Seiji Hitoshi - Academia.edu (original) (raw)
Papers by Seiji Hitoshi
Journal of Physiological Sciences, Aug 29, 2016
Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature into oligodendr... more Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature into oligodendrocytes (OLs), and form myelin in the postnatal brain. It has been proposed that early born OPCs derived from the ventral forebrain are eliminated postnatally and late-born OLs predominate in the adult mouse cortex. However, the temporal and regional niche for cortical OL generation, which persists throughout life in adult mammals, remains to be determined. Our recent study provides new insight into self-renewing and multipotent neural stem cells (NSCs). Our results, together with previous studies, suggest that NSCs at the dorsoventral boundary are uniquely specialized to produce myelin-forming OLs in the cortex during a restricted temporal window. These findings may help identify transcription factors or gene expression patterns which confer neural precursors with the characteristic ability of dorsoventral boundary NSCs to differentiate into OLs, and facilitate the development of new strategies for regenerative medicine of the damaged brain. Keywords Cortical oligodendrocyte Á Dorsoventral boundary Á Neural stem cells Á Wnts Á FGF …as the name ''interfascicular glia'' indicates only the principal feature of its constitutive elements, we have adopted the term ''oligodendroglia''…Unfortunately, we have not been able to observe the very first stages of genesis of the oligodendroglia… by Pío Del Río-Hortega [1]
Cerebral Cortex, Jun 23, 2015
Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature to become oligo... more Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature to become oligodendrocytes (OLs), and form myelin in the postnatal brain. Recently, it has been proposed that early-born OPCs derived from the ventral forebrain are eradicated postnatally and that late-born OLs predominate in the cortex of the adult mouse brain. However, intrinsic and extrinsic factors that specify the ability of self-renewing multipotent neural stem cells in the embryonic brain to generate cortical OL-lineage cells remain largely unknown. Using an inducible Cre/loxP system to permanently label Nestin-and Olig2lineage cells, we identified that cortical OL-lineage cells start differentiating from neural stem cells within a restricted temporal window just prior to E16.5 through P10. We then showed, by means of electroporation of a Cre expression plasmid into the VZ/SVZ of E15.5 reporter mouse brains, that neural precursor cells in the dorsal VZ/SVZ are inhibited by Wnt signaling from contributing to cortical OLs in the adult brain. In contrast, neural precursor cells present in the dorsoventral boundary VZ/SVZ produce a significant amount of OLs in the adult cortex. Our results suggest that neural stem cells at this boundary are uniquely specialized to produce myelin-forming OLs in the cortex.
The Journal of Physiological Sciences
Neural stem cells (NSCs) are maintained in the adult mammalian brain throughout the animal’s life... more Neural stem cells (NSCs) are maintained in the adult mammalian brain throughout the animal’s lifespan. NSCs in the subependymal zone infrequently divide and generate transit amplifying cells, which are destined to become olfactory bulb neurons. When transit amplifying cells are depleted, they are replenished by the quiescent NSC pool. However, the cellular basis for this recovery process remains largely unknown. In this study, we traced NSCs and their progeny after transit amplifying cells were eliminated by intraventricular infusion of cytosine β-D-arabinofuranoside. We found that although the number of neurosphere-forming NSCs decreased shortly after the treatment, they were restored to normal levels 3 weeks after the cessation of treatment. More importantly, the depletion of transit amplifying cells did not induce a significant expansion of the NSC pool by symmetric divisions. Our data suggest that the size of the NSC pool is hardly affected by brain damage due to antimitotic dru...
Development, 2002
Regional patterning in the developing mammalian brain is partially regulated by restricted gene e... more Regional patterning in the developing mammalian brain is partially regulated by restricted gene expression patterns within the germinal zone, which is composed of stem cells and their progenitor cell progeny. Whether or not neural stem cells, which are considered at the top of the neural lineage hierarchy, are regionally specified remains unknown. Here we show that the cardinal properties of neural stem cells (self-renewal and multipotentiality) are conserved among embryonic cortex, ganglionic eminence and midbrain/hindbrain, but that these different stem cells express separate molecular markers of regional identity in vitro, even after passaging. Neural stem cell progeny derived from ganglionic eminence but not from other regions are specified to respond to local environmental cues to migrate ventrolaterally, when initially deposited on the germinal layer of ganglionic eminence in organotypic slice cultures. Cues exclusively from the ventral forebrain in a 5 day co-culture paradigm...
Frontiers in Neuroscience, 2020
Early life stress can exert detrimental or beneficial effects on neural development and postnatal... more Early life stress can exert detrimental or beneficial effects on neural development and postnatal behavior depending on the timing, duration, strength, and ability to control the stressors. In this study, we utilized a maternal and social deprivation (MSD) model to investigate the effects of early life stress on neural stem cells (NSCs) and neurogenesis in the adult brain. We found that MSD during the stress-hyporesponsive period (SHRP) (early-MSD), when corticosterone secretion is suppressed, increased the size of the NSC population, whereas the same stress beyond the SHRP abrogated these effects. Early-MSD enhanced neurogenesis not only in the dentate gyrus of the hippocampus, one of the classic neurogenic regions, but also in the amygdala. In addition, mice exposed to early-MSD exhibited a reduction in amygdala/hippocampus-dependent fear memory. These results suggest that animals exposed to early life stress during the SHRP have reinforced stress resilience to cope with perceived stressors to maintain a normal homeostatic state.
IBRO Reports, 2019
Hydrangea macrophylla, widely cultivated in Northeast Asia, is well known to have various pharmac... more Hydrangea macrophylla, widely cultivated in Northeast Asia, is well known to have various pharmacological effects including antiinflammatory, anti-oxidant and anti-malaria effects. And it also has neurological effects such as improvement of dementia induced by scopolamine. Neurite outgrowth is a phenomenon that spreads the axons and dendrites from the cell body. Since it influences synaptic plasticity, the ability for brain to reconstitute or relocate itself, neurite outgrowth is a highly important process in learning and memory. A lot of natural compounds have already been reported to induce neurite outgrowth, but the effect of Hydrangea macrophylla on neurite outgrowth has not yet been studied. Therefore, in this study, we tested the effect of hydrangea macrophylla on neurite outgrowth in neuro2a cells. We first ascertained morphological changes and measured neurite-bearing cells and neurite lengths. Hydrangea macrophylla significantly increased the percentage of neurite-bearing cells and the length of neurite in a concentration-dependent manner without inducing cell death. And then, we have identified the mode of action of hydrangea macrophylla with peroxisome proliferator activated receptor gamma (PPAR␥) inhibitor (GW9662) and the Phosphoinositide 3-kinase (PI3K) inhibitor (LY294002). As a result, hydrangea macrophyllainduced neurite outgrowth was blocked by the PPAR␥ inhibitor. These results shown that hydrangea macrophylla induces neurite outgrowth through PPAR␥ signaling.
Journal of Neurochemistry, 2018
In the adult mammalian brain, neural stem cells (NSCs) reside in two neurogenic regions, the wall... more In the adult mammalian brain, neural stem cells (NSCs) reside in two neurogenic regions, the walls of the lateral ventricles, and the subgranular zone of the hippocampus, which generate new neurons for the olfactory bulb and dentate gyrus, respectively. These adult NSCs retain their self‐renewal ability and capacity to differentiate into neurons and glia as demonstrated by in vitro studies. However, their contribution to tissue repair in disease and injury is limited, lending credence to the claim by prominent neuropathologist Ramón y Cajal that ‘once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably’. However, recent progress toward understanding the fundamental biology of adult NSCs and their role in pathological conditions has provided new insight into the potential therapeutic utility of endogenous NSCs. In this short review, we highlight two topics: the altered behavior of NSCs after brain damage and the dysfunction of ...
Journal of Glycomics & Lipidomics, 2013
Sugar chains envelop the vast majority of the cell surface and thus have been considered to play ... more Sugar chains envelop the vast majority of the cell surface and thus have been considered to play pivotal roles in cell-to-cell and cell-to-extracellular matrix interactions. Recent studies have shown that expression of N-acetylglucosaminyltransferase (GnT) V is induced in hepatomas, and high-branched N-linked sugar chains play important roles in carcinogenesis and metastasis. However, the precise structural changes have not yet been studied in detail. Here, we compared sugar chains expressed in normal mouse liver, regenerating liver, three mouse hepatoma cell lines and Hepa 1-6-related tumors obtained by inoculation of Hepa 1-6 cells into liver or subcutaneous tissue of BALB/c nu/nu mice. The products of GnT V were found to be present in similar proportions in the mouse liver and in hepatomas, while there was a big difference in the amount of GnT IV products in these organs. Normal mouse liver and regenerating mouse liver contained small amounts of sugar chains produced by the action of GnT IV, while such chains were abundant in hepatoma cell lines and in Hepa 1-6-related tumors. Analysis of N-linked sugar chains in human livers and in hepatocellular carcinoma (HCC) revealed that both GnT IV and GnT V products are present in human liver, but their total content did not change during malignant transformation. Thus there was no increase in GnT V N-glycan products in hepatoma tissues in the mouse model or in humans. Figure 1: Products of GnT IV and GnT V enzyme reactions. The figure shows the sugar chain branches synthesized by GnT V or GnT IV.
Scientific reports, Apr 25, 2016
Nonhuman primates are valuable for human disease modelling, because rodents poorly recapitulate s... more Nonhuman primates are valuable for human disease modelling, because rodents poorly recapitulate some human diseases such as Parkinson's disease and Alzheimer's disease amongst others. Here, we report for the first time, the generation of green fluorescent protein (GFP) transgenic cynomolgus monkeys by lentivirus infection. Our data show that the use of a human cytomegalovirus immediate-early enhancer and chicken beta actin promoter (CAG) directed the ubiquitous expression of the transgene in cynomolgus monkeys. We also found that injection into mature oocytes before fertilization achieved homogenous expression of GFP in each tissue, including the amnion, and fibroblasts, whereas injection into fertilized oocytes generated a transgenic cynomolgus monkey with mosaic GFP expression. Thus, the injection timing was important to create transgenic cynomolgus monkeys that expressed GFP homogenously in each of the various tissues. The strategy established in this work will be useful ...
Japanese Journal of Medicine, 1991
A 44-year-old woman with scleroderma-like skin lesions and malignant hypertension following mammo... more A 44-year-old woman with scleroderma-like skin lesions and malignant hypertension following mammoplastyis reported. Sclerotic change is an unusual finding for ordinary finding progressive systemic sclerosis. On admission, she had severe high-renin hypertension and progressive renal failure, suggesting scleroderma renal crisis. With intensive treatment for hypertension including angiotensin-converting enzyme inhibitor, the blood pressure was well controlled. It was then suggested that she had malignant hypertension due to scleroderma after silicone injection, or the so-called humanadjuvant disease after cosmetic surgery.
Journal of Lipid Mediators and Cell Signalling, 1996
Gangliosides have attracted particular attention in the field of brain research, since they were ... more Gangliosides have attracted particular attention in the field of brain research, since they were found not only to be abundant in neural tissue but also to have intricate structures in synaptic membranes. A murine neuroblastoma cell line, Neuro2a, expresses negligible amounts of GM3 and b-series gangliosides, but significant amounts of a-series gangliosides (GM1 and GDla). With the transfection of cDNA encoding GD3 synthase, the de novo synthesis and expression of GD3 and b-series gangliosides occurred, and, furthermore, it induced the growth of axon-like neurites and cholinergic differentiation of Neuro2a cells. On the other hand, with the transfection of an c~ 1,2-fucosyltransferase, the axon-like neurite outgrowth was suppressed and dendrite-like neurites were outgrowth. These observations directly demonstrate the primary importance of the gene expression of a glycosyltransferase, and of the subsequent biosynthesis of gangliosides and their expression on the cell surface for neural cell development and differentiation.
Rinshō shinkeigaku = Clinical neurology, 1992
Several reports have suggested that anticholinergics have some associations with mental deteriora... more Several reports have suggested that anticholinergics have some associations with mental deterioration in Parkinson's disease (PD). We investigated the effect of anticholinergics on regional cerebral uptake of tracer in PD patients using N-isopropyl p-[I-123] iodoamphetamine SPECT. Sixteen pairs of region of interest (ROI) were located in the cortex, a pair in the basal ganglia, thalamus, and cerebellum. The size of each ROI was about 16 mm x 16 mm. Regional cerebral uptake ratio (rCUR) was calculated by the next equation: rCUR = (total count in an ORI)/(mean of total count in the cerebellar ROIs). The comparison consisted of two parts; (1) 7 PD patients (age 59-76 (65.4 +/- 6.7 mean +/- S.D.)) who had been on chronic anticholinergic therapy underwent SPECT and Wechsler Adult Intelligence Scale (WAIS) twice, for the first time when they were on anticholinergics and second a month after discontinuation of anticholinergics. All but two patients performed significantly better on WAI...
Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 2008
Adult neurogenesis occurs in the olfactory bulb and the dentate gyrus of the hippocampus. It has ... more Adult neurogenesis occurs in the olfactory bulb and the dentate gyrus of the hippocampus. It has been shown that exposure to psychosocial stress reduces cell proliferation in the dentate gyrus. However, little is known about how stress affects the proliferation kinetics of neural stem cells (NSCs) in the adult brain. We utilized a forced swim model of stress in the mouse and found that chronic stress decreased the number of NSCs. The reduction in NSC number persisted for weeks after the cessation of stress, but was reversed by treatment with antidepressant drugs, fluoxetine and imipramine. However, these antidepressants exhibit no direct effects on NSCs, suggesting that the effects of antidepressants on NSCs are mediated by serotonin. In contrast, mood stabilizing drugs, which are used to treat patients with bipolar disorder, act cell-autonomously on NSCs and enhance their self-renewal capability. Importantly, this enhancement is achieved at therapeutically relevant concentrations i...
Rinshō shinkeigaku = Clinical neurology, 2003
Neural stem cells are considered the ultimate lineage precursors to all neurons and glia. Despite... more Neural stem cells are considered the ultimate lineage precursors to all neurons and glia. Despite the significance of neural stem cells in the mammalian brain development, their ontogenesis remains unclear. We have established a colony-forming embryonic stem (ES) sphere assay, where ES cells were cultured in serum-free media in the presence of leukemia inhibitory factor (LIF) to form floating spheres. LIF-dependent ES cell-derived sphere cells showed self-renewal and neural multipotentiality, cardinal features of the neural stem cell, but retained some non-neural properties and broader potential. We dabbed the cells in the ES cell-derived sphere of primitive neural stem cells. LIF-dependent sphere-forming cells were also present in the epiblast of embryonic day 5.5-7.5 mouse embryos. The generation of the in vivo primitive neural stem cell was independent of Notch signaling but the activation of Notch pathway was necessary for the transition from the primitive neural stem cell to th...
Rinshō shinkeigaku = Clinical neurology, 1994
We described an autopsy case of 79-year-old woman with clinically unclassified senile dementia. T... more We described an autopsy case of 79-year-old woman with clinically unclassified senile dementia. The patient developed forgetfulness at the age of 73, and later, persecution mania, apathy and episodic stupor, but no extrapyramidal symptoms. Neuropathological examination revealed severe neuronal loss and gliosis of substantia nigra, moderate neuronal loss and marked grumose degeneration of dentate nucleus, and mild astrocytosis of subthalamic nucleus. Abundant neurofibrillary tangles (NFT) were observed in subthalamic nucleus, globus pallidus, substantia nigra, locus ceruleus, tegmentum of brain stem, pontine nucleus, inferior olive, and dentate nucleus. Gallyas silver impregnation method showed a wide distribution of argyrophilic grains and threads in cerebrum, brain stem and cerebellum. Although absence of clinical and neuropathological hallmarks excluded the diagnosis of progressive supranuclear palsy (PSP), the distribution of NFT and argyrophilic grains in this patient resembled ...
Rinshō shinkeigaku = Clinical neurology, 1992
We measured serum interleukin-6 (IL-6) levels in 14 patients with Crow-Fukase syndrome. Five out ... more We measured serum interleukin-6 (IL-6) levels in 14 patients with Crow-Fukase syndrome. Five out of 14 patients with Crow-Fukase syndrome showed high serum IL-6 levels above 10 pg/ml, which was statistically significant in comparison with control subjects with other neurological diseases. Serial studies of serum IL-6 levels in two patients revealed the increase before the exacerbation of clinical symptoms of edema, and pleural or cardiac effusion, and the fall after the treatment by high dose pulsed methylprednisolone. We suggest that serum IL-6 level appears to be a useful marker to predict its exacerbation. Also we performed immunohistochemical study on cutaneous angioma from three Crow-Fukase syndrome patients using anti-IL-6 antibody. The cytoplasm of endothelial cells of cutaneous angioma from two patients was positively stained, which might imply the abnormality of endothelial cells in Crow-Fukase syndrome.
Journal of Neuroscience, 2006
There are two types of neural stem cells (NSCs). Primitive NSCs [leukemia inhibitory factor (LIF)... more There are two types of neural stem cells (NSCs). Primitive NSCs [leukemia inhibitory factor (LIF) dependent but exogenous fibroblast growth factor (FGF) 2 independent] can be derived from mouse embryonic stem (ES) cells in vitro and from embryonic day 5.5 (E5.5) to E7.5 epiblast and E7.5-E8.5 neuroectoderm in vivo. Definitive NSCs (LIF independent but FGF2 dependent) first appear in the E8.5 neural plate and persist throughout life. Primitive NSCs give rise to definitive NSCs. Loss and gain of functions were used to study the role of vascular endothelial growth factor (VEGF)-A and its receptor, Flk1, in NSCs. The numbers of Flk1 knockout mice embryo-derived and ES cell-derived primitive NSCs were increased because of the enhanced survival of primitive NSCs. In contrast, neural precursor-specific, Flk1 conditional knockout mice-derived, definitive NSCs numbers were decreased because of the enhanced cell death of definitive NSCs. These effects were not observed in cells lacking Flt1, another VEGF receptor. In addition, the cell death stimulated by VEGF-A of primitive NSC and the cell survival stimulated by VEGF-A of definitive NSC were blocked by Flk1/Fc-soluble receptors and VEGF-A functionblocking antibodies. These VEGF-A phenotypes also were blocked by inhibition of the downstream effector nuclear factor B (NF-B). Thus, both the cell death of primitive NSC and the cell survival of definitive NSC induced by VEGF-A stimulation are mediated by bifunctional NF-B effects. In conclusion, VEGF-A function through Flk1 mediates survival (and not proliferative or fate change) effects on NSCs, specifically.
Neuroscience Research, 2010
e33 pain perception were also measured using the visual analog scale (VAS). Two major components,... more e33 pain perception were also measured using the visual analog scale (VAS). Two major components, N2 and P2 of LEPs, were recorded. The amplitude of P2 was significantly smaller in the Smoking session than in the Control session. A significant negative correlation was found between PNC and the amplitude of N2 as well as P2. The results were consistent with the hypothesis that smoking and/or nicotine have an antinociceptive effect, which supports most non-human studies and some human studies. Smoking of a single tobacco cigarette did not show a subjectively perceivable extent of reduction in the intensity of evoked pain. Folowing C fiber stimulation (second pain), ultralate LEPs were repeatedly measured in two sessions, one after smoking, and the other in abstinence from smoking. The dominant frequency of the background EEG alpha activity, heart rate and venous plasma nicotine concentration were also measured. The peak-to-peak amplitude of the two major components (N2 and P2) of ultralate LEPs was significantly correlated both with the plasma nicotine concentration and with the background alpha frequency. The results suggest an arousal effect of nicotine on C-fiber mediated pain. The effect of nicotine on C-fiber LEPs was in the opposite direction of that on A-delta fiber LEPs. The difference between C-and A-delta fibers might indicate a difference in effects of nicotine on first and second pain responses.
Journal of Physiological Sciences, Aug 29, 2016
Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature into oligodendr... more Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature into oligodendrocytes (OLs), and form myelin in the postnatal brain. It has been proposed that early born OPCs derived from the ventral forebrain are eliminated postnatally and late-born OLs predominate in the adult mouse cortex. However, the temporal and regional niche for cortical OL generation, which persists throughout life in adult mammals, remains to be determined. Our recent study provides new insight into self-renewing and multipotent neural stem cells (NSCs). Our results, together with previous studies, suggest that NSCs at the dorsoventral boundary are uniquely specialized to produce myelin-forming OLs in the cortex during a restricted temporal window. These findings may help identify transcription factors or gene expression patterns which confer neural precursors with the characteristic ability of dorsoventral boundary NSCs to differentiate into OLs, and facilitate the development of new strategies for regenerative medicine of the damaged brain. Keywords Cortical oligodendrocyte Á Dorsoventral boundary Á Neural stem cells Á Wnts Á FGF …as the name ''interfascicular glia'' indicates only the principal feature of its constitutive elements, we have adopted the term ''oligodendroglia''…Unfortunately, we have not been able to observe the very first stages of genesis of the oligodendroglia… by Pío Del Río-Hortega [1]
Cerebral Cortex, Jun 23, 2015
Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature to become oligo... more Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature to become oligodendrocytes (OLs), and form myelin in the postnatal brain. Recently, it has been proposed that early-born OPCs derived from the ventral forebrain are eradicated postnatally and that late-born OLs predominate in the cortex of the adult mouse brain. However, intrinsic and extrinsic factors that specify the ability of self-renewing multipotent neural stem cells in the embryonic brain to generate cortical OL-lineage cells remain largely unknown. Using an inducible Cre/loxP system to permanently label Nestin-and Olig2lineage cells, we identified that cortical OL-lineage cells start differentiating from neural stem cells within a restricted temporal window just prior to E16.5 through P10. We then showed, by means of electroporation of a Cre expression plasmid into the VZ/SVZ of E15.5 reporter mouse brains, that neural precursor cells in the dorsal VZ/SVZ are inhibited by Wnt signaling from contributing to cortical OLs in the adult brain. In contrast, neural precursor cells present in the dorsoventral boundary VZ/SVZ produce a significant amount of OLs in the adult cortex. Our results suggest that neural stem cells at this boundary are uniquely specialized to produce myelin-forming OLs in the cortex.
The Journal of Physiological Sciences
Neural stem cells (NSCs) are maintained in the adult mammalian brain throughout the animal’s life... more Neural stem cells (NSCs) are maintained in the adult mammalian brain throughout the animal’s lifespan. NSCs in the subependymal zone infrequently divide and generate transit amplifying cells, which are destined to become olfactory bulb neurons. When transit amplifying cells are depleted, they are replenished by the quiescent NSC pool. However, the cellular basis for this recovery process remains largely unknown. In this study, we traced NSCs and their progeny after transit amplifying cells were eliminated by intraventricular infusion of cytosine β-D-arabinofuranoside. We found that although the number of neurosphere-forming NSCs decreased shortly after the treatment, they were restored to normal levels 3 weeks after the cessation of treatment. More importantly, the depletion of transit amplifying cells did not induce a significant expansion of the NSC pool by symmetric divisions. Our data suggest that the size of the NSC pool is hardly affected by brain damage due to antimitotic dru...
Development, 2002
Regional patterning in the developing mammalian brain is partially regulated by restricted gene e... more Regional patterning in the developing mammalian brain is partially regulated by restricted gene expression patterns within the germinal zone, which is composed of stem cells and their progenitor cell progeny. Whether or not neural stem cells, which are considered at the top of the neural lineage hierarchy, are regionally specified remains unknown. Here we show that the cardinal properties of neural stem cells (self-renewal and multipotentiality) are conserved among embryonic cortex, ganglionic eminence and midbrain/hindbrain, but that these different stem cells express separate molecular markers of regional identity in vitro, even after passaging. Neural stem cell progeny derived from ganglionic eminence but not from other regions are specified to respond to local environmental cues to migrate ventrolaterally, when initially deposited on the germinal layer of ganglionic eminence in organotypic slice cultures. Cues exclusively from the ventral forebrain in a 5 day co-culture paradigm...
Frontiers in Neuroscience, 2020
Early life stress can exert detrimental or beneficial effects on neural development and postnatal... more Early life stress can exert detrimental or beneficial effects on neural development and postnatal behavior depending on the timing, duration, strength, and ability to control the stressors. In this study, we utilized a maternal and social deprivation (MSD) model to investigate the effects of early life stress on neural stem cells (NSCs) and neurogenesis in the adult brain. We found that MSD during the stress-hyporesponsive period (SHRP) (early-MSD), when corticosterone secretion is suppressed, increased the size of the NSC population, whereas the same stress beyond the SHRP abrogated these effects. Early-MSD enhanced neurogenesis not only in the dentate gyrus of the hippocampus, one of the classic neurogenic regions, but also in the amygdala. In addition, mice exposed to early-MSD exhibited a reduction in amygdala/hippocampus-dependent fear memory. These results suggest that animals exposed to early life stress during the SHRP have reinforced stress resilience to cope with perceived stressors to maintain a normal homeostatic state.
IBRO Reports, 2019
Hydrangea macrophylla, widely cultivated in Northeast Asia, is well known to have various pharmac... more Hydrangea macrophylla, widely cultivated in Northeast Asia, is well known to have various pharmacological effects including antiinflammatory, anti-oxidant and anti-malaria effects. And it also has neurological effects such as improvement of dementia induced by scopolamine. Neurite outgrowth is a phenomenon that spreads the axons and dendrites from the cell body. Since it influences synaptic plasticity, the ability for brain to reconstitute or relocate itself, neurite outgrowth is a highly important process in learning and memory. A lot of natural compounds have already been reported to induce neurite outgrowth, but the effect of Hydrangea macrophylla on neurite outgrowth has not yet been studied. Therefore, in this study, we tested the effect of hydrangea macrophylla on neurite outgrowth in neuro2a cells. We first ascertained morphological changes and measured neurite-bearing cells and neurite lengths. Hydrangea macrophylla significantly increased the percentage of neurite-bearing cells and the length of neurite in a concentration-dependent manner without inducing cell death. And then, we have identified the mode of action of hydrangea macrophylla with peroxisome proliferator activated receptor gamma (PPAR␥) inhibitor (GW9662) and the Phosphoinositide 3-kinase (PI3K) inhibitor (LY294002). As a result, hydrangea macrophyllainduced neurite outgrowth was blocked by the PPAR␥ inhibitor. These results shown that hydrangea macrophylla induces neurite outgrowth through PPAR␥ signaling.
Journal of Neurochemistry, 2018
In the adult mammalian brain, neural stem cells (NSCs) reside in two neurogenic regions, the wall... more In the adult mammalian brain, neural stem cells (NSCs) reside in two neurogenic regions, the walls of the lateral ventricles, and the subgranular zone of the hippocampus, which generate new neurons for the olfactory bulb and dentate gyrus, respectively. These adult NSCs retain their self‐renewal ability and capacity to differentiate into neurons and glia as demonstrated by in vitro studies. However, their contribution to tissue repair in disease and injury is limited, lending credence to the claim by prominent neuropathologist Ramón y Cajal that ‘once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably’. However, recent progress toward understanding the fundamental biology of adult NSCs and their role in pathological conditions has provided new insight into the potential therapeutic utility of endogenous NSCs. In this short review, we highlight two topics: the altered behavior of NSCs after brain damage and the dysfunction of ...
Journal of Glycomics & Lipidomics, 2013
Sugar chains envelop the vast majority of the cell surface and thus have been considered to play ... more Sugar chains envelop the vast majority of the cell surface and thus have been considered to play pivotal roles in cell-to-cell and cell-to-extracellular matrix interactions. Recent studies have shown that expression of N-acetylglucosaminyltransferase (GnT) V is induced in hepatomas, and high-branched N-linked sugar chains play important roles in carcinogenesis and metastasis. However, the precise structural changes have not yet been studied in detail. Here, we compared sugar chains expressed in normal mouse liver, regenerating liver, three mouse hepatoma cell lines and Hepa 1-6-related tumors obtained by inoculation of Hepa 1-6 cells into liver or subcutaneous tissue of BALB/c nu/nu mice. The products of GnT V were found to be present in similar proportions in the mouse liver and in hepatomas, while there was a big difference in the amount of GnT IV products in these organs. Normal mouse liver and regenerating mouse liver contained small amounts of sugar chains produced by the action of GnT IV, while such chains were abundant in hepatoma cell lines and in Hepa 1-6-related tumors. Analysis of N-linked sugar chains in human livers and in hepatocellular carcinoma (HCC) revealed that both GnT IV and GnT V products are present in human liver, but their total content did not change during malignant transformation. Thus there was no increase in GnT V N-glycan products in hepatoma tissues in the mouse model or in humans. Figure 1: Products of GnT IV and GnT V enzyme reactions. The figure shows the sugar chain branches synthesized by GnT V or GnT IV.
Scientific reports, Apr 25, 2016
Nonhuman primates are valuable for human disease modelling, because rodents poorly recapitulate s... more Nonhuman primates are valuable for human disease modelling, because rodents poorly recapitulate some human diseases such as Parkinson's disease and Alzheimer's disease amongst others. Here, we report for the first time, the generation of green fluorescent protein (GFP) transgenic cynomolgus monkeys by lentivirus infection. Our data show that the use of a human cytomegalovirus immediate-early enhancer and chicken beta actin promoter (CAG) directed the ubiquitous expression of the transgene in cynomolgus monkeys. We also found that injection into mature oocytes before fertilization achieved homogenous expression of GFP in each tissue, including the amnion, and fibroblasts, whereas injection into fertilized oocytes generated a transgenic cynomolgus monkey with mosaic GFP expression. Thus, the injection timing was important to create transgenic cynomolgus monkeys that expressed GFP homogenously in each of the various tissues. The strategy established in this work will be useful ...
Japanese Journal of Medicine, 1991
A 44-year-old woman with scleroderma-like skin lesions and malignant hypertension following mammo... more A 44-year-old woman with scleroderma-like skin lesions and malignant hypertension following mammoplastyis reported. Sclerotic change is an unusual finding for ordinary finding progressive systemic sclerosis. On admission, she had severe high-renin hypertension and progressive renal failure, suggesting scleroderma renal crisis. With intensive treatment for hypertension including angiotensin-converting enzyme inhibitor, the blood pressure was well controlled. It was then suggested that she had malignant hypertension due to scleroderma after silicone injection, or the so-called humanadjuvant disease after cosmetic surgery.
Journal of Lipid Mediators and Cell Signalling, 1996
Gangliosides have attracted particular attention in the field of brain research, since they were ... more Gangliosides have attracted particular attention in the field of brain research, since they were found not only to be abundant in neural tissue but also to have intricate structures in synaptic membranes. A murine neuroblastoma cell line, Neuro2a, expresses negligible amounts of GM3 and b-series gangliosides, but significant amounts of a-series gangliosides (GM1 and GDla). With the transfection of cDNA encoding GD3 synthase, the de novo synthesis and expression of GD3 and b-series gangliosides occurred, and, furthermore, it induced the growth of axon-like neurites and cholinergic differentiation of Neuro2a cells. On the other hand, with the transfection of an c~ 1,2-fucosyltransferase, the axon-like neurite outgrowth was suppressed and dendrite-like neurites were outgrowth. These observations directly demonstrate the primary importance of the gene expression of a glycosyltransferase, and of the subsequent biosynthesis of gangliosides and their expression on the cell surface for neural cell development and differentiation.
Rinshō shinkeigaku = Clinical neurology, 1992
Several reports have suggested that anticholinergics have some associations with mental deteriora... more Several reports have suggested that anticholinergics have some associations with mental deterioration in Parkinson's disease (PD). We investigated the effect of anticholinergics on regional cerebral uptake of tracer in PD patients using N-isopropyl p-[I-123] iodoamphetamine SPECT. Sixteen pairs of region of interest (ROI) were located in the cortex, a pair in the basal ganglia, thalamus, and cerebellum. The size of each ROI was about 16 mm x 16 mm. Regional cerebral uptake ratio (rCUR) was calculated by the next equation: rCUR = (total count in an ORI)/(mean of total count in the cerebellar ROIs). The comparison consisted of two parts; (1) 7 PD patients (age 59-76 (65.4 +/- 6.7 mean +/- S.D.)) who had been on chronic anticholinergic therapy underwent SPECT and Wechsler Adult Intelligence Scale (WAIS) twice, for the first time when they were on anticholinergics and second a month after discontinuation of anticholinergics. All but two patients performed significantly better on WAI...
Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 2008
Adult neurogenesis occurs in the olfactory bulb and the dentate gyrus of the hippocampus. It has ... more Adult neurogenesis occurs in the olfactory bulb and the dentate gyrus of the hippocampus. It has been shown that exposure to psychosocial stress reduces cell proliferation in the dentate gyrus. However, little is known about how stress affects the proliferation kinetics of neural stem cells (NSCs) in the adult brain. We utilized a forced swim model of stress in the mouse and found that chronic stress decreased the number of NSCs. The reduction in NSC number persisted for weeks after the cessation of stress, but was reversed by treatment with antidepressant drugs, fluoxetine and imipramine. However, these antidepressants exhibit no direct effects on NSCs, suggesting that the effects of antidepressants on NSCs are mediated by serotonin. In contrast, mood stabilizing drugs, which are used to treat patients with bipolar disorder, act cell-autonomously on NSCs and enhance their self-renewal capability. Importantly, this enhancement is achieved at therapeutically relevant concentrations i...
Rinshō shinkeigaku = Clinical neurology, 2003
Neural stem cells are considered the ultimate lineage precursors to all neurons and glia. Despite... more Neural stem cells are considered the ultimate lineage precursors to all neurons and glia. Despite the significance of neural stem cells in the mammalian brain development, their ontogenesis remains unclear. We have established a colony-forming embryonic stem (ES) sphere assay, where ES cells were cultured in serum-free media in the presence of leukemia inhibitory factor (LIF) to form floating spheres. LIF-dependent ES cell-derived sphere cells showed self-renewal and neural multipotentiality, cardinal features of the neural stem cell, but retained some non-neural properties and broader potential. We dabbed the cells in the ES cell-derived sphere of primitive neural stem cells. LIF-dependent sphere-forming cells were also present in the epiblast of embryonic day 5.5-7.5 mouse embryos. The generation of the in vivo primitive neural stem cell was independent of Notch signaling but the activation of Notch pathway was necessary for the transition from the primitive neural stem cell to th...
Rinshō shinkeigaku = Clinical neurology, 1994
We described an autopsy case of 79-year-old woman with clinically unclassified senile dementia. T... more We described an autopsy case of 79-year-old woman with clinically unclassified senile dementia. The patient developed forgetfulness at the age of 73, and later, persecution mania, apathy and episodic stupor, but no extrapyramidal symptoms. Neuropathological examination revealed severe neuronal loss and gliosis of substantia nigra, moderate neuronal loss and marked grumose degeneration of dentate nucleus, and mild astrocytosis of subthalamic nucleus. Abundant neurofibrillary tangles (NFT) were observed in subthalamic nucleus, globus pallidus, substantia nigra, locus ceruleus, tegmentum of brain stem, pontine nucleus, inferior olive, and dentate nucleus. Gallyas silver impregnation method showed a wide distribution of argyrophilic grains and threads in cerebrum, brain stem and cerebellum. Although absence of clinical and neuropathological hallmarks excluded the diagnosis of progressive supranuclear palsy (PSP), the distribution of NFT and argyrophilic grains in this patient resembled ...
Rinshō shinkeigaku = Clinical neurology, 1992
We measured serum interleukin-6 (IL-6) levels in 14 patients with Crow-Fukase syndrome. Five out ... more We measured serum interleukin-6 (IL-6) levels in 14 patients with Crow-Fukase syndrome. Five out of 14 patients with Crow-Fukase syndrome showed high serum IL-6 levels above 10 pg/ml, which was statistically significant in comparison with control subjects with other neurological diseases. Serial studies of serum IL-6 levels in two patients revealed the increase before the exacerbation of clinical symptoms of edema, and pleural or cardiac effusion, and the fall after the treatment by high dose pulsed methylprednisolone. We suggest that serum IL-6 level appears to be a useful marker to predict its exacerbation. Also we performed immunohistochemical study on cutaneous angioma from three Crow-Fukase syndrome patients using anti-IL-6 antibody. The cytoplasm of endothelial cells of cutaneous angioma from two patients was positively stained, which might imply the abnormality of endothelial cells in Crow-Fukase syndrome.
Journal of Neuroscience, 2006
There are two types of neural stem cells (NSCs). Primitive NSCs [leukemia inhibitory factor (LIF)... more There are two types of neural stem cells (NSCs). Primitive NSCs [leukemia inhibitory factor (LIF) dependent but exogenous fibroblast growth factor (FGF) 2 independent] can be derived from mouse embryonic stem (ES) cells in vitro and from embryonic day 5.5 (E5.5) to E7.5 epiblast and E7.5-E8.5 neuroectoderm in vivo. Definitive NSCs (LIF independent but FGF2 dependent) first appear in the E8.5 neural plate and persist throughout life. Primitive NSCs give rise to definitive NSCs. Loss and gain of functions were used to study the role of vascular endothelial growth factor (VEGF)-A and its receptor, Flk1, in NSCs. The numbers of Flk1 knockout mice embryo-derived and ES cell-derived primitive NSCs were increased because of the enhanced survival of primitive NSCs. In contrast, neural precursor-specific, Flk1 conditional knockout mice-derived, definitive NSCs numbers were decreased because of the enhanced cell death of definitive NSCs. These effects were not observed in cells lacking Flt1, another VEGF receptor. In addition, the cell death stimulated by VEGF-A of primitive NSC and the cell survival stimulated by VEGF-A of definitive NSC were blocked by Flk1/Fc-soluble receptors and VEGF-A functionblocking antibodies. These VEGF-A phenotypes also were blocked by inhibition of the downstream effector nuclear factor B (NF-B). Thus, both the cell death of primitive NSC and the cell survival of definitive NSC induced by VEGF-A stimulation are mediated by bifunctional NF-B effects. In conclusion, VEGF-A function through Flk1 mediates survival (and not proliferative or fate change) effects on NSCs, specifically.
Neuroscience Research, 2010
e33 pain perception were also measured using the visual analog scale (VAS). Two major components,... more e33 pain perception were also measured using the visual analog scale (VAS). Two major components, N2 and P2 of LEPs, were recorded. The amplitude of P2 was significantly smaller in the Smoking session than in the Control session. A significant negative correlation was found between PNC and the amplitude of N2 as well as P2. The results were consistent with the hypothesis that smoking and/or nicotine have an antinociceptive effect, which supports most non-human studies and some human studies. Smoking of a single tobacco cigarette did not show a subjectively perceivable extent of reduction in the intensity of evoked pain. Folowing C fiber stimulation (second pain), ultralate LEPs were repeatedly measured in two sessions, one after smoking, and the other in abstinence from smoking. The dominant frequency of the background EEG alpha activity, heart rate and venous plasma nicotine concentration were also measured. The peak-to-peak amplitude of the two major components (N2 and P2) of ultralate LEPs was significantly correlated both with the plasma nicotine concentration and with the background alpha frequency. The results suggest an arousal effect of nicotine on C-fiber mediated pain. The effect of nicotine on C-fiber LEPs was in the opposite direction of that on A-delta fiber LEPs. The difference between C-and A-delta fibers might indicate a difference in effects of nicotine on first and second pain responses.