show that the proposed method can learn latent space suitable for segmentation.
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http://dx.doi.org/10.3389/frobt.2019.00115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805757PMC
November 2019

Critical roles of serotonin-oxytocin interaction during the neonatal period in social behavior in 15q dup mice with autistic traits.

Sci Rep 2018 09 12;8(1):13675. Epub 2018 Sep 12.

Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan.

Disturbance of neurotransmitters and neuromodulators is thought to underlie the pathophysiology of autism spectrum disorder (ASD). Studies of 15q dup mouse models of ASD with human 15q11-13 duplication have revealed that restoring serotonin (5-HT) levels can partially reverse ASD-related symptoms in adults. However, it remains unclear how serotonin contributes to the behavioral symptoms of ASD. In contrast, oxytocin (OXT) has been found to involve social and affiliative behaviors. In this study, we examined whether serotonin-OXT interaction during the early postnatal period plays a critical role in the restoration of social abnormality in 15q dup mice. OXT or the 5-HT receptor agonist 8OH-DPAT treatment from postnatal day 7 (PD7) to PD21 ameliorated social abnormality in the three-chamber social interaction test in adult 15q dup mice. The effect of 8OH-DPAT was inhibited by blockade of OXT receptors in 15q dup mice. Thus, serotonin-OXT interaction via 5-HT receptors plays a critical role in the normal development of social behavior in 15q dup mice. Therefore, targeting serotonin-OXT interaction may provide a novel therapeutic strategy for treatment of ASD.
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http://dx.doi.org/10.1038/s41598-018-32042-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135829PMC
September 2018

Developmental Changes in Serotonergic Modulation of GABAergic Synaptic Transmission and Postsynaptic GABA Receptor Composition in the Cerebellar Nuclei.

Cerebellum 2018 Jun;17(3):346-358

Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan.

Outputs from the cerebellar nuclei (CN) are important for generating and controlling movement. The activity of CN neurons is controlled not only by excitatory inputs from mossy and climbing fibers and by γ-aminobutyric acid (GABA)-based inhibitory transmission from Purkinje cells in the cerebellar cortex but is also modulated by inputs from other brain regions, including serotonergic fibers that originate in the dorsal raphe nuclei. We examined the modulatory effects of serotonin (5-HT) on GABAergic synapses during development, using rat cerebellar slices. As previously reported, 5-HT presynaptically decreased the amplitudes of stimulation-evoked inhibitory postsynaptic currents (IPSCs) in CN neurons, with this effect being stronger in slices from younger animals (postnatal days [P] 11-13) than in slices from older animals (P19-21). GABA release probabilities accordingly exhibited significant decreases from P11-13 to P19-21. Although there was a strong correlation between the GABA release probability and the magnitude of 5-HT-induced inhibition, manipulating the release probability by changing extracellular Ca concentrations failed to control the extent of 5-HT-induced inhibition. We also found that the IPSCs exhibited slower kinetics at P11-13 than at P19-21. Pharmacological and molecular biological tests revealed that IPSC kinetics were largely determined by the prevalence of α subunits within GABA receptors. In summary, pre- and postsynaptic developmental changes in serotonergic modulation and GABAergic synaptic transmission occur during the second to third postnatal weeks and may significantly contribute to the formation of normal adult cerebellar function.
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http://dx.doi.org/10.1007/s12311-018-0922-9DOI Listing
June 2018

Differential effects of neonatal SSRI treatments on hypoxia-induced behavioral changes in male and female offspring.

Neuroscience 2017 Sep 1;360:95-105. Epub 2017 Aug 1.

Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. Electronic address:

Prenatal hypoxia induced by transient intrauterine ischemia is a serious clinical problem, and at present, effective treatments are lacking. Currently, it is unknown how prenatal hypoxia affects behaviors in adulthood. Therefore, we developed a mouse model that mimics prenatal hypoxia in humans using uterine artery occlusion in late gestation. We examined whether prenatal hypoxia induces behavioral changes in adult male and female offspring by conducting a series of behavioral tests. In adulthood, longer immobility was observed in the forced swim test in males, whereas females showed decreased inhibition in the prepulse inhibition test. We then investigated the effects of two different selective serotonin reuptake inhibitors (SSRIs), fluoxetine (FLX) and escitalopram (ESC), on these behavioral changes. These drugs affect the neurodevelopmental process and have long-term neurological consequences. FLX treatment from postnatal day 3 (P3) to P21 ameliorated the behavioral changes in both male and female mice. In comparison, ESC treatment ameliorated the behavioral changes only in female mice. Neurochemical analysis revealed that dopamine was increased in the female hippocampus, but not in males. Thus, neonatal SSRI treatment decreases dopamine levels in the hippocampus in females selectively. Our findings suggest that prenatal hypoxia is a risk factor for behavioral abnormalities in adulthood, and that neonatal SSRI treatment might have clinical potential for alleviating these long-term behavioral deficits.
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http://dx.doi.org/10.1016/j.neuroscience.2017.07.051DOI Listing
September 2017

Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice.

Sci Adv 2017 06 21;3(6):e1603001. Epub 2017 Jun 21.

RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.

Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms.
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http://dx.doi.org/10.1126/sciadv.1603001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479676PMC
June 2017

Influence of neonatal sevoflurane exposure on nerve development-related microRNAs and behavior of rats.

Biomed Res 2015 ;36(6):347-55

Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School.

Commonly used anesthetics adversely affect the developing brain, but the mechanisms remain unknown. We previously showed that the expressions of microRNAs (miRNAs) in major organs are affected by anesthetics. Therefore, we used TaqMan low-density array (TLDA) to analyze gene expression in the hippocampus of neonatal rats exposed to sevoflurane and performed behavioral tests after they reached adulthood to evaluate cognitive and memory function. Rat male pups at postnatal day 7 were exposed to 1.9% sevoflurane for 3 h, and the hippocampus-miRNA expression profile on postnatal day 8 was determined. Open field and fear conditioning tests conducted during postnatal weeks 7 and 8 indicated that sevoflurane-exposed rats, but not controls, exhibited anxiety-like disorders. TLDA analysis identified 20 differentially expressed miRNAs, which were not shared between postnatally and maturely sevoflurane-exposed rats. The level of rno-miR-632, which targets brain-derived neurotrophic factor and calcium channel, voltage-dependent, alpha 2/delta subunit 2, increased by 10-fold, indicating that exposure to sevoflurane during early neural development alters hippocampus-miRNA expression and may induce subsequent behavioral disorders.
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http://dx.doi.org/10.2220/biomedres.36.347DOI Listing
September 2016

Redox regulation of mammalian 3-mercaptopyruvate sulfurtransferase.

Methods Enzymol 2015 20;554:229-54. Epub 2015 Jan 20.

Department of Pharmacology, Nippon Medical School, Tokyo, Japan.

A cystine-catabolizing enzyme, 3-mercaptopyruvate sulfurtransferase catalyzes the trans-sulfuration reaction of mercaptopyruvate or thiosulfate to thiol-containing compounds or cyanide. During the catalytic process, persulfide is formed at the catalytic site cysteine residue and a sulfur-acceptor substrate donates the outer sulfur of the persulfide to form a new persulfide molecule. Subsequently, the molecule can be reduced by thioredoxin to form hydrogen sulfide. The enzyme is regulated by redox changes via two redox-sensing molecular switches consisting redox-sensitive cysteine residues. One switch is the catalytic cysteine in itself, which is oxidized to form a cysteine-sulfenate resulting in inhibition of catalytic activity. The sulfenate can be reduced by thioredoxin resulting in restoration of the activity. The redox potential of sulfenate is lower than that of glutathione and greater than that of thioredoxin. The other switch involves cysteine residues positioned on the surface of the enzyme. The oxidation the intermolecular disulfide linkage at these cysteine residues, leading to dimer formation, inhibits enzyme activity. On the other hand, reduction-associated monomer formation increases catalytic activity. Thioredoxin reduces the disulfide bond more effectively than dithiothreitol, although the specificity mechanism has not been identified. Congenital defects in this enzyme result in, mercaptolactate-cysteine disulfiduria associated with or without mental retardation. However, the pathogenesis has not been identified. Because 3-mercaptopyruvate sulfurtransferase serves as a cellular antioxidative protein, the other biological functions related to the inhabitant disease are being investigated.
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http://dx.doi.org/10.1016/bs.mie.2014.11.017DOI Listing
November 2015

Antioxidant enzyme, 3-mercaptopyruvate sulfurtransferase-knockout mice exhibit increased anxiety-like behaviors: a model for human mercaptolactate-cysteine disulfiduria.

Sci Rep 2013 ;3:1986

Isotope Research Center, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Human mercaptolactate-cysteine disulfiduria (MCDU) was first recognized and reported in 1968. Most cases of MCDU are associated with mental retardation, while the pathogenesis remains unknown. To investigate it, we generated homozygous 3-mercaptopyruvate sulfurtransferase (MST: EC 2.8.1.2) knockout (KO) mice using C57BL/6 embryonic stem cells as an animal model. The MST-KO mice showed significantly increased anxiety-like behaviors with an increase in serotonin level in the prefrontal cortex (PFC), but not with abnormal morphological changes in the brain. MCDU can be caused by loss in the functional diversity of MST; first, MST functions as an antioxidant protein. MST possessing 2 redox-sensing molecular switches maintains cellular redox homeostasis. Second, MST can produce H2S (or HS(-)). Third, MST can also produce SOx. It is concluded that behavioral abnormality in MST-KO mice is caused by MST function defects such as an antioxidant insufficiency or a new transducer, H2S (or HS(-)) and/or SOx deficiency.
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http://dx.doi.org/10.1038/srep01986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680806PMC
June 2014

Early intervention with fluoxetine reverses abnormalities in the serotonergic system and behavior of rats exposed prenatally to dexamethasone.

Neuropharmacology 2012 Aug 13;63(2):292-300. Epub 2012 Apr 13.

Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Many psychiatric disorders emerge after adolescence. Among a variety of predisposing factors, prenatal stress has been thought to cause the symptoms of anxiety disorders. We recently reported that prenatal dexamethasone (DEX) exposure, which mimics some aspects of prenatal stress, induced anxiety-related behaviors in male offspring when they reached adulthood. Before the emergence of behavioral changes, abnormalities occurred in the hypothalamic-pituitary-adrenal axis during postnatal development. In the present study, we found abnormalities in serotonin (5-HT) signaling, including decreased expression of 5-HT(1A) receptor (5-HT(1A)-R) mRNA in the medial prefrontal cortex (mPFC) and 5-HT content in the hippocampus at postnatal week (PW) 4. These results support using early therapeutic interventions with serotonergic drugs to prevent late-emerging anxiety symptoms. To test this hypothesis, we treated rat pups born to DEX-administered mothers with fluoxetine (FLX), a selective serotonin reuptake inhibitor commonly used as an anti-anxiety medication, via breast milk from postnatal day (PD) 2-21. Anxiety-related behaviors examined at PW11-13 were not observed in the prenatally DEX-exposed offspring that were treated with FLX. Likewise, FLX increased 5-HT concentrations in the mPFC and ventral hippocampus at PW3 and normalized 5-HT(1A)-R mRNA concentrations in the mPFC at PW4. The decrease in brain-derived neurotrophic factor (BDNF) protein in the mPFC and dorsal hippocampus was also restored at PW4. Furthermore, administration of the 5-HT(1A)-R full agonist (R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin from PD2 to 21 also prevented the emergence of behavioral abnormalities in the prenatally DEX-exposed offspring, implicating the involvement of 5-HT(1A)-Rs in the neonatal FLX effect. Collectively, an early pharmacological intervention to normalize serotonergic transmission effectively suppressed the emergence of symptoms induced by prenatal DEX exposure in rats.
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http://dx.doi.org/10.1016/j.neuropharm.2012.03.027DOI Listing
August 2012

Distribution and pharmacological characterization of primate NK-2 tachykinin receptor in the central nervous system of the rhesus monkey.

Neurosci Lett 2011 Sep 6;503(1):23-6. Epub 2011 Aug 6.

Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Tachykinin NK-2 receptor, a cognate receptor for neurokinin A, expressed in the brain has been suggested as a new target for the treatment of psychiatric disorders. In rodents, treatment with NK-2 receptor agonists causes anxiogenic effects, while NK-2 receptor antagonists show anxiolytic and antidepressant-like effects. However, information about the distribution and functions of NK-2 receptors in the central nervous system (CNS) in primates is still lacking. Here, we examined the distribution and pharmacological profile of NK-2 receptors in the rhesus monkey (Macaca mulatta) to clarify the molecular basis of NK-2-mediated tachykininergic functions in the primate CNS. NK-2 receptors cloned from the rhesus monkey brain showed similar pharmacological properties to those of human NK-2 receptors. Substantial expression levels of NK-2 mRNA were observed in all the brain regions examined, including areas pertinent to the emotional networks such as the prefrontal cortex, cingulate cortex and amygdala. These findings suggest that NK-2 receptors may play important roles in the pathophysiology of psychiatric disorders.
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http://dx.doi.org/10.1016/j.neulet.2011.07.057DOI Listing
September 2011

Effects of stress memory by fear conditioning on nerve-mast cell circuit in skin.

J Dermatol 2011 Jun 2;38(6):553-61. Epub 2010 Nov 2.

Departments of Dermatology, Nippon Medical School, Tokyo, Japan.

Inflammatory skin disorder aggravates when a horrific memory is evoked, but the mechanism of this effect is unclear. The objective of the present study was to examine the effects of evocation of a horrific memory on the skin and mast cells in an animal model. A sound stimulus linked to an electric shock was given to C57BL/6 mice (7-week old, males). One, 3 and 5 days later, the mice received the sound stimulus again. The reactions of mice that received the initial sound stimulus were compared with those of mice that did not receive the initial stimulus. A freezing phenomenon was observed when the sound stimulus was given to mice that received the initial stimulus, which indicated evocation of a past memory of fear. The degranulation rate of dermal mast cells and the length of substance P (SP)-positive nerve fibers of the skin significantly increased on days 1 and 3, the SP level decreased significantly, and the number of SP-expressing cells in the dorsal root ganglion significantly increased on day 1. These findings suggest that prior experience of severe stress linked to a stimulus subsequently evokes fear associated with the same stimulus and results in activation of dermal mast cells and skin nerves.
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http://dx.doi.org/10.1111/j.1346-8138.2010.01045.xDOI Listing
June 2011

Chronic stress enhances synaptic plasticity due to disinhibition in the anterior cingulate cortex and induces hyper-locomotion in mice.

Neuropharmacology 2010 Mar-Apr;58(4-5):746-57. Epub 2009 Dec 24.

Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.

The anterior cingulate cortex (ACC) is involved in the pathophysiology of a variety of mental disorders, many of which are exacerbated by stress. There are few studies, however, of stress-induced modification of synaptic function in the ACC that is relevant to emotional behavior. We investigated the effects of chronic restraint stress (CRS) on behavior and synaptic function in layers II/III of the ACC in mice. The duration of field excitatory postsynaptic potentials (fEPSPs) was longer in CRS mice than in control mice. The frequency of miniature inhibitory postsynaptic currents (mIPSCs) recorded by whole-cell patch-clamping was reduced in CRS mice, while miniature excitatory postsynaptic currents (mEPSCs) remained unchanged. Paired-pulse ratios (PPRs) of the fEPSP and evoked EPSC were larger in CRS. There was no difference in NMDA component of evoked EPSCs between the groups. Both long-term potentiation (LTP) and long-term depression of fEPSP were larger in CRS mice than in control mice. The differences between the groups in fEPSP duration, PPRs and LTP level were not observed when the GABA(A) receptor was blocked by bicuculline. Compared to control mice, CRS mice exhibited hyper-locomotive activity in an open field test, while no difference was observed between the groups in anxiety-like behavior in a light/dark choice test. CRS mice displayed decreased freezing behavior in fear conditioning tests compared to control mice. These findings suggest that CRS facilitates synaptic plasticity in the ACC via increased excitability due to disinhibition of GABA(A) receptor signalling, which may underlie induction of behavioral hyper-locomotive activity after CRS.
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http://dx.doi.org/10.1016/j.neuropharm.2009.12.011DOI Listing
September 2010

Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia.

Schizophr Res 2008 Apr 4;101(1-3):58-66. Epub 2008 Mar 4.

Department of Pharmacology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Neurotrophic factors (NFs) play a pivotal role in the development of the central nervous system. They are thus also suspected of being involved in the etiology of schizophrenia. Previous studies reported a decreased level of serum brain-derived neurotrophic factor (BDNF) in schizophrenia, whereas the association of epidermal growth factor (EGF) with this illness remains controversial. Using a two-site enzyme immunoassay, we conducted the simultaneous measurement of serum BDNF and EGF levels in a group of patients with chronic schizophrenia (N=74) and a group of normal controls matched in age, body mass index, smoking habit and sex (N=87). We found that, compared to normal controls, patients with chronic schizophrenia exhibited lower serum levels of both BDNF and EGF across all ages examined (21-59 years). The serum levels of BDNF and EGF were negatively correlated in the controls (r=-0.387, P=0.0002) but not in the patients. Clinical parameters such as duration of illness and psychiatric rating scale also showed no robust correlations with the NF levels. Collectively, these results suggest that pervasive, abnormal signaling of NFs underlies the pathophysiology of chronic schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2008.01.017DOI Listing
April 2008

Prenatal dexamethasone exposure affects anxiety-like behaviour and neuroendocrine systems in an age-dependent manner.

Neurosci Res 2008 Apr 23;60(4):364-71. Epub 2007 Dec 23.

Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Prenatal stress has been reported to alter the development of the central nervous system functions. This alteration is thought to be partly caused by increased fetal exposure to glucocorticoid. To clarify how prenatal stress affects neuroendocrine systems and behaviour in an age-dependent manner, we administered a synthetic glucocorticoid, dexamethasone, as a stressor to pregnant rats at gestational days 16-21 and examined the developmental changes in behaviour, hypothalamic corticotropin-releasing factor mRNA expression, corticosterone response and glucocorticoid receptor expression in male offspring. Prenatal dexamethasone exposure decreased corticotropin-releasing factor mRNA in the hypothalamus and disturbed the plasma corticosterone response to restraint stress in the offspring at postnatal week 4 (PW4). In contrast, it was not until PW10 that increased anxiety-like behaviour emerged in the dexamethasone-exposed offspring. In association with the acquisition of increased anxiety-like behaviour at PW10, glucocorticoid receptor expression was decreased in the amygdala in dexamethasone-exposed offspring at PW7 and PW10. Thus, our longitudinal analysis suggests that prenatal exposure to glucocorticoid hampers neuroendocrinological development in the offspring during early life, and that this disturbance results in the induction of increased anxiety-like behaviour in adulthood.
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http://dx.doi.org/10.1016/j.neures.2007.12.005DOI Listing
April 2008

Dynamic changes in nerve growth factor and substance P in the murine hair cycle induced by depilation.

J Dermatol 2006 Dec;33(12):833-41

Department of Dermatology, Nippon Medical School, Bunkyo-Ku, Tokyo, Japan.

Increasing evidence suggests that various neurotrophins and neuropeptides play an important role in the progression of hair follicle cycling. Among them, nerve growth factor (NGF) and substance P (SP) have attracted special interest recently. However, the interaction between these factors during hair cycling has not yet been systematically studied. We therefore investigated the mutual relationships between NGF and SP and the mechanism by which the anagen stage of the hair cycle is initiated. Fluctuations in numbers of SP-positive nerve fibers and variations in amounts of SP, NGF, and another neurotrophic factor, glial cell-derived neurotrophic factor, in skin in the C57BL/6 mouse depilation-induced hair cycle model, together with the spatiotemporal expression patterns of each of these factors, were followed simultaneously by enzyme-linked immunosorbent assay and immunohistochemistry. The main finding was that a surge in NGF expression and a rapid increase in NGF content in skin is an initial event within 1 day after depilation, followed by elevation of SP content and numbers of SP-containing fibers 2 days after the increase in NGF. Our findings suggest that a rapid and abundant increase in NGF plays a key role in the induction and progression of anagen hair cycling through keratinocyte growth promotion. NGF may also induce plastic changes such as sprouting and hyperplasia in dermal nerve fibers and enhance their SP production. Elevated levels of SP in skin may additionally contribute to the progression of consecutive anagen hair cycles.
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http://dx.doi.org/10.1111/j.1346-8138.2006.00191.xDOI Listing
December 2006

Expression changes of cation chloride cotransporters in the rat spinal cord following intraplantar formalin.

Neurosci Res 2006 Dec 27;56(4):435-40. Epub 2006 Sep 27.

Anesthesiology and Clinical Physiology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo, Japan.

Cation chloride cotransporters, K(+)-Cl(-) cotransporter 2 (KCC2) and Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) are reported to be expressed in the neurons in the spinal cord and regulate intracellular Cl(-) concentration. Evidence has been accumulating that the expression of cation chloride cotransporters changes in inflammatory or neuropathic pain, and such changes take a part in pathophysiology of the persistent pain states. However, it is largely unknown how these cotransporters contribute to hyperalgesia in the acute pain state. We, therefore, investigated expression changes of KCC2 and NKCC1 in the spinal dorsal horn of the rat after the intraplantar injection of formalin as an acute nociceptive stimulus. The rats showed two phases (phases 1 and 2) of increase in pain-related behavior in response to formalin. We found that expression of KCC2-like immunoreactivity (IR) was reduced in lamina I and II in the lumbar spinal cord on the stimulated side in phase 1, and then recovered gradually. In contrast, the number of NKCC1-like IR-positive cells was unchanged over the period examined. These results suggest that KCC2, rather than NKCC1, mainly contributes to modulating excitability of the dorsal spinal cord neurons in the initial stage of formalin-evoked hyperalgesia.
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http://dx.doi.org/10.1016/j.neures.2006.08.012DOI Listing
December 2006

Role of substance P in stress-derived degranulation of dermal mast cells in mice.

J Dermatol Sci 2006 Apr 10;42(1):47-54. Epub 2006 Jan 10.

Nippon Medical School, Department of Dermatology, 1-1-5 Sendagi, 113-8603 Tokyo, Japan.

Background: The interaction between nerves and mast cells can effect regulation of the immune system and inflammatory responses. Recent studies have shown that various stressors can induce degranulation of dermal mast cells in animals.

Objectives: This study was conducted to confirm that substance P (SP) was involved in the degranulation of dermal mast cells in stress conditions.

Methods: Using a communication box system, foot shock stress (FS) and psychological stress (PS) were administered to mice and the degranulation rate of dermal mast cells, the number of SP-positive nerve fibers and changes in SP content were determined. The inhibitory effect of a non-peptide NK1-receptor antagonist on these changes was investigated.

Results: Both FS and PS significantly enhanced the degranulation of dermal mast cells and increased the number of SP-positive nerve fibers. FS significantly decreased dermal SP content whereas SP was increased by PS. These changes were inhibited by intraperitoneal injection of NK(1) receptor antagonist.

Conclusions: It was considered that SP released from the nerve ending, had an important role in the degranulation of dermal mast cells. Results of this study suggest that the tachykinin receptor antagonist exhibited an inhibitory effect on aggravated stress-induced dermatitis.
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http://dx.doi.org/10.1016/j.jdermsci.2005.12.004DOI Listing
April 2006

Distribution and pharmacological characterization of primate NK-1 and NK-3 tachykinin receptors in the central nervous system of the rhesus monkey.

Br J Pharmacol 2006 Feb;147(3):316-23

Department of Pharmacology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Much attention has focused on tachykinin receptors as therapeutic targets for neuropsychiatric disorders, although their expressional distributions in the primate central nervous system (CNS) remain unclear. We cloned the genes encoding the NK-1 and NK-3 tachykinin receptors (referred to as rmNK-1 and rmNK-3) from the rhesus monkey (Macaca mulatta) brain and examined their pharmacological profiles and regional distributions in the CNS. The deduced rmNK-1 amino-acid sequence differed by only two amino acids from the human NK-1 (hNK-1). The deduced rmNK-3 amino-acid sequence was two amino acids shorter than human NK-3 (hNK-3), with a seven-amino-acid difference in sequence. Ligand binding studies revealed that the affinity of rmNK-1 to substance P (SP) was comparable to that of hNK-1 in cell lines that expressed individual receptors stably. Nonpeptide antagonists had similar effects on the binding of rmNK-1 and hNK-1. Affinity of rmNK-3 for NKB was stronger than for SP and the IC50 value was comparable with that of hNK-3. Ca2+ imaging showed that activations of both rmNK-1 and rmNK-3 by specific ligands, SP and senktide, induced increased intracellular Ca2+ in cell lines that stably expressed individual primate tachykinin receptors. The amounts of rmNK-1 and rmNK-3 mRNAs were quantitatively determined in the monkey CNS. The expression of rmNK-1 was observed in all of the cortical and subcortical regions, including the hippocampus and the amygdala. The putamen contained the most NK-1 mRNA in the brain, with less rmNK-3 mRNA found in the cortex compared to rmNK-1 mRNA. In the monkey hippocampus and amygdala, rmNK-1 mRNA was present at markedly higher concentrations than rmNK-3 mRNA. The present results provide an insight into the distinct physiological nature and significance of the NK-1 and NK-3 tachykinin systems in the primate CNS. These findings are indispensable for establishing model systems in the search for a subtype-specific tachykinin receptor agonist and antagonist for the treatment of neuropsychiatric disorders.
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http://dx.doi.org/10.1038/sj.bjp.0706561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751306PMC
February 2006

Differential expression of GABA(A) receptor subunits in the distinct nuclei of the rat amygdala.

Brain Res Mol Brain Res 2005 Jul 19;138(1):17-23. Epub 2005 Apr 19.

Department of Pediatrics, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Detailed knowledge of the anatomical distribution of different GABA(A) receptor subunits is crucial for understanding the physiological actions of GABA in individual brain areas and for developing drugs acting through the individual GABA receptor subtypes. Since the amygdala is a key brain structure in the processing of emotional information with distinct functions in each nucleus, GABA(A) receptors in the amygdala are an important target of treatment for emotional disorders. In this study, we analyzed by quantitative RT-PCR the expression levels of all GABA(A) receptor subunits in distinct nuclei of the amygdala, the central (Ce) and the lateral/basolateral (LA/BLA) amygdala. We found the strongest expression of the gamma(2) subunit mRNA in both the Ce and LA/BLA, modest expressions of alpha(1), alpha(2) and alpha(3) mRNAs in the LA/BLA and alpha(2) and gamma(1) mRNAs in the Ce, and weak expressions of alpha(6), rho(2) and rho(3) mRNAs in both regions. We further revealed the significantly different expressions of alpha(1), alpha(3), alpha(5), gamma(1), gamma(2), delta, epsilon and theta subunit mRNAs in the Ce and LA/BLA. Differences in the expression levels of GABA(A) receptor subunits suggest different sensitivity to a variety of drugs including benzodiazepines and anesthetics in amygdala nuclei with distinct functions.
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http://dx.doi.org/10.1016/j.molbrainres.2005.03.013DOI Listing
July 2005

NGF and GDNF differentially regulate TRPV1 expression that contributes to development of inflammatory thermal hyperalgesia.

Eur J Neurosci 2004 Nov;20(9):2303-10

Department of Anaesthesiology, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyo-ku, Kyoto 602-8566, Japan.

The transient receptor potential ion channel, TRPV1 plays an essential role in the development of inflammatory thermal hyperalgesia. We investigated the dependence of inflammatory TRPV1 induction on neurotrophic factor. Rat dorsal root ganglia (DRG) neurons were classified according to immunostaining for trk-A and IB4 and the effects of antibodies against NGF or GDNF on TRPV1 expression within the groups were then analysed by immunohistochemical means. The data were compared with the time course of trophic factor expression and the effects of their antibodies on thermal hyperalgesia against radiant heat after inflammation. Although the levels of both NGF and GDNF were increased by inflammation, NGF rapidly and transiently increased whereas GDNF increased gradually over a period of approximately one week. TRPV1 expression was increased within both trk-A positive and IB4 positive neurons after inflammation. Increased TRPV1 expression within trk-A positive neurons was prevented by anti-NGF but not by anti-GDNF, whereas TRPV1 induction within the IB4 positive group was blocked by anti-GDNF but not by anti-NGF. Both antibodies prevented the short latency of withdrawing an inflamed paw from radiant heat. These results suggest that inflammation differentially increases both NGF and GDNF, which facilitate TRPV1 expression within distinctive neurons to induce thermal hyperalgesia.
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http://dx.doi.org/10.1111/j.1460-9568.2004.03701.xDOI Listing
November 2004

Research on fear/anxiety.

J Nippon Med Sch 2004 Apr;71(2):82-3

Department of Pharmacology, Nippon Medical School.

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http://dx.doi.org/10.1272/jnms.71.82DOI Listing
April 2004

Decreased expression of glial cell line-derived neurotrophic factor signaling in rat models of neuropathic pain.

Br J Pharmacol 2003 Dec 27;140(7):1252-60. Epub 2003 Oct 27.

Department of Pharmacology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

1. In an attempt to clarify whether glial cell line-derived neurotrophic factor (GDNF), a survival factor for subpopulations of primary afferent neurons, is involved in the states of neuropathic pain, we observed changes in the expressions of GDNF and its signal-transducing receptor Ret after nerve injury in two rat models of neuropathic pain. 2. In the rats treated with sciatic nerve ligation (chronic constrictive injury (CCI) model) or spinal nerve ligation at L5 (SNL model), the thresholds of paw withdrawal in response to mechanical or heat stimuli began to decrease on the injured side within the first week after the operation and the decreases in the thresholds persisted for more than 2 weeks. 3. In CCI-treated rats, the GDNF contents in L4 and L5 dorsal root ganglia (DRGs) on the injured side were markedly decreased at day 7 after the operation and stayed at low levels at day 14. In SNL-treated rats, comparable reductions of GDNF levels in L4 and L5 DRGs on the injured side were observed at 14 postoperative days. 4. Significant decreases of the percentages of DRG neurons expressing Ret were also observed at L4 DRGs in CCI-treated rats at 7 and 14 postoperative days and in SNL-treated rats at 14 days. 5. In CCI- or SNL-treated rats, continuous intrathecal administration of GDNF (12 microg day-1) using an osmotic pump suppressed the increased sensitivities to nociceptive stimuli to control levels. 6. The present results suggested that the dysfunction of GDNF signaling in the nociceptive afferent system may contribute to the development and/or maintenance of neuropathic pain states.
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http://dx.doi.org/10.1038/sj.bjp.0705550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574137PMC
December 2003

Expression changes of glial cell line-derived neurotrophic factor in a rat model of neuropathic pain.

J Med Dent Sci 2003 Mar;50(1):87-92

Anesthesiology and Clinical Physiology, Department of Oral Restitution, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University, Japan.

To reveal roles of neurotrophic factors in plastic changes of the primary afferent neurons following nerve injury, we investigated expression of glial cell line-derived neurotrophic factor (GDNF) as well as nerve growth factor (NGF) in a neuropathic pain model of the rat. The rats exhibited hyperalgesia and allodynia on the injured left side for at least 2 weeks after chronic constrictive injury to the sciatic nerve. Accompanied by the behavioral changes, expression of GDNF decreased in the dorsal root ganglia (DRGs) and the sciatic nerve on the injured side on the fourteenth day after the surgery. In contrast, the amount of NGF in DRGs was unchanged in spite of disturbance of NGF transport in the nerve. The present results suggest that decreased expression of GDNF takes some part in development and/or maintenance of neuropathic pain.
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March 2003

Quantitative analyses of expression of GDNF and neurotrophins during postnatal development in rat skeletal muscles.

Neurosci Res 2003 Apr;45(4):391-9

Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Neurotrophic factors are thought to be critically involved in formation and maintenance of the neuromuscular system. To know precise expression levels of these factors in the muscles during the postnatal period, we developed competitive RT-PCR and two-site enzyme immunoassay and quantitatively measured neurotrophic factors in the rat gastrocnemius and soleus muscles during the postnatal development. mRNAs of glial cell line-derived neurotrophic factor (GDNF) in the gastrocnemius and the soleus muscles were expressed in the highest amount among the neurotrophic factors at birth and dramatically decreased in the first 3 months, while GDNF proteins substantially existed at 3 months of age. Neurotrophin-3 and brain-derived neurotrophic factor in the gastrocnemius muscle kept constant expression in mRNA and protein during the postnatal period. In contrast, mRNA of neurotrophin-4 increased in the first 2 weeks. In the soleus muscles all the neurotrophic factor proteins increased with age for the first month, contrasting with their expressions in the gastrocnemius. The present results showed that GDNF is constitutively supplied to the neuromuscular junction (NMJ) during postnatal development and into adulthood, suggesting its importance in maintenance of the NMJ. Expression of other neurotrophins was also regulated independently during development possibly according to their own roles in the neuromuscular circuit.
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http://dx.doi.org/10.1016/s0168-0102(03)00010-5DOI Listing
April 2003