Researchers Database

takase kenkichi

    Psychology Professor
Last Updated :2021/10/17

Researcher Information

Degree

  • Ph. D(2010/10 University of Tsukuba)

URL

Research funding number

  • 80381474

J-Global ID

Profile

  • How do the biological, psychological, and social factors cause sex-specific abnormal behaviors in a specific development stage? This is the question that motivates the research in my laboratory, and I would like to provide the findings which lead to the development of intervention techniques for correcting sex-specific abnormal behaviors in a specific development stage. Moreover, I am also interested in the development of the methodology which expands the utility of animal models, since mice and rats are used in my research, as animal models for the study of human abnormal behaviors. Furthermore, our laboratory is promoting the collaboration between psychology and other disciplines to expand the research area of psychology.

Research Interests

  • トランスレータブル生物指標   トランスレータブル行動指標   発達段階・性別特異的行動異常   ヒストン脱アセチル化酵素   睡眠   摂食   カルシニューリン   統合失調症   アセチルコリン   学習・記憶   エストロジェン   アンドロジェン   性分化   性差   老化   発達   環境   生理学的・生化学的・形態学的解析   網羅的行動解析   マウス   ラット   ハト   ヒト   

Research Areas

  • Humanities & social sciences / Educational psychology
  • Humanities & social sciences / Experimental psychology
  • Humanities & social sciences / Clinical psychology

Academic & Professional Experience

  • 2021/10 - Today  Keio UniversityFaculty of Letters非常勤講師(兼務)
  • 2021/04 - Today  The Open University of Japan客員教授(兼務)
  • 2021/04 - Today  Toho University医学部 医学科 解剖学講座 微細形態学分野客員教授(兼務)
  • 2020/12 - Today  National Institute of Science and Technology Policy客員研究官
  • 2019/08 - Today  公立大学法人 首都大学東京大学院人間健康科学研究科 ヘルスプロモーション学域非常勤講師(兼務)
  • 2018/01 - Today  国立特別支援教育総合研究所特別支援教育専門研修 知的障害教育コース非常勤講師(兼務)
  • 2017/06 - Today  Jichi Medical University大学院医学研究科 博士課程 発達生物心理学専攻科/修士課程 発達生物心理科学専攻科教授
  • 2016/04 - Today  Jichi Medical University大学院医学研究科 総合教育学専攻科教授
  • 2015/03 - Today  公立大学法人 横浜市立大学医学部 医学科 麻酔科学教室客員教授(兼務)
  • 2014/08 - Today  Jichi Medical UniversitySchool of Medicine教授
  • 2012/04 - Today  Yokohama City UniversitySchool of Medicine Medical Course 非常勤講師(兼務)
  • 2020/04 - 2021/03  Toho University医学部 医学科 解剖学講座 微細形態学分野客員講師(兼務)
  • 2015/04 - 2021/03  Jichi Medical University学生生活支援センターセンター員(兼務)
  • 2020/03 - 2020/08  Mitsubishi Research Institute, Inc.未来構想センターアドバイザー(兼務)
  • 2013/08 - 2014/07  Toho UniversitySchool of Medicine, Faculty of Medicine講師
  • 2013/04 - 2014/03  公立大学法人 横浜市立大学医学部 医学科 麻酔科学教室客員研究員(兼務)
  • 2013/04 - 2014/03  University of Tokyo Health Sciences保健医療学部 リハビリテーション学科非常勤講師(兼務)
  • 2011/04 - 2013/07  Toho UniversitySchool of Medicine, Faculty of Medicine助教
  • 2012/04 - 2013/03  真野美容専門学校非常勤講師(兼務)
  • 2011/04 - 2012/03  University of Human Arts and SciencesDivision of Human Sciences, Department of Human Sciences非常勤講師(兼務)
  • 2008/04 - 2011/03  Himeji Dokkyo UniversityFaculty of Pharmaceutical Sciences, Department of Pharmaceutical Health Care講師
  • 2005/04 - 2008/03  公立大学法人 横浜市立大学医学部 医学科 生理学教室助手
  • 2006/04 - 2007/03  Mejiro UniversityFaculty of Human and Social Sciences, Department of Psychological Counseling非常勤講師(兼務)
  • 2004/04 - 2005/03  Yokohama City UniversitySchool of Medicine Medical Course , Physiology助手

Education

  • 2010/10 - 2010/10  University of Tsukuba  大学院人間総合科学研究科  感性認知脳科学専攻 博士(行動科学)取得(指導教官 一谷幸男)
  • 2002/04 - 2004/03  Yokohama City University  Graduate  Graduate School of Medicine
  • 1998/04 - 2002/03  Ritsumeikan University  College of Letters  哲学科 心理学専攻(指導教官 藤健一)

Association Memberships

  • THE JAPANESE PSYCHOLOGICAL ASSOCIATION   JAPAN SOCIETY DEVELOPMENTAL PSYCHOLOGY   THE JAPANESE SOCIETY FOR ANIMAL PSYCHOLOGY   JAPANESE ASSOCIATION OF BEHAVIORAL SCIENCE   JAPANESE ASSOCIATION OF STUDENT COUNSELING   THE JAPAN NEUROSCIENCE SOCIETY   

Published Papers

  • Ryo Niikura, Tomoyuki Miyazaki, Kumiko Yonezaki, Kazuhiro Uchimoto, Kenkichi Takase, Takahisa Goto
    Behavioural pharmacology 2020/05 [Refereed][Not invited]
     
    Halogenated ethers, such as desflurane, sevoflurane, and isoflurane, are known to exert an array of effects besides sedation. However, the postanesthetic effects of desflurane remain undiscovered as no study has explored these effects systematically. Phenotypic screening using behavioral test batteries is a powerful method to identify such effects. In the present study, we behaviorally phenotyped desflurane-treated mice to investigate postanesthetic effects. We applied comprehensive behavioral test batteries measuring sensorimotor functions, anxiety, depression, sociability, attention, and learning abilities, starting 7 days after anesthesia performed with 8.0% desflurane for 6 h. Although our previous study revealed postanesthetic effects of isoflurane in adult mice, in the current study, desflurane-treated mice exhibited no such effects in any behavioral test. To further examine whether desflurane affect behavior in more early time point, we built up a new additional test battery, which carried out 1 day or 3 days after exposure to desflurane. Mice treated with desflurane 1 day before testing showed more slips than other two groups in the first trial, suggesting mild acute side effects of desflurane on motor coordination. These results suggest the safety of desflurane in clinical settings and imply that postanesthetic effects are unique to each halogenated ether.
  • Motoshi Kikuchi, Kenkichi Takase, Morisada Hayakawa, Hiroko Hayakawa, Shin-Ichi Tominaga, Tsukasa Ohmori
    Molecular brain 13 (1) 74 - 74 2020/05 [Refereed][Not invited]
     
    Psychoneuroimmunological studies have clearly demonstrated that both cellular and humoral immunity are related to major depression. Soluble ST2 is regarded as a key molecule regulating immune system as well as cell proliferation. Indeed, soluble ST2 is reported to reduce IL-33-induced IL-6 and TNF-α production in macrophages and IL-33-induced IL-5 and IL-13 production in type 2 innate lymphoid cells. Elevated serum concentrations of soluble ST2 have been reported in patients with neuropsychiatric disorders, suggesting pathophysiological roles of soluble ST2 in behavioral phenotypes. Nevertheless, the relation between soluble ST2 and depressive behavior remain to be uncovered. To complement this point, we performed broad behavioral phenotyping, utilizing transgenic mice with a high concentration of serum ST2 in the present study. Soluble ST2 overexpression mice (ST2 Tg mice) were generated on a C3H/HeJ background. ST2 Tg mice crossed onto the BALB/c genetic background were used. Before starting tests, each mouse was observed in a clean cage for a general health check and neurological screening tests. In Experiment I, comprehensive behavioral phenotyping was performed to reveal the role of soluble ST2 on sensorimotor functions, anxiety-like behaviors, depression-like behaviors, social behaviors, and learning and memory functions. In Experiment II, to confirm the role of soluble ST2 on depression-like behaviors, a depression test battery (two bottle choice test, forced swimming test, and tail suspension test) was applied. The general health check indicated good general health and normal gross appearance for ST2 Tg mice. Further, the neurological reflexes of all the mice were normal. We found that soluble ST2 overexpression resulted in decreased social interaction. Moreover, depression-like behaviors of ST2 Tg mice were observed in two well-established behavioral paradigms, the forced swimming test and the tail suspension test. Nevertheless, hedonic reaction to sucrose was observed in ST2 Tg mice similar to WT mice. These results suggest the depression in the ST2 Tg mice. In conclusion, through a series of experiments, we established the animal model for assessing role of soluble ST2 in neuropsychiatric disorders, and revealed the possible involvement of soluble ST2 in depressive behavior.
  • Kakizaki M, Tsuneoka Y, Takase K, Kim SJ, Choi J, Ikkyu A, Abe M, Sakimura K, Yanagisawa M, Funato H
    iScience 20 1 - 13 2019/09 [Refereed][Not invited]
     
    Orexins are hypothalamic neuropeptides that regulate feeding, energy expenditure, and sleep. Although orexin-deficient mice are susceptible to obesity, little is known about the roles of the orexin receptors in long-term energy metabolism. Here, we performed the metabolic characterization of orexin receptor-deficient mice. Ox1r-deficient mice were resistant to diet-induced obesity, and their food intake was similar between chow and high-fat food. Ox2r-deficient mice exhibited less energy expenditure than wild-type mice when fed a high-fat diet. Neither Ox1r-deficient nor Ox2r-deficient mice showed body weight gain similar to orexin-deficient mice. Although the presence of a running wheel suppressed diet-induced obesity in wild-type mice, the effect was weaker in orexin neuron-ablated mice. Finally, we did not detect abnormalities in brown adipose tissues of orexin-deficient mice. Thus, each orexin receptor signaling has a unique role in energy metabolism, and orexin neurons are involved in the interactive effect of diet and exercise on body weight gain.
  • ヒトのモデル動物としてのマウス・ラットを対象とした行動アセスメント研究の現状と課題
    髙瀨堅吉
    行動科学 56 (1) 21 - 30 2017/09 [Refereed][Invited]
  • Tsuneoka Y, Yoshida S, Takase K, Oda S, Kuroda M, Funato H
    Scientific reports 7 (1) 9809  2045-2322 2017/08 [Refereed][Not invited]
     
    Testosterone is involved in male sexual, parental and aggressive behaviors through the androgen receptor (AR) and estrogen receptor (ER) alpha expressed in the brain. Although several studies have demonstrated that ER alpha and AR in the medial preoptic area (MPOA) are required for exhibiting sexual and aggressive behaviors of male mice, the molecular characteristics of ER alpha-and ARexpressing cells in the mouse MPOA are largely unknown. Here, we performed in situ hybridization for neurotransmitters and neuropeptides, combined with immunohistochemistry for ER alpha and AR to quantitate and characterize gonadal steroid receptor-expressing cells in the MPOA subregions of male mice. Prodynorphin, preproenkephalin (Penk), cocaine-and amphetamine-related transcript, neurotensin, galanin, tachykinin (Tac) 1, Tac2 and thyrotropin releasing hormone (Trh) have distinct expression patterns in the MPOA subregions. Gad67-expressing cells were the most dominant neuronal subtype among the ER alpha-and AR-expressing cells throughout the MPOA. The percentage of ER alpha- and AR-immunoreactivities varied depending on the neuronal subtype. A substantial proportion of the neurotensin-, galanin-, Tac2-and Penk-expressing cells in the MPOA were positive for ER alpha and AR, whereas the vast majority of the Trh-expressing cells were negative. These results suggest that testosterone exerts differential effects depending on both the neuronal subtypes and MPOA subregions.
  • Tsuneoka Y, Tsukahara S, Yoshida S, Takase K, Oda S, Kuroda M, Funato H
    Frontiers in neuroanatomy 11 26  1662-5129 2017/03 [Refereed][Not invited]
     
    The brain shows various sex differences in its structures. Various mammalian species exhibit sex differences in the sexually dimorphic nucleus of the preoptic area (SDNPOA) and parts of the extended amygdala such as the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr) and posterodorsal part of the medial amygdala (MePD). The SDN-POA and BNSTpr are male-biased sexually dimorphic nuclei, and characterized by the expression of calbindin D-28K (calbindin 1). However, calbindinimmunoreactive cells are not restricted to the SDN-POA, but widely distributed outside of the SDN-POA. To find genes that are more specific to sexually dimorphic nuclei, we selected candidate genes by searching the Allen brain atlas and examined the detailed expressions of the candidate genes using in situ hybridization. We found that the strong expression of monooxygenase DBH-like 1 (Moxd1) was restricted to the SDN-POA, BNSTpr and MePD. The numbers of Moxd1-positive cells in the SDN-POA, BNSTpr and MePD in male mice were larger than those in female mice. Most of the Moxd1positive cells in the SDN-POA and BNSTpr expressed calbindin. Neonatal castration of male mice reduced the number of Moxd1-positive cells in the SDN-POA, whereas gonadectomy in adulthood did not change the expression of the Moxd1 gene in the SDN-POA in both sexes. These results suggest that the Moxd1 gene is a suitable marker for sexual dimorphic nuclei in the POA, BNST and amygdala, which enables us to manipulate sexually dimorphic neurons to examine their roles in sex-biased physiology and behaviors.
  • Tada H, Miyazaki T, Takemoto K, Takase K, Jitsuki S, Nakajima W, Koide M, Yamamoto N, Komiya K, Suyama K, Sano A, Taguchi A, Takahashi T
    Proceedings of the National Academy of Sciences of the United States of America 113 (45) E7097 - E7105 0027-8424 2016/10 [Refereed][Not invited]
     
    Social separation early in life can lead to the development of impaired interpersonal relationships and profound social disorders. However, the underlying cellular and molecular mechanisms involved are largely unknown. Here, we found that isolation of neonatal rats induced glucocorticoid-dependent social dominance over nonisolated control rats in juveniles from the same litter. Furthermore, neonatal isolation inactivated the actin-depolymerizing factor (ADF)/cofilin in the juvenile medial prefrontal cortex (mPFC). Isolation-induced inactivation of ADF/cofilin increased stable actin fractions at dendritic spines in the juvenile mPFC, decreasing glutamate synaptic AMPA receptors. Expression of constitutively active ADF/cofilin in the mPFC rescued the effect of isolation on social dominance. Thus, neonatal isolation affects spines in the mPFC by reducing actin dynamics, leading to altered social behavior later in life.
  • Nakamura H, Yamashita N, Kimura A, Kimura Y, Hirano H, Makihara H, Kawamoto Y, Jitsuki-Takahashi A, Yonezaki K, Takase K, Miyazaki T, Nakamura F, Tanaka F, Goshima Y
    Genes to cells : devoted to molecular & cellular mechanisms 21 (10) 1059 - 1079 1356-9597 2016/09 [Refereed][Not invited]
     
    Collapsin response mediator protein 2 (CRMP2) plays a key role in axon guidance, dendritic morphogenesis and cell polarization. CRMP2 is implicated in various neurological and psychiatric disorders. However, invivo functions of CRMP2 remain unknown. We generated CRMP2 gene-deficient (crmp2(-/-)) mice and examined their behavioral phenotypes. During 24-h home cage monitoring, the activity level during the dark phase of crmp2(-/-) mice was significantly higher than that of wild-type (WT) mice. Moreover, the time during the open arm of an elevated plus maze was longer for crmp2(-/-) mice than for WT mice. The duration of social interaction was shorter for crmp2(-/-) mice than for WT mice. Crmp2(-/-) mice also showed mild impaired contextual learning. We then examined the methamphetamine-induced behavioral change of crmp2(-/-) mice. Crmp2(-/-) mice showed increased methamphetamine-induced ambulatory activity and serotonin release. Crmp2(-/-) mice also showed altered expression of proteins involved in GABAergic synapse, glutamatergic synapse and neurotrophin signaling pathways. In addition, SNAP25, RAB18, FABP5, ARF5 and LDHA, which are related genes to schizophrenia and methamphetamine sensitization, are also decreased in crmp2(-/-) mice. Our study implies that dysregulation of CRMP2 may be involved in pathophysiology of neuropsychiatric disorders.
  • Takase K, Tsuneoka Y, Oda S, Kuroda M, Funato H
    Obesity (Silver Spring, Md.) 24 (4) 886 - 894 1930-7381 2016/02 [Refereed][Not invited]
     
    ObjectiveHigh-fat diet (HFD) consumption causes obesity, which is associated with well-known increased health risks. Moreover, obesity has been associated with altered sensorimotor and emotional behaviors of humans and mice. This study attempted to dissociate the influence of HFD-induced obesity on behaviors from the influence of HFD consumption itself. MethodsC57BL male mice were randomly allocated to a low-fat diet (LFD) group, an HFD-induced obesity (DIO) group, or a pair-fed HFD-feeding nonobese (HFD) group. A comprehensive behavioral test battery was performed on all three groups to assess sensorimotor functions, anxiety- and depression-like behaviors, reward-related behaviors, social behaviors, and learning/memory functions. ResultsBoth the DIO and HFD groups exhibited disturbed olfaction, blunted ethanol preference, and enhanced social interactions. The DIO group exhibited blunted sucrose preference, shorter latency before falling off during the rotarod test, and a lower response to mechanical stimuli. ConclusionsThe HFD-fed nonobese mice showed altered behaviors related to olfaction, social interactions, and rewards that were similar to those of the DIO mice. This finding suggests that HFD consumption alters a variety of behaviors independent of obesity.
  • Yonezaki K, Uchimoto K, Miyazaki T, Asakura A, Kobayashi A, Takase K, Goto T
    PloS one 3 10 (3) e0122118  1932-6203 2015/03 [Refereed][Not invited]
     
    Isoflurane was previously the major clinical anesthetic agent but is now mainly used for veterinary anesthesia. Studies have reported widespread sites of action of isoflurane, suggesting a wide array of side effects besides sedation. In the present study, we phenotyped isoflurane-treated mice to investigate the postanesthetic behavioral effects of isoflurane. We applied comprehensive behavioral test batteries comprising sensory test battery, motor test battery, anxiety test battery, depression test battery, sociability test battery, attention test battery, and learning test battery, which were started 7 days after anesthesia with 1.8% isoflurane. In addition to the control group, we included a yoked control group that was exposed to the same stress of handling as the isoflurane-treated animals before being anesthetized. Our comprehensive behavioral test batteries revealed impaired latent inhibition in the isoflurane-treated group, but the concentration of residual isoflurane in the brain was presumably negligible. The yoked control group and isoflurane-treated group exhibited higher anxiety in the elevated plus-maze test and impaired learning function in the cued fear conditioning test. No influences were observed in sensory functions, motor functions, antidepressant behaviors, and social behaviors. A number of papers have reported an effect of isoflurane on animal behaviors, but no systematic investigation has been performed. To the best of our knowledge, this study is the first to systematically investigate the general health, neurological reflexes, sensory functions, motor functions, and higher behavioral functions of mice exposed to isoflurane as adults. Our results suggest that the postanesthetic effect of isoflurane causes attention deficit in mice. Therefore, isoflurane must be used with great care in the clinical setting and veterinary anesthesia.
  • 高瀬堅吉
    行動医学研究 20 (2) 52 - 57 2014/10 [Refereed][Invited]
  • Takase K, Kikuchi K, Tsuneoka Y, Oda S, Kuroda M, Funato H
    PloS one 6 9 (6) e99961  1932-6203 2014/06 [Refereed][Not invited]
     
    The demand for meta-analyses in basic biomedical research has been increasing because the phenotyping of genetically modified mice does not always produce consistent results. Melanin-concentrating hormone (MCH) has been reported to be involved in a variety of behaviors that include feeding, body-weight regulation, anxiety, sleep, and reward behavior. However, the reported behavioral and metabolic characteristics of MCH signaling-deficient mice, such as MCH-deficient mice and MCH receptor 1 (MCHR1)-deficient mice, are not consistent with each other. In the present study, we performed a meta-analysis of the published data related to MCH-deficient and MCHR1-deficient mice to obtain robust conclusions about the role of MCH signaling. Overall, the meta-analysis revealed that the deletion of MCH signaling enhanced wakefulness, locomotor activity, aggression, and male sexual behavior and that MCH signaling deficiency suppressed non-REM sleep, anxiety, responses to novelty, startle responses, and conditioned place preferences. In contrast to the acute orexigenic effect of MCH, MCH signaling deficiency significantly increased food intake. Overall, the meta-analysis also revealed that the deletion of MCH signaling suppressed the body weight, fat mass, and plasma leptin, while MCH signaling deficiency increased the body temperature, oxygen consumption, heart rate, and mean arterial pressure. The lean phenotype of the MCH signaling-deficient mice was also confirmed in separate meta-analyses that were specific to sex and background strain (i.e., C57BL/6 and 129Sv). MCH signaling deficiency caused a weak anxiolytic effect as assessed with the elevated plus maze and the open field test but also caused a weak anxiogenic effect as assessed with the emergence test. MCH signaling-deficient mice also exhibited increased plasma corticosterone under non-stressed conditions, which suggests enhanced activity of the hypothalamic-pituitary-adrenal axis. To the best of our knowledge, the present work is the first study to systematically compare the effects of MCH signaling on behavioral and metabolic phenotypes.
  • Oda S, Funato H, Sato F, Adachi-Akahane S, Ito M, Takase K, Kuroda M
    The Journal of comparative neurology 522 (9) 2089 - 2106 0021-9967 2014/04 [Refereed][Not invited]
     
    Vesicular glutamate transporter isoforms, VGluT1-VGluT3, accumulate glutamate into synaptic vesicles and are considered to be important molecules in glutamatergic transmission. Among them, VGluT2 mRNA is expressed predominantly throughout the dorsal thalamus, whereas VGluT1 mRNA is expressed in a few thalamic nuclei. In the thalamic nuclei that project to the retrosplenial cortex (RSC), VGluT1 mRNA is expressed strongly in the anterodorsal thalamic nucleus (AD), is expressed moderately in the anteroventral and laterodorsal thalamic nuclei, and is not expressed in the anteromedial thalamic nucleus. Thus, it has been strongly suggested that a subset of thalamocortical projections to RSC possesses both VGluT1 and VGluT2. In this study, double-labeled neuronal somata showing both VGluT1 and VGluT2 immunolabelings were found exclusively in the ventral region of AD (vAD). Many double-labeled axon terminals were also found in two major targets of vAD, the rostral part of the reticular thalamic nucleus and layers Ia and III-IV of the retrosplenial granular b cortex (RSGb). Some were also found in layer Ia of the retrosplenial granular a cortex (RSGa). These axon terminals contain significant amounts of both VGluTs. Because the subset of thalamocortical projections to RSC has a unique molecular basis in the glutamatergic transmission system, it might play an important role in the higher cognitive functions processed in the RSC. Furthermore, double-labeled axon terminals of a different type were distributed in RSGb and RSGa. Because they are small and the immunoreactivity of VGluT2 is significantly weaker than that of VGluT1, they seemed to be a subset of corticocortical terminals. J. Comp. Neurol. 522:2089-2106, 2014. (c) 2013 Wiley Periodicals, Inc.
  • Takase K, Sakimoto Y, Kimura F, Mitsushima D
    Scientific reports 4 3738  2045-2322 2014/01 [Refereed][Not invited]
     
    To determine the developmental trajectory of hippocampal function in rats, we examined 24-h changes in extracellular acetylcholine (ACh) levels and contextual learning performance. Extracellular ACh significantly correlated with spontaneous behavior, exhibiting a 24-h rhythm in juvenile (4-week-old), pubertal (6-week-old), and adult (9- to 12-week-old) rats. Although juveniles of both sexes exhibited low ACh levels, adult males had higher ACh levels than adult females. Moreover, juveniles exhibited much more spontaneous activity than adults when they showed equivalent ACh levels. Similarly, juveniles of both sexes exhibited relatively low contextual learning performance. Because contextual learning performance was significantly increased only in males, adult males exhibited better performance than adult females. We also observed a developmental relationship between contextual learning and ACh levels. Scopolamine pretreatment blocked contextual learning and interrupted the correlation. Since long-term scopolamine treatment after weaning impaired contextual learning in juveniles, the cholinergic input may participate in the development of hippocampus.
  • Takase K, Oda S, Kuroda M, Funato H
    PloS one 3 8 (3) e58473  1932-6203 2013/03 [Refereed][Not invited]
     
    Monoaminergic and neuropeptidergic neurons regulate a wide variety of behaviors, such as feeding, sleep/ wakefulness behavior, stress response, addiction, and social behavior. These neurons form neural circuits to integrate different modalities of behavioral and environmental factors, such as stress, maternal care, and feeding conditions. One possible mechanism for integrating environmental factors through the monoaminergic and neuropeptidergic neurons is through the epigenetic regulation of gene expression via altered acetylation of histones. Histone deacetylases (HDACs) play an important role in altering behavior in response to environmental factors. Despite increasing attention and the versatile roles of HDACs in a variety of brain functions and disorders, no reports have detailed the localization of the HDACs in the monoaminergic and neuropeptidergic neurons. Here, we examined the expression profile of the HDAC protein family from HDAC1 to HDAC11 in corticotropin-releasing hormone, oxytocin, vasopressin, agouti-related peptide (AgRP), pro-opiomelanocortin (POMC), orexin, histamine, dopamine, serotonin, and noradrenaline neurons. Immunoreactivities for HDAC1,- 2,- 3,- 5,- 6,- 7,- 9, and - 11 were very similar among the monoaminergic and neuropeptidergic neurons, while the HDAC4, - 8, and - 10 immunoreactivities were clearly different among neuronal groups. HDAC10 expression was found in AgRP neurons, POMC neurons, dopamine neurons and noradrenaline neurons but not in other neuronal groups. HDAC8 immunoreactivity was detected in the cytoplasm of almost all histamine neurons with a pericellular pattern but not in other neuropeptidergic and monoaminergic neurons. Thus, the differential expression of HDACs in monoaminergic and neuropeptidergic neurons may be crucial for the maintenance of biological characteristics and may be altered in response to environmental factors.
  • 遺伝子改変マウス行動表現型解析の現状とその課題―MCH/ MHCR1ノックアウトマウス行動表現型解析を例として―
    高瀬堅吉, 小田哲子, 黒田優, 船戸弘正
    行動科学 51 (2) 143 - 154 2013/03 [Refereed][Invited]
  • Kikuchi T, Tan H, Mihara T, Uchimoto K, Mitsushima D, Takase K, Morita S, Goto T, Andoh T, Kamiya Y
    Neuroscience 237 151 - 160 0306-4522 2013/02 [Refereed][Not invited]
  • Yagami T, Yamamoto Y, Kohma H, Takase K
    Letters in drug design & discovery 9 (6) 557 - 567 1570-1808 2012/07 [Refereed][Not invited]
     
    Intensive insulin therapy to control blood glucose level increases survival among critically ill patients in intensive care unit and hospital. Hyperglycemia is potentially harmful because it acts as a procoagulant, induces insulin resistance, causes apoptosis, impairs neutrophil function, increases the infection rate and is associated with the risk of morbidity and mortality. Hyperglycemia and insulin resistance are virtually universally in sepsis, which is the leading cause of death in critically ill patients. Initially, sepsis is characterized by a hyper-inflammatory response; but as sepsis persists, there is a shift toward an anti-inflammatory immunosuppressive state. The intensive insulin therapy also reduces the infection rate and the mortality in septic patients. Arachidonate cascade is one of the factors associated with hyperglycemia, sepsis and infection. The cascade is involved in the upregulation of proinflammtory cytokines and the dysfunction of immune cells. Especially, we focused on prostaglandin D-2 (PGD(2)), which is produced from innate and adaptive immune cells. PGD(2) is non-enzymatically metabolized to 15-deoxy-Delta(12,14)-PGJ(2), (15d-PGJ(2)). 15d-PGJ(2) is an endogenous ligand for the nuclear receptor, peroxysome proliferators-activated receptor gamma (PPAR gamma) and induces apoptosis in the both immune cells. This review presents plausible roles of arachidonate cascade in hyperglycemia-impaired immunity. Furthermore, we shed light on therapeutic potentials of PPAR gamma ligands for critically ill patients under the insulin resistant state.
  • Miyazaki T, Takase K, Nakajima W, Tada H, Ohya D, Sano A, Goto T, Hirase H, Malinow R, Takahashi T
    The Journal of clinical investigation 122 (7) 2690 - 2701 0021-9738 2012/06 [Refereed][Not invited]
     
    Stressful events during early childhood can have a profound lifelong influence on emotional and cognitive behaviors. However, the mechanisms by which stress affects neonatal brain circuit formation are poorly understood. Here, we show that neonatal social isolation disrupts molecular, cellular, and circuit developmental processes, leading to behavioral dysfunction. Neonatal isolation prevented long-term potentiation and experience-dependent synaptic trafficking of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors normally occurring during circuit formation in the rodent barrel cortex. This inhibition of AMPA receptor trafficking was mediated by an increase of the stress glucocorticoid hormone and was associated with reduced calcium/calmodulin-dependent protein kinase type II (CaMKII) signaling, resulting in attenuated whisker sensitivity at the cortex. These effects led to defects in whisker-dependent behavior in juvenile animals. These results indicate that neonatal social isolation alters neuronal plasticity mechanisms and perturbs the initial establishment of a normal cortical circuit, which potentially explains the long-lasting behavioral effects of neonatal stress.
  • Takase K, Yamamoto Y, Yagami T
    Behavioural brain research 1 232 (1) 306 - 315 0166-4328 2012/06 [Refereed][Not invited]
     
    Adverse experiences in early life profoundly influence the developing nervous, endocrine, and immune systems, and also affect human behaviour during adult life and are considered in the pathogenesis of psychiatric disorders. Numerous studies have provided evidence that maternal deprivation in the middle of a stress hyporesponsive period (SHRP) causes multiple behavioural and physiological abnormalities that mimic positive symptoms of schizophrenia in humans. To investigate the neurochemical characteristics of maternal deprivation in the middle of the SHRP in the context of a possible animal model of the symptoms of schizophrenia, we examined calcineurin expression in the hippocampus of maternally deprived rats. To investigate other behavioural characteristics, we behaviourally phenotyped the rats by applying a comprehensive behavioural test battery. The results indicate that maternal deprivation in the middle of the SHRP has no effects on general health, neurological reflexes, sensory function, or motor function, but does have sex-specific effects on a type of anxiety-related behaviour in the open field test and male-specific effects on hippocampal calcineurin expression, social behaviour, and objective memory function. An interpretation of our results and previous studies in the context of the neurodevelopmental hypothesis of schizophrenia suggests that maternal deprivation in the middle of the SHRP in rats models some positive and negative aspects of schizophrenia. The findings regarding the sex-specific effects of maternal deprivation in the middle of the SHRP may become a strong tool for investigating sex differences in the pathogenesis and pathology of schizophrenia in humans. (C) 2012 Elsevier B.V. All rights reserved.
  • Fujita M, Yagami T, Fujio M, Tohji C, Takase K, Yamamoto Y, Sawada K, Yamamori M, Okamura N
    Cancer letters 2 312 (2) 219 - 227 0304-3835 2011/12 [Refereed][Not invited]
     
    Agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) have been examined as chemopreventive and chemotherapeutic agents. The aim was to investigate the cytotoxicity of troglitazone (TGZ) and its mechanisms in terms of PPAR gamma dependency and the p38 mitogen-activated protein kinase (MAPK) pathway in three human renal cell carcinoma (RCC) cell lines, 786-O, Caki-2 and ACHN cells. TGZ induced apoptosis and exerted cytotoxicity in a PPAR gamma-independent manner. We demonstrated that TGZ activated the p38 MAPK pathway and was involved in the cytotoxicity of TGZ. It was also revealed that TGZ induced G(2)/M cell cycle arrest through activation of p38 MAPK. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
  • 空間学習能力の性差出現に関わる海馬を神経支配するコリン作動性ニューロンの機能的性差
    高瀬堅吉
    心理学評論 53 (4) 526 - 544 2011/03 [Refereed][Not invited]
  • Yamamoto Y, Takase K, Kishino J, Fujita M, Okamura N, Sakaeda T, Fujimoto M, Yagami T
    PloS one 3 6 (3) e17552  1932-6203 2011/03 [Refereed][Not invited]
     
    15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is one of factors contributed to the neurotoxicity of amyloid beta (A beta), a causative protein of Alzheimer's disease. Type 2 receptor for prostaglandin D-2 (DP2) and peroxysome-proliferator activated receptor gamma (PPAR gamma) are identified as the membrane receptor and the nuclear receptor for 15d-PGJ(2), respectively. Previously, we reported that the cytotoxicity of 15d-PGJ(2) was independent of DP2 and PPAR gamma, and suggested that 15d-PGJ(2) induced apoptosis through the novel specific binding sites of 15d-PGJ(2) different from DP2 and PPAR gamma. To relate the cytotoxicity of 15d-PGJ(2) to amyloidoses, we performed binding assay [H-3]15d-PGJ(2) and specified targets for 15d-PGJ(2) associated with cytotoxicity. In the various cell lines, there was a close correlation between the susceptibilities to 15d-PGJ(2) and fibrillar A beta. Specific binding sites of [H-3]15d-PGJ(2) were detected in rat cortical neurons and human bronchial smooth muscle cells. When the binding assay was performed in subcellular fractions of neurons, the specific binding sites of [H-3]15d-PGJ(2) were detected in plasma membrane, nuclear and cytosol, but not in microsome. A proteomic approach was used to identify protein targets for 15d-PGJ(2) in the plasma membrane. By using biotinylated 15d-PGJ(2), eleven proteins were identified as biotin-positive spots and classified into three different functional proteins: glycolytic enzymes (Enolase2, pyruvate kinase M1 (PKM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH)), molecular chaperones (heat shock protein 8 and T-complex protein 1 subunit alpha), cytoskeletal proteins (Actin beta, F-actin-capping protein, Tubulin beta and Internexin alpha). GAPDH, PKM1 and Tubulin beta are A beta-interacting proteins. Thus, the present study suggested that 15d-PGJ(2) plays an important role in amyloidoses not only in the central nervous system but also in the peripheral tissues.
  • Yagami T, Takase K, Yamamoto Y, Ueda K, Takasu N, Okamura N, Sakaeda T, Fujimoto M
    Experimental cell research 14 316 (14) 2278 - 2290 0014-4827 2010/08 [Refereed][Not invited]
     
    In the central nervous system, fibroblast growth factor 2 (FGF2) is known to have important functions in cell survival and differentiation. In addition to its roles as a neurotrophic factor, we found that FGF2 caused cell death in the early primary culture of cortical neurons. FGF2-induced neuronal cell death showed apoptotic characters, e.g., chromatin condensation and DNA fragmentation. The ultrastructural morphology of FGF2-treated neurons indicated apoptotic features such as progressive cell shrinkage, blebbing of the plasma membrane, loss of cytosolic organelles, clumping of chromatin, and fragmentation of DNA. Tyrosine kinase inhibitors significantly rescued neurons from FGF2-induced apoptosis. FGF2 potentiated a marked influx of Ca(2+) into neurons before apoptosis. Both a calcium chelator and L-type voltage-sensitive Ca(2+) channel (L-VSCC) blockers attenuated FGF2-induced apoptosis, whereas other blockers of VSCCs such as N-type and P/Q-types did not. Blockers of L-VSCCs significantly suppressed FGF2-enhanced Ca(2+) influx into neurons. Moreover, FGF2 also generated reactive oxygen species (ROS) before apoptosis. Radical scavengers reduced not only the FGF2-generated ROS, but also the FGF2-induced Ca(2+) influx and apoptosis. In conclusion, we demonstrated that FGF2 caused apoptosis via L-VSCCs in the early neuronal culture. (C) 2010 Elsevier Inc. All rights reserved.
  • 空間認知能力の性差は氏か育ちか?-性差形成要因をめぐるヒトとラットにおける研究の動向-
    高瀬堅吉
    行動科学 48 (1) 69 - 82 2009/12 [Refereed][Invited]
  • Takase K, Kimura F, Yagami T, Mitsushima D
    Neuroscience 1 159 (1) 7 - 15 0306-4522 2009/03 [Refereed][Not invited]
     
    The difference in visual object recognition by males and females suggests a sex-specific function in the medial prefrontal cortex (mPFC). In the present study, we performed an in vivo microdialysis study in three groups of rats (males, diestrous females, and proestrous females) to examine the potential sex difference in acetylcholine (ACh) release in the mPFC. The dialysate was automatically collected from the mPFC every 20 min for 24 In under freely moving conditions and the spontaneous locomotor activity was simultaneously monitored. Although ACh release in the mPFC during the dark phase was significantly greater than during the light phase in both sexes, the female rats consistently exhibited a significantly greater mean ACh release than the males. Spontaneous locomotor activity during the dark phase was also significantly greater than during the light phase in both sexes, but the females exhibited significantly greater spontaneous locomotor activity than the males. In addition, both sexes of rats were found to have significant positive correlations between ACh release and spontaneous locomotor activity, but females were found to have significantly greater correlation coefficients than males. Stereological methods were used to examine the number of choline acetyltransferase immunoreactive cells in the nucleus basalis magnocellularis and the horizontal diagonal band of Broca. The number of choline acetyltransferase immunoreactive cells in the nucleus basalis magnocellularis was also greater in females than males, suggesting a contribution to the higher ACh release in females. In contrast, no sex difference in the choline acetyltransferase immunoreactive cells was observed in the horizontal diagonal band of Broca. This is the first report to show a sex difference in the 24-h ACh release profile in the mPFC of behaving rats. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Mitsushima D, Takase K, Takahashi T, Kimura F
    Journal of neuroendocrinology 4 21 (4) 400 - 405 0953-8194 2009/03 [Refereed][Not invited]
     
    Acetylcholine (ACh) release in the dorsal hippocampus increases during stress, exploration or learning, exhibiting sex-specific 24-h release profile. We review the role of gonadal steroids on the ACh release in the dorsal hippocampus. In our studies, we found that male rats showed higher extracellular ACh levels than females, but gonadectomy decreased ACh levels in both sexes of rats and subsequently eliminated the sex difference. To examine the sex difference under comparable gonadal steroid levels, we implanted steroid capsules after gonadectomy. Oestradiol supplementation maintained circulating oestradiol to the levels in proestrous female rats, whereas testosterone capsules maintained circulating testosterone to the levels similar to intact male rats. Under comparable gonadal steroids levels, ACh levels were sex-specific. Testosterone replacement in orchidectomised rats clearly restored ACh levels, which were greater than ovariectomised testosterone-primed rats. Similarly, oestradiol replacement in ovariectomised rats successfully restored ACh levels, which were higher than orchidectomised oestradiol-primed rats. These results suggest sex-specific activational effects of gonadal steroids on ACh release. To further examine the organisational effect, female pups were neonatally treated with oil, testosterone, oestradiol, or dihydrotestosterone. These rats were bilaterally ovariectomised and a testosterone capsule was implanted at postnatal week 8. Neonatal treatment of either testosterone or oestradiol clearly increased ACh levels, whereas neonatal dihydrotestosterone treatment failed to change levels. These results suggest that: (i) gonadal steroids maintain the sex-specific ACh release in the dorsal hippocampus and (ii) neonatal activation of oestrogen receptors is sufficient to mediate masculinisation of the septo-hippocampal cholinergic system.
  • Mitsushima D, Takase K, Funabashi T, Kimura F
    The Journal of neuroscience : the official journal of the Society for Neuroscience 12 29 (1) 3808 - 3815 0270-6474 2009/03 [Refereed][Not invited]
     
    Extracellular acetylcholine (ACh) levels in the dorsal hippocampus increases during learning or exploration, exhibiting a sex-specific 24 h release profile. To examine the activational effect of gonadal steroid hormones on the sex-specific ACh levels and its correlation with spontaneous locomotor activity, we observed these parameters simultaneously for 24 h. Gonadectomy severely attenuated the ACh levels, whereas the testosterone replacement in gonadectomized males or 17 beta-estradiol replacement in gonadectomized females successfully restored the levels. 17 beta-Estradiol-priming in gonadectomized males could not restore the ACh levels, and testosterone replacement in gonadectomized females failed to raise ACh levels to those seen in testosterone-primed gonadectomized males, revealing a sex-specific activational effect. Spontaneous locomotor activity was not changed in males by gonadectomy or the replacement of gonadal steroids, but 17 beta-estradiol enhanced the activity in gonadectomized females. Gonadectomy severely reduced the correlation between ACh release and activity levels, but the testosterone replacement in gonadectomized males or 17 beta-estradiol replacement in gonadectomized females successfully restored it. To further analyze the sex-specific effect of gonadal steroids, we examined the organizational effect of gonadal steroids on the ACh release in female rats. Neonatal testosterone or 17 beta-estradiol treatment not only increased the ACh levels but also altered them to resemble male-specific ACh release properties without affecting levels of spontaneous locomotor activity. We conclude that the activational effects of gonadal steroids maintaining the ACh levels and the high correlation with spontaneous locomotor activity are sex-specific, and that the organizational effects of gonadal steroids suggest estrogen receptor-mediated masculinization of the septo-hippocampal cholinergic system.
  • Mitsushima D, Takase K, Funabashi T, Kimura F
    Endocrinology 2 149 (2) 802 - 811 0013-7227 2008/02 [Refereed][Not invited]
     
    To examine the role of gonadal steroid hormones in the stress responses of acetylcholine (ACh) levels in the hippocampus and serum corticosterone levels, we observed these parameters simultaneously in intact, gonadectomized, or gonadectomized steroid-primed rats. In both sexes of rats, neither gonadectomy nor the replacement of gonadal steroid hormone affected the baseline levels of ACh. However, gonadectomy severely attenuated the stress response of ACh, whereas the replacement of corresponding gonadal hormone successfully restored the response to intact levels. The gonadal hormones affected the serum corticosterone levels in a different manner; the testosterone replacement in orchidectomized rats suppressed the baseline and the stress response of corticosterone levels, whereas the 17 beta-estradiol replacement in ovariectomized rats increased the levels. We further found that letrozole or flutamide administration in intact male rats attenuated the stress response of ACh. In addition, flutamide treatment increased the baseline levels of corticosterone, whereas letrozole treatment attenuated the stress response of corticosterone. Moreover, we found a low positive correlation between the ACh levels and corticosterone levels, depending on the presence of gonadal steroid hormone. We conclude that: 1) gonadal steroid hormones maintain the stress response of ACh levels in the hippocampus, 2) the gonadal steroid hormone independently regulates the stress response of ACh in the hippocampus and serum corticosterone, and 3) the sex-specific action of gonadal hormone on the cholinergic stress response may suggest a neonatal sexual differentiation of the septohippocampal cholinergic system in rats.
  • Takase K, Mitsushima D, Funabashi T, Kimura F
    Physiology & behavior 3 93 (3) 553 - 559 0031-9384 2008/02 [Refereed][Not invited]
     
    We previously reported that feeding with powdered diet after weaning (3 weeks of age) enhanced spatial ability, and increased the amount of acetylcholine (ACh) released in the dorsal hippocampus in female rats. In the present study, to specify the time when feeding conditions caused these effects, a radial 8-arm maze task and an in vivo microdialysis study were performed in both sexes of rats. In rats fed standard laboratory diet (i.e., pelleted diet), males learned the radial 8-arm maze faster than females. Moreover, the ACh release showed a distinct diurnal rhythm which was high during the dark phase and low during the light phase, but males showed a greater amount of ACh released in the dorsal hippocampus than females. However, in rats fed powdered diet after 6 weeks of age, no significant sex differences were observed in the radial 8-arm maze task or in the amount of ACh released, since feeding with powdered diet enhanced spatial ability, and increased the amount of ACh released only in females. These results suggest that feeding conditions after 6 weeks of age may contribute to the sex difference in the spatial ability associated with the changes in the amount of ACh released in the dorsal hippocampus in rats. (C) 2007 Elsevier Inc. All rights reserved.
  • Takase K, Mitsushima D, Funabashi T, Kimura F
    Brain research 1154 105 - 115 0006-8993 2007/06 [Refereed][Not invited]
     
    The sex differences in various motor functions suggest a sex-specific neural basis in the nonprimary or primary motor area. To examine the sex difference in the 24-h profile of acetylcholine (ACh) release in the rostral frontal cortex area 2 (rFr2), which is equivalent to the premotor/supplementary motor area in primates, we performed an in vivo microdialysis study in both sexes of rats fed pelleted or powdered diet. The dialysate was automatically collected from the rFr2 for 24 h under freely moving conditions. Moreover, the number of cholinergic neurons in the nucleus basalis magnocellularis (NBM) was examined. Further, to confirm the relation between ACh release in the rFr2 and motor function, the spontaneous locomotor activity was monitored for 24 h. Both sexes showed a distinct 24-h rhythm of ACh release, which was high during the dark phase and low during the light phase. Female rats, however, showed a greater ACh release and more cholinergic neurons in the NBM than male rats. Similarly, spontaneous locomotor activity also showed a 24-h rhythm, which paralleled the changes in ACh release in both sexes, and these changes were again greater in female rats than in male rats. In addition, feeding with powdered diet significantly increased the ACh release and spontaneous locomotor activity. The present study is the first to report the sex difference in the 24-h profile of ACh release in the rFr2 in rats. The sex specific ACh release in the rFr2 may partly contribute to the sex difference in motor function in rats. (C) 2007 Elsevier B.V. All rights reserved.
  • Mitsushima D, Yamada K, Takase K, Funabashi T, Kimura F
    The European journal of neuroscience 11 24 (11) 3245 - 3254 0953-816X 2006/12 [Refereed][Not invited]
     
    The sex difference in the emotional response to stress suggests a sex-specific stress response in the amygdala. To examine the sex difference in extracellular levels of serotonin (5HT) and dopamine (DA) in the basolateral amygdala (BLA) and their responses to restraint stress, in vivo microdialysis studies were performed in male and female rats. In experiment I, dialysates were collected from the BLA at 15-min intervals under the freely moving condition. Mean extracellular levels of 5HT or DA in the BLA were higher in male rats than in female rats. In experiment II, rats were subjected to restraint stress for 60 min to examine the stress response of 5HT or DA levels. Although restraint stress significantly increased extracellular 5HT levels in both sexes of rats, female rats showed a greater response than male rats. Moreover, restraint stress significantly increased extracellular DA levels in female rats, but not in male rats. In experiment III, rats were subjected to restraint stress for 30 min to examine behavioral responses to restraint stress. Although no sex difference was observed in the number of audible vocalizations, male rats defecated a larger number of fecal pellets than female rats. In experiment IV, rats were tested for freezing behavior to examine contextual fear responses. Conditioned male rats showed a longer freezing time than conditioned female rats. We found sex differences in the extracellular levels of 5HT and DA in the BLA and their responses to restraint stress, which may be involved in the sex-specific emotional response to stress in rats.
  • Takase K, Mitsushima D, Masuda J, Mogi K, Funabashi T, Endo Y, Kimura F
    Neuroscience 2 136 (2) 593 - 599 0306-4522 2005/10 [Refereed][Not invited]
     
    We have reported in the past that female rats fed a powdered diet showed better spatial learning and memory functions than female rats a fed pelleted diet. In the present study, we examined the effects of feeding with powdered diet on acetylcholine release in the hippocampus in both sexes of rats. After weaning (3 weeks of age), rats were fed either standard pelleted diet or powdered diet, and after maturation (9-12 weeks of age), they were used in an in vivo microdialysis study, in which no eserine (a cholinesterase inhibitor) was added to the perfusate. The dialysate was collected from the dorsal hippocampus at 20-min intervals underfreely moving conditions for more than 24 h. Acetylcholine in the dialysate was measured by high performance liquid chromatography. As we reported previously, the acetylcholine release showed a clear daily rhythm in both sexes, and males showed significantly greater acetylcholine release in the hippocampus than females in rats fed pelleted diet. Conversely, in rats fed powdered diet, no sex difference in the acetylcholine release was observed, since feeding with powdered diet significantly increased the acetylcholine release only in females. To further examine the number of cholinergic neurons in the medial septum and horizontal limb of the diagonal band of Broca, immunocytochemistry for choline acetyltransferase was performed in both sexes of rats fed either standard pelleted diet or powdered diet. However, neither sex nor feeding conditions affect the number of choline acetyltransferase immunoreactive cells in the areas. These results suggest that powdered diet after weaning enhances spontaneous acetylcholine release in the hippocampus in female rats without changes in the number of cholinergic neurons in the areas. It is possible that this effect of feeding contributes to improve the performance in spatial learning and memory functions in female rats fed powdered diet. (c) 2005 Published by Elsevier Ltd on behalf of IBRO.
  • Takase K, Funabashi T, Mogi K, Mitsushima D, Kimura F
    Neuroscience research 2 53 (2) 169 - 175 0168-0102 2005/10 [Refereed][Not invited]
     
    We determined whether feeding with powdered diet improved the visuospatial ability in female rats by checking the expression of N-methyl-D-aspartate receptor (NMDAR) subunit 1 (NR1) mRNA in the hippocampus. In rats fed standard pelleted diet, males performed better than females in a radial 8-arm maze task as we reported previously. We found that the expression of NR1 mRNA, which may be the key mediator in visuospatial ability in the hippocampus, was also higher in males than in females. However, in rats fed powdered diet, no sex difference was seen in the radial 8-arm maze task and the expression of NR1 mRNA in the hippocampus, since feeding with powdered diet improved the visuospatial ability with increases in the expression of NR1 mRNA in the hippocampus in females. We suggest that the sex difference in visuospatial ability is at least in part due to feeding conditions. (c) 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Books etc

  • 子安増生・丹野義彦・箱田裕司(監修) (Joint workRNA・核酸・Gタンパク質・染色体・タンパク質・DNA・メッセンジャーRNA・免疫抗体反応・モノアミン・モノアミン酸化酵素・モノアミン酸化酵素阻害剤)
    有斐閣 2021/02 9784641002661 1002
  • 髙瀨堅吉 (Single work)
    徳間書店 2020/12 4198651051 232 
    大学生に急増する自閉症(ASD)。本当の自分がわからない若者たち。スマホとネットの世界しか知らないデジタルネイティブの心に、何が起こっているのかーー。 そして急激なデジタル変革は、50代を社会からはじき出そうとしている! 今の若者は、小中学生からスマホとネット環境の中で育ったデジタル・ネイティブ世代。SNSで「承認欲求」を満たし、自分がないから「悩んだことがない」。一方、コミュニケーションが苦手な人は、ますます生きにくくなっている。 そして、デジタル変革が進む中で、新たな50代問題が噴出してきている。 大学生のカウンセリングにもあたっている著者が、心理学の視点からこれらの問題を解き明かし、デジタル社会に生きるすべての人に警鐘を鳴らす。 第1章 今の若者はデジタルネイティブ世代 第2章 大学生に急増する自閉症(ASD) 第3章 本当の自分がわからない若者たち 第4章 心はどのように育つのか 第5章 拡散した心はどうなるのか ~不登校、ニート、8050問題~ 第6章 デジタル社会を生き抜く道はあるのか 終わりに 時代が変わり、不適応な心が適応的になる?
  • 髙瀨堅吉 (Single work)
    誠信書房 2020/10 441441671X 182 
    心理職の活躍する保健医療領域での「共通言語」は、生物学上の言葉が中心となる。また、世界規模で増えている心理学と生命科学の共同研究などでも、生物学の基礎は必須のものとなる。 しかし、私立大学の入試で生物学での受験可能校が少ないこともあり、公認心理師試験や現場に出てからも、生物学に苦手意識を抱える人が少なくない。 そこで、心理学部出身で今は医学部で教鞭を執る著者が、現場で必須の知識をできるかぎり噛み砕いて解説。各章のコラムも、生物学とこころの密接なつながりを感じさせてくれる。大学のテキストにはもちろん、現場に出てからの“虎の巻"としても使える書。
  • 坂本敏郎, 上北朋子, 田中芳幸 (Joint work第9章 心の病と発達系の障害)
    ナカニシヤ出版 2020/04 9784779514722 176
  • 大隅典子, 紺野登, 行方史郎, 高瀬堅吉, 山田胡瓜, 千葉雅也, タカハシショウコ, 中尾悠里, 駒井章治, 行木陽子, 須田桃子, サリー楓 (Joint work心理学者から見たデジタル社会とヒトの心)
    集英社 2020/04 
    人の知性はどう変わる? AI(人工知能)に関し、人がどういうふうに関わり、どう使っていくのか。12人の慧眼が照らし出すAI社会の甘夢あるいは悪夢。何か答えを求めるのではなく、議論して探る、それ自体が目的となる会議のありようを模索するアゴラ市民会議。その一環として2019年に実施したイベント「どんな未来を生きていく? ~AIと共生する人間とテクノロジーのゆくえ~」を電子書籍化したものです。
  • 日本心理学諸学会連合 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2020/03 4788961008 480
  • 日本健康心理学会 (Joint work第2章 生理学的メカニズム(発達・加齢))
    丸善出版 2019/10 4621303767 746
  • 日本医学教育学会地域医療教育委員会・全国地域医療教育協議会 合同編集委員会 (Joint work第3章-3 医療に関連した人文・社会科学領域)
    診断と治療社 2019/07 4787823841 184
  • 野尻, 英一, 高瀬, 堅吉, 松本, 卓也 (Joint editor第1章 心理学──心の世界の探究者からみた自閉症)
    ミネルヴァ書房 2019/04 9784623086481 xi, 367, 6p
  • 日本心理学諸学会連合 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2019/03 4788961040 480
  • 遠藤 公久 (Joint work第3章 学習)
    弘文堂 2019/02 4335651856 296
  • 繁桝算男, サトウタツヤ, 高瀬堅吉, 村上郁也, 澤幸祐, 川口潤, 山祐嗣, 中村真, 上原泉, 敷島千鶴, 小塩真司, 村本由紀子, 石垣琢麿, 繁桝 算男, 繁桝 算男, 野島 一彦 (Joint work2章 心の生物学的基盤)
    遠見書房 2018/04 4866160527 200
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2018/03 4788961032 480
  • 堀忠雄, 尾﨑久記, 坂田省吾, 山田冨美雄, 堀 忠雄, 尾﨑 久記, 坂田 省吾, 山田 冨美雄 (Joint work5章 脳と行動の遺伝子操作)
    北大路書房 2017/06 4762829722 320
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2017/03 4788960982
  • 永井良三, 監修, 自治医科大学総合教育部門, 編, 永井良三, 自治医大総合教育 (Joint work心理 心を理解する、心を調べる~心理学でわかること、わからないこと~)
    西村書店 2016/06 4890134646 354
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2016/06 4788961024 240
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2016/03 4788960974 480
  • Ian Q. Whishaw, Bryan Kolb, Ian Q.Whishaw, Bryan Kolb (Supervisor)
    西村書店 2015/09 4890134565 435
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2015/05 4788960966 376
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2015/03 4788960958 413
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2014/03 4788960907 436
  • 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2013/03 4788960893 440
  • Jacqueline N. Crawley, 高瀬 堅吉, 柳井 修一 (Supervisor)
    西村書店 2012/09 4890134271 407
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2012/03 4788960885 436
  • W.F. ボロン, E.L. ブールペープ, 泉井 亮, 河南 洋, 久保川 学 (Joint translation9部 生殖系)
    泉井亮 西村書店 2011/09 4890134131 1363
  • 大川一郎, 宇都宮博, 日下菜穂子, 奥村由美子, 土田宣明 (Single workTopics11 脳科学と加齢、Topics25 100歳老人の心理的特徴)
    ミネルヴァ書房 2011/04 4623058956 291
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2011/03 4788960877 440
  • Takase K, Mitsushima D, Andres Costa, Eugenio Villalba (Joint workSex difference in learning and memory: effects of sex differentiation, development, and environments on the forebrain cholinergic system)
    Nova Science Pub Inc 2010/09 1608768767 293
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2009/06 4788960834 324
  • 日本心理学諸学会連合, 心理学検定局, 日本心理学諸学会連合, 心理学検定局 (Joint work6 神経・生理)
    実務教育出版 2009/04 4788960826 376

Conference Activities & Talks

  • マウスの行動表現型解析をツールとした基礎・臨床医学研究との連携  [Invited]
    髙瀨堅吉
    第74回東邦医学会総会(招聘講演)  2020/11
  • シチズンサイエンス推進に向けたこれまでの活動報告と実践における課題  [Invited]
    髙瀨堅吉
    科学技術社会論学会第18回年次研究大会 オーガナイズドセッション「オープンサイエンス・市民科学・サイエンスカフェ・SDGs」  2019/11
  • 免疫関連たんぱく質ST2過剰発現マウスの行動表現型解析  [Invited]
    髙瀨堅吉
    日本心理学会第83回大会 シンポジウム「免疫系の行動科学・心理学」  2019/09
  • 認定心理士の会の新たな取り組み‐シチズン・サイエンス  [Invited]
    髙瀨堅吉
    日本心理学会第82回大会 シンポジウム「シチズン・サイエンスを通じた“心理学の再現性の危機”への挑戦‐認定心理士の会の新たな取り組み‐」  2018/09
  • 公認心理師・心理学研究者が潜在的フィールドで活躍する際に求められる知識・技術  [Invited]
    髙瀨堅吉
    日本心理学会第82回大会 シンポジウム「公認心理師・心理学研究者の潜在的フィールド‐広がる活躍の場と求められる知識・技術‐」  2018/09
  • 母子の分離が脳機能に与える影響  [Invited]
    髙瀨堅吉
    北海道心理学会第64回大会 シンポジウム「子供を取り囲む環境‐育まれる心、育む心‐」  2017/10
  • 認定心理士の会 今後の活動の展望  [Invited]
    髙瀨堅吉
    日本心理学会第81回大会 シンポジウム「社会で活きている心理学‐認定心理士の会/認定心理士の活動をアカデミアへ還流する‐」  2017/09
  • Research evaluation disparities: possibly influenced by research field and generation?  [Not invited]
    Takase K
    Y-KAST - YAJ Bilateral Workshop "Institutional and Scientific Challenges for Young Scientists in Asia"  2017/03
  • ヒトのモデル動物としてのマウス・ラットを対象とした行動アセスメント研究の現状と課題  [Not invited]
    高瀬堅吉
    日本行動科学学会第33回ウィンターカンファレンス シンポジウム  2017/02
  • Meta-analysis of genetically modified mice on behavioral and biological phenotypes  [Invited]
    Takase K, Kikuchi K, Funato H
    31st International Congress of Psychology (ICP2016) Invited symposia “Frontiers in the psychological research using animal models -Harmonized translational study elucidating the operating principles underlying human psychological processes-”  2016/07
  • 医学と心理学の学際先端領域におけるキャリア形成の枠組み  [Invited]
    高瀬堅吉
    日本心理学会第79回大会 シンポジウム「広がる心理学‐学際性の先端領域と新しいキャリア形成の枠組み‐」  2015/09
  • 社会行動障害への多角的アプローチ‐動物からヒト、基礎から臨床‐(ストレス不応期の母子分離ストレスが社会行動に与える影響)  [Invited]
    高瀬堅吉
    日本心理学会第79回大会 シンポジウム「社会行動障害への多角的アプローチ‐動物からヒト、基礎から臨床‐」  2015/09
  • 人間の生涯発達の理解を目指す生理心理学研究‐乳幼児(仔)期~思春期・成体期‐  [Not invited]
    高瀬堅吉
    日本心理学会第78回大会 シンポジウム「人間の生涯発達の理解を目指す生理心理学研究」  2014/09
  • 行動医学のコアカリキュラム提案に向けたJABSの取り組みと求められる役割  [Invited]
    高瀬堅吉
    第20回日本行動医学会学術総会 シンポジウム「行動医学のコアカリキュラムの提案」  2014/03
  • これからの教育心理学を考える‐動物実験とどのように付き合うのか?‐  [Not invited]
    高瀬堅吉
    日本心理学会第77回大会 シンポジウム「これからの教育心理学を考える‐動物実験、生物学的指標とどのように付き合うのか?‐」  2013/09
  • 摂食関連ペプチドMCHの多様な役割と、各行動に与える効果量のメタ分析  [Invited]
    高瀬堅吉
    日本行動科学学会2012年度年次大会 シンポジウム「日本におけるこれからの行動科学‐求められる学際性と国際性‐」  2012/09
  • 養育環境・生活環境によってつくられる高次脳機能の性差  [Invited]
    高瀬堅吉
    日本行動科学学会第25回ウィンターカンファレンス(25周年記念大会) シンポジウム「神経科学と行動科学を繋ぐ架け橋‐尖鋭的若手研究者からのメッセージ‐」  2009/03

MISC

  • マウスの行動表現型解析をツールとした基礎・臨床医学研究との連携
    髙瀨堅吉  東邦医学会雑誌  2021  [Not refereed][Invited]
  • シチズンサイエンスを推進する社会システムの構築を目指して
    日本学術会議若手アカデミー  提言  2020/09  [Refereed][Not invited]
  • 学術とSDGsのネクストステップ ー社会とともに考えるためにー
    科学と社会委員会, 科学と社会企画分科会  報告  2020/09  [Refereed][Not invited]
  • 科学的エビデンスを主体としたスポーツの在り方 - Evidence Based Sports for Diverse Humanity (EBS4DH) -
    日本学術会議科学的エビデンスに基づく「スポーツの価値」の普及の在り方に関する委員会  提言  2020/06  [Refereed][Not invited]
  • 科学的エビデンスに基づく「スポーツの価値」の普及の在り方
    日本学術会議科学的エビデンスに基づく「スポーツの価値」の普及の在り方に関する委員会  回答  2020/06  [Refereed][Not invited]
  • 心の基礎研究を通して社会を診る
    髙瀨堅吉  学術の動向  25-  (4)  104  -111  2020/04  [Not refereed][Invited]
  • 心理学におけるシチズン・サイエンスの可能性
    髙瀨堅吉  学術の動向  23-  (11)  40  -45  2018/11  [Not refereed][Invited]
  • 狩野光伸, 岸村顕広, 平田佐智子, 髙瀨堅吉  SciREX Quarterly  7-  2017/12  [Not refereed][Invited]
  • 第2回若手科学者サミット開催報告
    髙瀨堅吉  学術の動向  22-  (9)  110  -111  2017/09  [Not refereed][Invited]
  • 発達段階・性別特異的行動異常の生物・心理・社会モデルに基づく検討-動物とヒトの研究、基礎と臨床をつなぐ古くて新しい心理学研究モデルの提案-
    高瀬堅吉  立命館文学  641-  233  -243  2015/03  [Not refereed][Invited]
  • 視床とコリン作動性ネットワーク
    高瀬堅吉, 黒田優  Clinical neuroscience  30-  (6)  655  -657  2012/05  [Not refereed][Invited]
  • 飼育環境によって性差が生まれる海馬の空間認知機能:新脳の関わる認知機能には本来,性差はない
    貴邑冨久子, 美津島大, 遠藤豊, 舩橋利也, 高瀬堅吉  性差と医療  3-  (12)  1289  -1291  2006/11  [Not refereed][Invited]

Awards & Honors

  • 2005/07 日本神経内分泌学会 若手研究奨励賞
     
    受賞者: 高瀬堅吉

Research Grants & Projects

  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2020/04 -2025/03 
    Author : 板井美浩
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2019/04 -2024/03 
    Author : 高瀬堅吉
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2020/04 -2023/03 
    Author : 菊地元史
  • 文部科学省:科学研究費補助金(基盤研究(B))
    Date (from‐to) : 2019/04 -2022/03 
    Author : 後藤隆久
  • 社会技術研究開発センター(RISTEX):戦略的創造研究推進事業(社会技術研究開発)
    Date (from‐to) : 2018/10 -2021/09 
    Author : 庄司昌彦
  • シチズンサイエンスの普及にむけた概念整理とプラットフォーム構築の提案
    公益財団法人サントリー文化財団:サントリー文化財団研究助成「学問の未来を拓く」
    Date (from‐to) : 2019/08 -2020/07 
    Author : 中村征樹
  • 自閉症学(Autism Studies)共創思考サロン
    大阪大学共創機構 産学共創本部:未来共創思考サロン活動支援プログラム
    Date (from‐to) : 2018/08 -2019/03 
    Author : 野尻英一
  • 文部科学省:科学研究費補助金(基盤研究(B))
    Date (from‐to) : 2016 -2018 
    Author : 後藤隆久
  • 文部科学省:科学研究費補助金(挑戦的萌芽研究)
    Date (from‐to) : 2016 -2017 
    Author : 後藤隆久
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2013 -2016 
    Author : 高瀬堅吉, 黒田 優, 小田 哲子, 船戸 弘正
     
    これまで代表者は、げっ歯類を対象とした網羅的行動解析、生理学的、生化学的解析を展開し、出生後の環境が、個体の学習・記憶機能および統合失調症発症に与える影響について明らかにした。また、現所属機関に赴任後、食環境が脳機能に与える影響とその分子機構について、網羅的行動解析、形態学的解析を組み合わせた手法で検討し、高脂肪食を継続的に給餌したマウスが様々な行動変容を呈することをパイロット研究の結果から示した。多様な行動変容は、脳局所における機能的、形態的変化ではなく、脳全体における変化が仮定され、その原因として脳全体に広く投射する神経修飾物質分泌ニューロンの機能的変化が示唆される。そこで、神経修飾物質を標的とした遺伝子改変マウスの行動表現型に関する複数の報告と、肥満マウスの行動表現型に関するデータを比較したところ、肥満マウスの行動変容はメラニン凝集ホルモン(melanin-concentrating hormone、MCH)を欠損したマウスの行動変容と類似しており、簡易的に測定可能な行動表現型項目において相同性を示すことを示唆した。平成26年度は、パイロット研究で得られた肥満マウスの行動表現型をさらに精緻に検討し、これまでにファスト・スクリーニングで得られるほぼすべての行動表現型についてデータを得ることに成功した。また、MCH欠損マウスとの詳細な比較を行うために、これまで報告されたMCH欠損マウスのほぼすべてのデータに対してメタ分析を行い、肥満マウスが呈する表現型との定量的比較を可能にするメタ分析結果を得た。この結果はPLoS One誌に投稿し、現在Minor Revisionの評価を頂き、再投稿準備中である。これにより、神経修飾物質分泌ニューロンに発現するヒストン脱アセチル化酵素ファミリー発現の検討および肥満マウスの脳のMCH投射領域におけるMCH含有量の測定の準備を整えることができた。
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2013 -2015 
    Author : 杉岡幸三, 高瀬 堅吉
     
    本研究は、学習、注意また活動性などの機能に深く関与する海馬および大脳皮質の機能不全に焦点をしぼり、ラット胎生15、17、19日齢(それぞれM15群、M17群、M19群)に、神経毒性を有するメチルアゾキシメタノール(MAM)を投与することによって、脳の発生学的形態異常を有するADHDもしくはLDモデル動物を作成し、これらの動物に対して、新生児期から成体期に至る様々な時期に、種々の実験パラメーターを用いた多面的行動分析を行うとともに脳の組織学的分析を行った。1)新生児期に分析した正向反射・背地走性では、雌雄のM17群の反射獲得の遅延が観察された、2)離乳期でのOF事態での活動性の分析では、雄のM17群が寡動傾向を示したが、若齢期および成体期では群間に差異はなかった、また3)恐怖条件付け後の、装置に対する文脈記憶を凍結行動を指標として分析したところ、雌のM15およびM17群の凍結行動表出時間は短く、参照記憶の障害を示した。所定の行動実験終了後に測定した脳重は、M15群では対照群の83%、M17群では91%、M19群では95%であった。脳の組織学的分析では、1)M15群では皮質の層構築異常および海馬錐体細胞層の層構築異常および異所性の細胞集塊が観察され、2)M17群では皮質第II層の発達不全が観察された。以上のことは、本研究のM15およびM17群の行動学的結果のいくつかがADHD児で観察される注意欠陥・学習障害と類似するとともに、これらの行動異常が脳の皮質および海馬の発生学的形態異常と関係する可能性を示唆するものである。
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2013 -2015 
    Author : 船戸弘正, 高瀬 堅吉
     
    近年、肥満人口が世界的に増加し、我が国でも肥満、糖尿病に関連した社会的損失は甚大である。C57BL/6 マウスは高脂肪高カロリー餌で飼育すると肥満し、耐糖能低下を示すことから、ヒトの肥満および糖尿病のよいモデルとなる。最近、代表者はオレキシンがオレキシン1型受容体と2型受容体を介して、体重調節と糖代謝制御とをそれぞれ独立した経路で制御することを示した。本研究では、オレキシン1 型受容体と2型受容体それぞれの体重調節及び糖代謝への影響を部位特異的遺伝子改変マウスを用いて明らかにする。オレキシン2型受容体アゴニストによる、高脂肪食誘導性肥満抑制作用は野生型マウスおよびオレキシン神経欠損マウスで再現性良く認められている。Fosを用いた検討から、縫線核群内の特定の神経細胞集団が関与していると考えられる。高脂肪食による耐糖能低下を緩和する効果も認められる。このことは、オレキシン2型受容体が創薬標的として大きな可能性を秘めていることを意味する。オレキシンAでは作用はやや弱いが、この点はさらなる検討が必要である。オレキシン1型受容体Floxマウスやオレキシン2型受容体Floxマウスは繁殖コロニーを増やしている。
  • 文部科学省:科学研究費補助金(基盤研究(B))
    Date (from‐to) : 2013 -2015 
    Author : 後藤隆久, 宮崎 智之, 高瀬 堅吉, 内本 一宏
     
    まず初めに通常の成体マウスを用いて行動テストバッテリーの構築を行った。動物センターに防音室および行動実験機材の搬入を行い、セットアップを行った。テストバッテリーは大きく分けて、「感覚」、「運動」、「不安」、「鬱様」、「社会性」、「注意」、「記憶」であり、それぞれに2~5種類の行動実験が含まれている。具体的には、「感覚」には、視覚前肢置き直しテスト・二瓶選択テスト・馴化脱馴化テスト・ホットプレートテストが、「運動」には、ローターロッドテスト・ビームテスト・ワイアハングテストが、「不安」には、高架式十字迷路テスト・オープンフィールドテスト・明暗選択テストが、「鬱様」には、ボーソルト強制水泳テスト・尾懸垂テストが、「社会性」には、社会性行動測定テスト・チューブテスト・性行動測定テストが、「注意」には、プレパルスインヒビションテスト・潜在制止テストが、「記憶」には、物体再認テスト・空間認識テスト・社会的再認テスト・恐怖条件付けテストが含めれている。それら2~5種類の行動実験の順番が適切でないと、前の行動実験が翌日以降の行動実験の結果に対して干渉してしまう。従って、私たちが考えた順番で行った各行動実験の結果が、過去に報告された各行動実験の基準値を再現できるかをはじめに確認した。立ち上げより半年でその再現実験が完了したため、続いてイソフルランに曝露したマウスを用いて実験を行った。1.8%のイソフルランに2時間曝露したマウスを用いて上記テストバッテリーを行い、間もなくデータを取り終えるところである。
  • オレキシンによるエネルギー代謝調節機構の解明
    ネスレ栄養科学会議:2012年度研究助成
    Date (from‐to) : 2012 -2012 
    Author : 船戸弘正
  • 摂食・睡眠調節神経回路におけるHDACファミリー発現の検討
    東邦大学:東邦大学医学部プロジェクト研究
    Date (from‐to) : 2012 -2012 
    Author : 高瀬堅吉
  • ヒストン脱アセチル化酵素による神経ペプチドを介したマウス行動制御の分子機構解明
    東邦大学:医学研究科推進研究費
    Date (from‐to) : 2012 -2012 
    Author : 船戸弘正
  • 文部科学省:科学研究費補助金(若手研究(B))
    Date (from‐to) : 2011 -2012 
    Author : 高瀬堅吉
     
    申請者は、ストレス不応期中期に母子分離を施した雄性ラットで不安が高まり、社会性が低下することを発見した。さらに、プロテオーム解析を用いて、この行動異常への関連が示唆される脳内分子を複数列挙することに成功し、その多くが神経細胞の可塑性に関わるタンパク質であることを明らかにした。先行研究は、ストレス不応期中期の母子分離操作が思春期後に統合失調症の陽性症状を模した行動表現型を導くことを報告しており、今回、申請者が得た行動表現型異常は、統合失調症の陰性症状に該当することが明らかとなった。そこで、統合失調症に関わりがあり、かつ、神経細胞の可塑性に関わるタンパク質の発現が統合失調症の責任部位と目される海馬体で変化していると考え、海馬体におけるカルシニューリンの発現量を調べた。その結果、母子分離操作を施された雄性ラットで当該分子の発現量が減少していることが示された。
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2010 -2012 
    Author : 杉岡幸三, 高瀬 堅吉, 谷口 泰造
     
    本研究は、学習、注意また活動性などの機能に深く関与する海馬、および海馬と密接な線維連絡を有する脳部位の機能不全に焦点をしぼり、ラット胎生15もしくは17日齢(それぞれM15群、M17群)に、神経毒性を有するメチルアゾキシメタノール(MAM)を投与することによって、脳の発生学的形態異常を有するADHDモデル動物を作成し、これらの動物に対して、新生児期から成体期に至る様々な時期に、種々の実験パラメーターを用いた多面的行動分析を行うとともに脳の組織学的分析を行ったものである。成体期に行った本年度の研究においては、1)聴覚性刺激先向提示抑制(PPI)事態での驚愕反射の程度および刺激先向提示による驚愕反射の抑制(PPI)の程度を分析したところ、M15群は雌雄とも有意に大きい驚愕反射を示すとともに、PPIの程度は小さく、注意欠陥の傾向を示した、また2)恐怖条件付け後の、装置に対する文脈記憶を凍結行動を指標として分析したところ、M15群は雌雄とも凍結行動表出時間は短く、参照記憶の障害を示した。脳重に関してM15群では重度の、M17群では軽度の小頭(脳)症を示すとともに、脳の組織学的分析では、1)M15群では皮質の層構築異常および海馬錐体細胞層の層構築異常および異所性の細胞集塊が観察され、2)M17群では皮質第II層の発達不全が観察されるとともに、数例において線条体に変性細胞が観察された。また、カルビンジンによる免疫染色を行ったところ、海馬苔状線維の軸索がM15群およびM17群ともに2層性を示し、この異常な線維連絡はM15群において顕著であった。以上のことから、本研究の行動学的結果のいくつかがADHD児で観察される注意欠陥・学習障害と類似するとともに、これらの行動異常が脳の皮質および海馬の発生学的形態異常と関係する可能性を示唆するものである。
  • 性ホルモンがオレキシンによる体重制御機構に及ぼす影響の研究
    東邦大学:東邦大学医学部プロジェクト研究
    Date (from‐to) : 2011 -2011 
    Author : 高瀬堅吉
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2008 -2010 
    Author : 矢上達郎
     
    15-deoxy-Δ^<12,14>-prostaglandin J_2(15d-PGJ_2)膜特異的結合部位の神経変性への関与を見出し、プロテオーム解析により11種の標的タンパク質を同定した。標的は、解糖系酵素(神経特異的エノラーゼ・ピルビン酸キナーゼM1・グリセルアルデヒド3リン酸脱水素酵素)、分子シャペロン(熱ショックタンパク質8・Tコンプレックスタンパク質1)および細胞骨格タンパク質(アクチンβ・Fアクチンキャッピングタンパク質、チューブリンβ・インターネキシンα)に分類された。
  • 文部科学省:科学研究費補助金(基盤研究(B))
    Date (from‐to) : 2008 -2010 
    Author : 高橋琢哉
     
    幼少時のストレスは生涯にわたって認知情緒行動に影響を及ぼす。しかしながらストレスが幼若時の脳回路形成に及ぼす影響のメカニズムについてはよくわかっていない。本課題では幼若期の社会的隔離が脳回路形成に及ぼす影響を分子レベルで解析している。幼若期の社会的隔離はバレル皮質における経験依存的AMPA受容体シナプス移行を雄においては阻害するが、雌においては阻害しない。
  • 文部科学省:科学研究費補助金(若手研究(B))
    Date (from‐to) : 2008 -2009 
    Author : 高瀬堅吉
     
    本研究は、老化に伴うコリン作動性神経の活動低下を予防するための各性に適した生活環境(食事量、運動量)を同定することを目的として行った。平成21年度に、研究の途上、偶然にも、ラットを乳児期後期から幼児期初期(生後9日目と11日目)の間で低栄養状態にすると、感覚、運動、認知機能は正常であるにも関わらず、雄性ラットのみが、情動性を測定する試験において、不安行動を亢進し、特定箇所を執拗に探索する行動(常同行動)を呈し、さらに、社会性を測定する試験において他個体との関わりを減少させることを発見した(Takase et al., 2009)。これら一連の行動異常は、雌性ラットにはまったく認められなかった。研究結果は、成熟後の脳機能を育むために必要な乳幼児期の生活環境が雌雄で異なることを示している。雄性ラットは、乳幼児期における低栄養状態に非常に脆弱であり、この時期における栄養状態が成熟後の情動性や社会性にまで影響を与えることが示唆された。
  • 生後の社会的隔離が恐怖条件づけ依存的AMPA受容体シナプス移行へ与える影響の性差
    横浜市立大学:研究戦略プロジェクト
    Date (from‐to) : 2007 -2007 
    Author : 高瀬堅吉
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2006 -2007 
    Author : 美津島大
     
    雌雄のウィスター系ラットを実験に用いる。性腺の摘除および性腺ステロイドホルモンの処置は実験の2週間前に行い、20%17β-estradiol封入チューブ(体重250gあたり15mm)、100%testosterone封入チューブ(体重250gあたり30mm)を背側皮下に植え込み、2週間後に実験を行った。In vivo microdialysis実験はペントバルビタール麻酔下で、脳定位固定装置を用いて背側海馬にガイドカニューラを植え込み、固定した。実験前日に、microdialysis用プローブ(Eicom Co.外径0.31mm)をガイドカニューラを介して、背側海馬に刺入した。人工脳脊髄液を1.2μl/分の流速で環流しながら自由行動状態を維持し、翌日からin vivo microdialysis実験を行い、20分ごとに24時間以上連続して脳内環流液の採取とAChの定量を続けた。同時に、各ラットの自発行動量をACTMONITORを用いて数値化し、ACh分泌量との相関解析も行った。その結果、雄性におけるtestosteroneや雌性における17β-estradiolは、ACh分泌量と自発行動量の相関を維持することが判明した。また、この相関は背側海馬のCA1領域で特に顕著であることが判明した。CA3やDG領域でも正の相関は得られたが、CA1領域と比べて有意に低かった。次に、海馬各領...
  • 文部科学省:科学研究費補助金(若手研究(B))
    Date (from‐to) : 2006 -2007 
    Author : 高瀬堅吉
     
    地図を読む、幾何学の問題を解くなどの視空間的能力において、男性は女性と比べて優位性を示すことが報告されており、このような性差はヒトのみならずサルやラットなどの他の哺乳類でも確認されている。従来、視空間的能力の性差は、脳の性分化により引き起こされると考えられていた。しかし我々は、ラットを用いた一連の研究から、この視空間的能力の性差が生後の環境の影響でつくられることを明らかにした(Endo et al.,1994;Takase et al.,2005a;Takase et al.,2005b)。とは言え、生後のどの時期の環境が視空間的能力の性差をつくるのか未だ不明であった。そこで我々は、雌雄ラットが性成熟する6週齢以降の時期に注目した。この時期はヒトでは思春期以降にあたる(Ojeda and Urbanski,1994)。本研究では視空間的能力という高次脳機能の性差が、思春期以降の環境によってつくられることを明らかにし、思春期以降の環境がどのように視空間的能力の性差をつくるのか、海馬体に注目し、その神経基盤の解明を試みた。現在まで、1)雌雄ラット海馬体内アセチルコリン分泌量は発達に伴い増加すること、2)6週齢以降は雄性ラットの分泌量が雌性ラットに比べて顕著に増加すること、3)その性差は6週齢以降の給餌環境の操作により解消されることを明らかにし、その結果を論文にまとめた(Takas...
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2005 -2007 
    Author : 舩橋利也
     
    1)鼻板培養によるGnRHサージ発生器モデル 胎生13.5日齢のolfactory placodeを10日回転培養し、サージ発生器を刺激することがin vivoで知られているcAMPを増加させる分解酵素阻害剤を投与した。その結果、容量依存性にGnRHの分泌を増加させた。従って、本モデルは、サージ発生器としての特徴を持っていることが示唆された。 2)GT1-1細胞によるGnRHサージ発生器モデル GT1-1細胞をカバーグラス上に培養し、カルシウムイメージングと細胞外電気活動の同時測定を、多点電極皿を用いて、同時測定を試みた。その結果、複数のGT1-1細胞の同期した細胞電気活動と、それらと同期したカルシウム変動が観察された。現在、エストロジェンを添加して、GnRH1の分泌変化とカルシウム変動の同時測定を試みている。 3)グルタミン酸ニューロンとLHサージに関するin vivoの実験 グルタミン酸ニューロンのサージ発生器活動における役割を明らかにする目的で、レンチウイルスを用いて、グルタミン酸型AMPA受容体のシナプスへの移行を阻止するdominant negativeを視索前野に発現させる実験を行った。その結果、LHサージには影響がなかった。しかし、思春期に発現させると成熟後のLHサージが減弱することが明らかとなった。 4)pCREB とLHサージに関するin vivoの実験 ア...
  • 海馬体内アセチルコリン分泌動態の生後発達変化と性差発現時期の解明
    横浜市立大学:研究戦略プロジェクト
    Date (from‐to) : 2006 -2006 
    Author : 高瀬堅吉
  • 文部科学省:科学研究費補助金(基盤研究(C))
    Date (from‐to) : 2005 -2006 
    Author : 貴邑冨久子
     
    1.ホルマリン侵害刺激に対する痛み行動の性差 正常雄性ラットおよび発情前期ラットの足底皮下にホルマリンを投与すると、二相性の痛み行動が惹起された。その中間相5-10分の痛み行動は、雌性ラットの方が有意に強く、従って、雌性ラットの方がホルマリン侵害刺激に対する感受性の高いこと確認された。またこの性差はエストロジェン依存性であることがわかった。 2.pCREBによる痛み受容脳領域のマッピングとその経時的変化 雄性ラットおよび発情前期ラットを用いてホルマリンテストを行い、pCREB免疫陽性細胞の発現の変化を、投与前を0分として、5、10,30,120分後に検討した。その結果、分界条床核外側部において、発情前期のラットではpCREB発現が、ホルマリン投与後5分において、有意に増加した。すなわち、行動上の痛覚過敏性と一致して、この領域のCREBがリン酸化されることが明らかとなった。 3.性腺ステロイドホルモンの役割 ホルマリン投与によるpCREB発現に性差の認められた分界条床核外側部において、雌性ラットの性腺を摘除すると反応性が消失し、エストロジェンを補充すると、ホルマリンに対する反応性が回復した。 以上、ホルマリン侵害刺激に対する痛み行動には性差が存在し、分界条床核外側部および側座核が関与すること、その性差は、性腺ステロイドホルモンに対する感受性の性差に起因することが推測された。 さ...
  • ラット前頭前野の各領域における24時間のアセチルコリン分泌動態と性差
    横浜総合医学振興財団:横浜総合医学振興財団萌芽的研究助成
    Date (from‐to) : 2005 -2005 
    Author : 高瀬堅吉
  • 粉エサによる飼育が成熟したラットの脳機能の性差に与える影響
    横浜市立大学:横浜市立大学研究奨励交付金
    Date (from‐to) : 2004 -2004 
    Author : 高瀬堅吉

Teaching Experience

  • biology and neuroscience Ibiology and neuroscience I Keio University

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  • 公認心理師
  • Clinical Developmental Psychologist
  • JPA Certified Psychologist


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