Updated on 2024/06/26

写真a

 
KASAI Atsushi
 
Organization
Research Institute of Environmental Medicine Division of Stress Recognition and Response Professor
Graduate School
Graduate School of Medicine
Title
Professor
External link

Degree 1

  1. Ph.D.(Pharmaceutical Sciences) ( 2007.3   Osaka University ) 

Research Interests 13

  1. psychiatric disorder

  2. 発達障害

  3. claustrum

  4. anxiety

  5. stress

  6. imaging

  7. 社会性行動

  8. 不公平嫌悪

  9. claustrum

  10. psychiatric disorders

  11. brain-wide imaging

  12. stress

  13. emotion

Research Areas 2

  1. Life Science / Neuroscience-general

  2. Life Science / Pharmacology

Research History 7

  1. Nagoya University   Research Institute of Environmental Medicine Division of Stress Recognition and Response   Professor

    2024.4

  2. Osaka University   Associate professor

    2020.6 - 2024.3

  3. Osaka University   Lecturer

    2020.4 - 2020.6

  4. Osaka University   Assistant Professor

    2014.9 - 2020.3

  5. Osaka University   Designated assistant professor

    2012.5 - 2014.9

  6. University of California, Los Angeles   Postdoctoral researcher

    2011.4 - 2012.4

  7. Setsunan University   Assistant Professor

    2007.4 - 2011.3

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Education 2

  1. Osaka University

    2002.4 - 2007.3

  2. University of Shizuoka

    1997.4 - 2002.3

Professional Memberships 5

  1. Japanese Society of Neuropsychopharmacology

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  2. THE JAPANESE SOCIETY FOR NEUROCHEMISTRY

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  3. Society for Neuroscience

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  4. THE PHARMACEUTICAL SOCIETY OF JAPAN

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  5. THE JAPANESE PHARMACOLOGICAL SOCIETY

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Committee Memberships 2

  1. The Japanese Society for Neurochemistry   Publicity Commitee  

    2019.5   

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    Committee type:Academic society

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  2. The Japanese Pharmacological Society   Fellow  

    2012   

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    Committee type:Academic society

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Awards 7

  1. 日本薬学会薬理系薬学部会奨励賞

    2022.8   日本薬学会  

  2. 日本神経化学会優秀賞

    2022.7   日本神経化学会  

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    Award type:Award from Japanese society, conference, symposium, etc. 

  3. 第10回武田科学振興財団 薬科学シンポジウム Excellent Poster Award

    2020.1   武田科学振興財団  

    笠井淳司

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  4. Young Investigator's Award

    2014.12   Comprehensive Brain Science Network  

    Kasai Atsushi

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  5. 大阪大学総長奨励賞

    2014.7   大阪大学  

  6. Young Researcher’s Award

    2011.7   The Pharmaceutical Society of Japan  

    Kasai Atsushi

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  7. 日本血管生物医学会Young Investigator Award

    2010.12   日本血管生物医学会  

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Papers 71

  1. (R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice. Reviewed International journal

    Rei Yokoyama, Yukio Ago, Hisato Igarashi, Momoko Higuchi, Masato Tanuma, Yuto Shimazaki, Takafumi Kawai, Kaoru Seiriki, Misuzu Hayashida, Shun Yamaguchi, Hirokazu Tanaka, Takanobu Nakazawa, Yasushi Okamura, Kenji Hashimoto, Atsushi Kasai, Hitoshi Hashimoto

    Molecular psychiatry     2024.2

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    Chronic social isolation increases the risk of mental health problems, including cognitive impairments and depression. While subanesthetic ketamine is considered effective for cognitive impairments in patients with depression, the neural mechanisms underlying its effects are not well understood. Here we identified unique activation of the anterior insular cortex (aIC) as a characteristic feature in brain-wide regions of mice reared in social isolation and treated with (R)-ketamine, a ketamine enantiomer. Using fiber photometry recording on freely moving mice, we found that social isolation attenuates aIC neuronal activation upon social contact and that (R)-ketamine, but not (S)-ketamine, is able to counteracts this reduction. (R)-ketamine facilitated social cognition in social isolation-reared mice during the social memory test. aIC inactivation offset the effect of (R)-ketamine on social memory. Our results suggest that (R)-ketamine has promising potential as an effective intervention for social cognitive deficits by restoring aIC function.

    DOI: 10.1038/s41380-024-02419-6

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  2. Molecular basis of astrocyte diversity and morphology across the CNS in health and disease Reviewed International journal

    Fumito Endo, Atsushi Kasai, Joselyn S. Soto, Xinzhu Yu, Zhe Qu, Hitoshi Hashimoto, Viviana Gradinaru, Riki Kawaguchi, Baljit S. Khakh

    Science   Vol. 378 ( 6619 ) page: 514 - +   2022.11

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    Astrocytes, a type of glia, are abundant and morphologically complex cells. Here, we report astrocyte molecular profiles, diversity, and morphology across the mouse central nervous system (CNS). We identified shared and region-specific astrocytic genes and functions and explored the cellular origins of their regional diversity. We identified gene networks correlated with astrocyte morphology, several of which unexpectedly contained Alzheimer’s disease (AD) risk genes. CRISPR/Cas9–mediated reduction of candidate genes reduced astrocyte morphological complexity and resulted in cognitive deficits. The same genes were down-regulated in human AD, in an AD mouse model that displayed reduced astrocyte morphology, and in other human brain disorders. We thus provide comprehensive molecular data on astrocyte diversity and mechanisms across the CNS and on the molecular basis of astrocyte morphology in health and disease.

    DOI: 10.1126/science.adc9020

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  3. Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses. Reviewed International journal

    Misaki Niu, Atsushi Kasai, Masato Tanuma, Kaoru Seiriki, Hisato Igarashi, Takahiro Kuwaki, Kazuki Nagayasu, Keita Miyaji, Hiroki Ueno, Wataru Tanabe, Kei Seo, Rei Yokoyama, Jin Ohkubo, Yukio Ago, Misuzu Hayashida, Ken-Ichi Inoue, Masahiko Takada, Shun Yamaguchi, Takanobu Nakazawa, Shuji Kaneko, Hiroyuki Okuno, Akihiro Yamanaka, Hitoshi Hashimoto

    Science Advances   Vol. 8 ( 11 ) page: eabi6375   2022.3

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    The processing of stress responses involves brain-wide communication among cortical and subcortical regions; however, the underlying mechanisms remain elusive. Here, we show that the claustrum (CLA) is crucial for the control of stress-induced anxiety-related behaviors. A combined approach using brain activation mapping and machine learning showed that the CLA activation serves as a reliable marker of exposure to acute stressors. In TRAP2 mice, which allow activity-dependent genetic labeling, chemogenetic activation of the CLA neuronal ensemble tagged by acute social defeat stress (DS) elicited anxiety-related behaviors, whereas silencing of the CLA ensemble attenuated DS-induced anxiety-related behaviors. Moreover, the CLA received strong input from DS-activated basolateral amygdala neurons, and its circuit-selective optogenetic photostimulation temporarily elicited anxiety-related behaviors. Last, silencing of the CLA ensemble during stress exposure increased resistance to chronic DS. The CLA thus bidirectionally controls stress-induced emotional responses, and its inactivation can serve as a preventative strategy to increase stress resilience.

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  4. Direct visualization of an antidepressant analog using surface-enhanced Raman scattering in the brain Reviewed

    Masato Tanuma, Atsushi Kasai, Kazuki Bando, Naoyuki Kotoku, Kazuo Harada, Masafumi Minoshima, Kosuke Higashino, Atsushi Kimishima, Masayoshi Arai, Yukio Ago, Kaoru Seiriki, Kazuya Kikuchi, Satoshi Kawata, Katsumasa Fujita, Hitoshi Hashimoto

    JCI Insight   Vol. 5 ( 6 )   2020.3

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    DOI: 10.1172/jci.insight.133348

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  5. Whole-brain block-face serial microscopy tomography at subcellular resolution using FAST. Reviewed International journal

    Kaoru Seiriki, Atsushi Kasai, Takanobu Nakazawa, Misaki Niu, Yuichiro Naka, Masato Tanuma, Hisato Igarashi, Kosei Yamaura, Atsuko Hayata-Takano, Yukio Ago, Hitoshi Hashimoto

    Nature protocols   Vol. 14 ( 5 ) page: 1509 - 1529   2019.5

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    Here, we describe an optimized and detailed protocol for block-face serial microscopy tomography (FAST). FAST enables high-speed serial section fluorescence imaging of fixed brains at an axonal spatial resolution and subsequent image data processing. It renders brain-wide anatomical and functional analyses, including structural profiling of nuclear-stained brain at the single-cell level, cell-type-specific mapping with reporter animal brains and neuronal tracing with anterograde/retrograde labeling. Light-sheet fluorescence microscopy of cleared brains is advantageous in regard to imaging speed, but its spatial resolution is generally limited, whereas the opposite is true for conventional confocal microscopy. FAST offers a solution to overcome these technical limitations. This protocol describes detailed procedures for assembling the FAST hardware, sample preparation, imaging and image processing. A single imaging session takes as little as 2.4 h per mouse brain, and sample preparation requires 1 to several days, depending on pretreatments; however, multiple samples can be prepared simultaneously. We anticipate that FAST will contribute to unbiased and hypothesis-free approaches for a better understanding of brain systems.

    DOI: 10.1038/s41596-019-0148-4

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  6. High-Speed and Scalable Whole-Brain Imaging in Rodents and Primates Reviewed

    Kaoru Seiriki, Atsushi Kasai, Takeshi Hashimoto, Wiebke Schulze, Misaki Niu, Shun Yamaguchi, Takanobu Nakazawa, Ken-ichi Inoue, Shiori Uezono, Masahiko Takada, Yuichiro Naka, Hisato Igarashi, Masato Tanuma, James A. Waschek, Yukio Ago, Kenji F. Tanaka, Atsuko Hayata-Takano, Kazuki Nagayasu, Norihito Shintani, Ryota Hashimoto, Yasuto Kunii, Mizuki Hino, Junya Matsumoto, Hirooki Yabe, Takeharu Nagai, Katsumasa Fujita, Toshio Matsuda, Kazuhiro Takuma, Akemichi Baba, Hitoshi Hashimoto

    NEURON   Vol. 94 ( 6 ) page: 1085 - +   2017.6

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    Subcellular resolution imaging of the whole brain and subsequent image analysis are prerequisites for understanding anatomical and functional brain networks. Here, we have developed a very high-speed serial-sectioning imaging system named FAST (block-face serial microscopy tomography), which acquires high-resolution images of a whole mouse brain in a speed range comparable to that of light-sheet fluorescence microscopy. FAST enables complete visualization of the brain at a resolution sufficient to resolve all cells and their subcellular structures. FAST renders unbiased quantitative group comparisons of normal and disease model brain cells for the whole brain at a high spatial resolution. Furthermore, FAST is highly scalable to non-human primate brains and human postmortem brain tissues, and can visualize neuronal projections in a whole adult marmoset brain. Thus, FAST provides new opportunities for global approaches that will allow for a better understanding of brain systems in multiple animal models and in human diseases.

    DOI: 10.1016/j.neuron.2017.05.017

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  7. Clozapine Induces Neuronal Activation in the Medial Prefrontal Cortex in a Projection Target-Biased Manner Reviewed

    Hirato Y., Seiriki K., Kojima L., Yamada S., Rokujo H., Takemoto T., Nakazawa T., Kasai A., Hashimoto H.

    Biological and Pharmaceutical Bulletin   Vol. 47 ( 2 ) page: 478 - 485   2024.2

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    The medial prefrontal cortex (mPFC) is associated with various behavioral controls via diverse projections to cortical and subcortical areas of the brain. Dysfunctions and modulations of this circuitry are related to the pathophysiology of schizophrenia and its pharmacotherapy, respectively. Clozapine is an atypical antipsychotic drug used for treatment-resistant schizophrenia and is known to modulate neuronal activity in the mPFC. However, it remains unclear which prefrontal cortical projections are activated by clozapine among the various projection targets. To identify the anatomical characteristics of neurons activated by clozapine at the mesoscale level, we investigated the brain-wide projection patterns of neurons with clozapine-induced c-Fos expression in the mPFC. Using a whole-brain imaging and virus-mediated genetic tagging of activated neurons, we found that clozapine-responsive neurons in the mPFC had a wide range of projections to the mesolimbic, amygdala and thalamic areas, especially the mediodorsal thalamus. These results may provide key insights into the neuronal basis of the therapeutic action of clozapine.

    DOI: 10.1248/bpb.b23-00835

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  8. Long-lasting anti-despair and anti-anhedonia effects of (S)-norketamine in social isolation-reared mice. Reviewed

    Rei Yokoyama, Momoko Higuchi, Wataru Tanabe, Shinji Tsukada, Hisato Igarashi, Kaoru Seiriki, Takanobu Nakazawa, Atsushi Kasai, Yukio Ago, Hitoshi Hashimoto

    Journal of pharmacological sciences   Vol. 154 ( 2 ) page: 72 - 76   2024.2

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    Alternatives to ketamine without psychotomimetic properties for the treatment of depression have attracted much attention. Here, we examined the anti-despair and anti-anhedonia effects of the ketamine metabolites (S)-norketamine ((S)-NK), (R)-NK, (2S,6S)-hydroxynorketamine, and (2R,6R)-hydroxynorketamine in a mouse model of depression induced by social isolation. All ketamine metabolites examined had acute (30 min after administration) anti-despair-like effects in the forced swim test, but only (S)-NK showed a long-lasting (1 week) effect. Additionally, only (S)-NK improved reduced motivation both 30 min and 24 h after injection in the female encounter test. These results suggest that (S)-NK has potent and long-lasting antidepressant-like effects.

    DOI: 10.1016/j.jphs.2023.12.005

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  9. Activity-dependent organization of prefrontal hub-networks for associative learning and signal transformation. Reviewed International journal

    Masakazu Agetsuma, Issei Sato, Yasuhiro R Tanaka, Luis Carrillo-Reid, Atsushi Kasai, Atsushi Noritake, Yoshiyuki Arai, Miki Yoshitomo, Takashi Inagaki, Hiroshi Yukawa, Hitoshi Hashimoto, Junichi Nabekura, Takeharu Nagai

    Nature communications   Vol. 14 ( 1 ) page: 5996 - 5996   2023.10

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    Abstract

    Associative learning is crucial for adapting to environmental changes. The encoding of associative learning involves the dorso-medial prefrontal cortex (dmPFC), and is underpinned by interactions within the resident neuronal population. However, the nature of this population coding is poorly understood. Here we developed a pipeline for computational dissection and longitudinal two-photon imaging of neural population activities in the mouse dmPFC during fear-conditioning procedures, enabling us to detect learning-dependent changes in the dmPFC topology. Through regularized regression methods and graphical modeling, we found fear conditioning organized neuronal ensembles encoding conditioned responses (CR), with enhancing their coactivity, functional connectivity, and association with conditioned stimuli (CS). This suggests that fear conditioning drives dmPFC reorganization to generate novel associative circuits for CS-to-CR transformation. Importantly, neurons strongly responding to unconditioned stimuli (US) during conditioning anterogradely became a hub of the CR ensemble. Altogether, we demonstrate learning-dependent dynamic modulation of population coding structured on an activity-dependent hub-network formation within the dmPFC.

    Teaser

    Optical and computational dissection uncovered how prefrontal cortical networks are rewired to encode new associative memory

    Significance statement

    Animals learn to adapt to changing environments. Associative learning is one of the simplest types of learning that has been intensively studied over the past century. Recent development in molecular, genetic, and optogenetic methods has enabled the identification of a neural population encoding the associative memory in the brain. However, it remains unclear how information is stored and processed by the neural population to encode and retrieve the associative memory. To investigate the nature of this population coding, we developed an optical and computational dissection method, demonstrating how associative learning drives reorganization of the neural network in the dorso-medial prefrontal cortex and generates novel circuits for associative memory and signal transformation.

    DOI: 10.1038/s41467-023-41547-5

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  10. Dorsal raphe serotonergic neurons preferentially reactivate dorsal dentate gyrus cell ensembles associated with positive experience International journal

    Nagai Yuma, Kisaka Yuri, Nomura Kento, Nishitani Naoya, Andoh Chihiro, Koda Masashi, Kawai Hiroyuki, Seiriki Kaoru, Nagayasu Kazuki, Kasai Atsushi, Shirakawa Hisashi, Nakazawa Takanobu, Hashimoto Hitoshi, Kaneko Shuji

    Cell Reports   Vol. 42 ( 3 ) page: 112149 - 112149   2023.3

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    Major depressive disorder (MDD) is among the most common mental illnesses. Serotonergic (5-HT) neurons are central to the pathophysiology and treatment of MDD. Repeatedly recalling positive episodes is effective for MDD. Stimulating 5-HT neurons of the dorsal raphe nucleus (DRN) or neuronal ensembles in the dorsal dentate gyrus (dDG) associated with positive memories reverses the stress-induced behavioral abnormalities. Despite this phenotypic similarity, their causal relationship is unclear. This study revealed that the DRN 5-HT neurons activate dDG neurons; surprisingly, this activation was specifically observed in positive memory ensembles rather than neutral or negative ensembles. Furthermore, we revealed that dopaminergic signaling induced by activation of DRN 5-HT neurons projecting to the ventral tegmental area mediates an increase in active coping behavior and positive dDG ensemble reactivation. Our study identifies a role of DRN 5-HT neurons as specific reactivators of positive memories and provides insights into how serotonin elicits antidepressive effects.

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  11. High-throughput line-illumination Raman microscopy with multislit detection Reviewed International journal

    Kentaro Mochizuki, Yasuaki Kumamoto, Shunsuke Maeda, Masato Tanuma, Atsushi Kasai, Masashi Takemura, Yoshinori Harada, Hitoshi Hashimoto, Hideo Tanaka, Nicholas Isaac Smith, Katsumasa Fujita

    Biomedical Optics Express   Vol. 14 ( 3 ) page: 1015 - 1026   2023.3

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    Raman microscopy is an emerging tool for molecular imaging and analysis of living samples. Use of Raman microscopy in life sciences is, however, still limited because of its slow measurement speed for spectral imaging and analysis. We developed a multiline-illumination Raman microscope to achieve ultrafast Raman spectral imaging. A spectrophotometer equipped with a periodic array of confocal slits detects Raman spectra from a sample irradiated by multiple line illuminations. A comb-like Raman hyperspectral image is formed on a two-dimensional detector in the spectrophotometer, and a hyperspectral Raman image is acquired by scanning the sample with multiline illumination array. By irradiating a sample with 21 simultaneous illumination lines, we achieved high-throughput Raman hyperspectral imaging of mouse brain tissue, acquiring 1108800 spectra in 11.4 min. We also measured mouse kidney and liver tissue as well as conducted label-free live-cell molecular imaging. The ultrafast Raman hyperspectral imaging enabled by the presented technique will expand the possible applications of Raman microscopy in biological and medical fields.

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    Other Link: https://opg.optica.org/viewmedia.cfm?URI=boe-14-3-1015&seq=0

  12. Pre-treatment of oncolytic reovirus improves tumor accumulation and intratumoral distribution of PEG-liposomes. Reviewed International journal

    Maho Eguchi, Seiya Hirata, Ikuho Ishigami, Naomi Shuwari, Ryosuke Ono, Masashi Tachibana, Masato Tanuma, Atsushi Kasai, Hitoshi Hashimoto, Ken-Ichi Ogawara, Hiroyuki Mizuguchi, Fuminori Sakurai

    Journal of controlled release : official journal of the Controlled Release Society   Vol. 354   page: 35 - 44   2023.2

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    PEGylated liposomes (PEG-liposomes) are a promising drug delivery vehicle for tumor targeting because of their efficient tumor disposition profiles via the enhanced permeability and retention (EPR) effect. However, tumor targeting of PEG-liposomes, particularly their delivery inside the tumors, is often disturbed by physical barriers in the tumor, including tumor cells themselves, extracellular matrices, and interstitial pressures. In this study, B16 melanoma tumor-bearing mice were injected intravenously with oncolytic reovirus before administration of PEG-liposomes to enhance PEG-liposomes' tumor disposition. Three days after reovirus administration, significant expression of reovirus sigma 3 protein, elevation of apoptosis-related gene expression, and activation of caspase 3 in the tumors were found. Apoptotic cells were found inside the tumors. These data indicated that reovirus efficiently replicated in the tumors and induced apoptosis of tumor cells. The tumor disposition levels of PEG-liposomes were approximately doubled by reovirus pre-administration, compared with a PBS-pretreated group. PEG-liposomes were widely distributed in the tumors of reovirus-pretreated mice, whereas in the PBS-pretreated group, PEG-liposomes were found mainly around or inside the blood vessels in the tumors. Pre-treatment with reovirus also improved the tumor accumulation of PEG-liposomes in human pancreatic BxPC-3 tumors. 3D imaging analysis of whole BxPC-3 tumors demonstrated that pretreatment with reovirus led to the enhancement of PEG-liposome accumulation inside the tumors. Combination treatment with reovirus and paclitaxel-loaded PEG-liposomes (PTX-PEG-liposomes) significantly suppressed B16 tumor growth. These results provide important information for clinical use of combination therapy of reovirus and nanoparticle-based drug delivery system (DDS).

    DOI: 10.1016/j.jconrel.2022.12.050

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  13. Decreased Expression of EP3 Receptor mRNA in the Brain of Mouse Model of Autism Spectrum Disorder. Reviewed International journal

    Kusnandar Anggadiredja, Neng Fisheri Kurniati, Atsushi Kasai, Hitoshi Hashimoto

    MicroRNA (Shariqah, United Arab Emirates)   Vol. 12 ( 3 ) page: 221 - 226   2023

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    BACKGROUND: Accumulating evidence has implicated the role of neuroinflammation in the pathology of autism spectrum disorder (ASD), a neurodevelopmental disorder. OBJECTIVES: To investigate the expression of prostaglandin EP3 (EP3) receptor mRNA in the brain of ASD mouse model. METHODS: Pregnant mice were injected with valproic acid (VPA) 500 mg/kg intraperitoneally at 12.5 d gestation. The offspring were tested at the age of 5-6 weeks old for their social interaction behavior. Each mouse was assessed for prostaglandin EP3 receptor expression in the prefrontal cortical, hippocampal and cerebellar areas one day after the behavioral test. RESULTS: Compared to the naive, mice born to dams treated with VPA demonstrated a significantly shorter duration of sniffing behavior, a model of social interaction. Results further showed that the expression of EP3 receptor mRNA was significantly lower in all three brain regions of the mice born to VPA-treated dams. CONCLUSION: The present study provides further evidence of the relevance of the arachidonic acid cascade as an essential part of neuroinflammation in the pathology of ASD.

    DOI: 10.2174/2211536612666230427152647

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  14. Parabrachial-to-parasubthalamic nucleus pathway mediates fear-induced suppression of feeding in male mice. Reviewed International journal

    Takashi Nagashima, Suguru Tohyama, Kaori Mikami, Masashi Nagase, Mieko Morishima, Atsushi Kasai, Hitoshi Hashimoto, Ayako M Watabe

    Nature Communications   Vol. 13 ( 1 ) page: 7913 - 7913   2022.12

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    Feeding behavior is adaptively regulated by external and internal environment, such that feeding is suppressed when animals experience pain, sickness, or fear. While the lateral parabrachial nucleus (lPB) plays key roles in nociception and stress, neuronal pathways involved in feeding suppression induced by fear are not fully explored. Here, we investigate the parasubthalamic nucleus (PSTN), located in the lateral hypothalamus and critically involved in feeding behaviors, as a target of lPB projection neurons. Optogenetic activation of lPB-PSTN terminals in male mice promote avoidance behaviors, aversive learning, and suppressed feeding. Inactivation of the PSTN and lPB-PSTN pathway reduces fear-induced feeding suppression. Activation of PSTN neurons expressing pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide enriched in the PSTN, is sufficient for inducing avoidance behaviors and feeding suppression. Blockade of PACAP receptors impaires aversive learning induced by lPB-PSTN photomanipulation. These findings indicate that lPB-PSTN pathway plays a pivotal role in fear-induced feeding suppression.

    DOI: 10.1038/s41467-022-35634-2

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  15. Acute social defeat stress activated neurons project to the claustrum and basolateral amygdala. Reviewed International journal

    Masato Tanuma, Misaki Niu, Jin Ohkubo, Hiroki Ueno, Yuka Nakai, Yoshihisa Yokoyama, Kaoru Seiriki, Hitoshi Hashimoto, Atsushi Kasai

    Molecular Brain   Vol. 15 ( 1 ) page: 100 - 100   2022.12

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    We recently reported that a neuronal population in the claustrum (CLA) identified under exposure to psychological stressors plays a key role in stress response processing. Upon stress exposure, the main inputs to the CLA come from the basolateral amygdala (BLA); however, the upstream brain regions that potentially regulate both the CLA and BLA during stressful experiences remain unclear. Here by combining activity-dependent viral retrograde labeling with whole brain imaging, we analyzed neurons projecting to the CLA and BLA activated by exposure to social defeat stress. The labeled CLA projecting neurons were mostly ipsilateral, excluding the prefrontal cortices, which had a distinctly labeled population in the contralateral hemisphere. Similarly, the labeled BLA projecting neurons were predominantly ipsilateral, aside from the BLA in the opposite hemisphere, which also had a notably labeled population. Moreover, we found co-labeled double-projecting single neurons in multiple brain regions such as the ipsilateral ectorhinal/perirhinal cortex, entorhinal cortex, and the contralateral BLA. These results suggest that CLA and BLA receive inputs from neuron collaterals in various brain regions during stress, which may regulate the CLA and BLA forming in a stress response circuitry.

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  16. Oxytocin ameliorates impaired social behavior in a mouse model of 3q29 deletion syndrome. Reviewed International journal

    Tomoya Takemoto, Masayuki Baba, Kazumasa Yokoyama, Kohei Kitagawa, Kazuki Nagayasu, Yukio Ago, Kaoru Seiriki, Atsuko Hayata-Takano, Atsushi Kasai, Daisuke Mori, Norio Ozaki, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa

    Molecular Brain   Vol. 15 ( 1 ) page: 26 - 26   2022.3

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    Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by specific social symptoms, restricted interests, stereotyped repetitive behaviors, and delayed language development. The 3q29 microdeletion (3q29del), a recurrent copy number variant, confers a high risk for ASD and schizophrenia, and serves as an important pathological model for investigating the molecular pathogenesis of a large number of neurodevelopmental and psychiatric conditions. Recently, mouse models carrying a deletion of the chromosomal region corresponding to the human 3q29 region (Df/+ mice) were generated and demonstrated neurodevelopmental and psychiatric conditions associated behavioral abnormalities, pointing to the relevance of Df/+ mice as a model for these conditions with high construct and face validity. Currently, the molecular pathogenesis of these behavioral phenotypes in Df/+ mice remains unclear. The oxytocin (OXT) system plays a central role in social behavior across species and has a potential role in ASD. In this study, to elucidate the molecular mechanisms behind impaired social behavior in Df/+ mice, we investigated the possible involvement of OXT signaling in impaired social behavior in Df/+ mice. We demonstrated that OXT administration restored the impaired social behavior in Df/+ mice. We also demonstrated that the number of OXT-positive cells in the paraventricular nucleus (PVN) was significantly lower in Df/+ mice than in wild-type (WT) littermates. Consistent with this, the level of OXT peptide in the cerebral cortex of Df/+ mice was lower than in WT littermates. Our study may provide important insights into the molecular pathophysiological basis of neurodevelopmental and psychiatric conditions, including ASD.

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  17. Multiple alterations in glutamatergic transmission and dopamine D2 receptor splicing in induced pluripotent stem cell-derived neurons from patients with familial schizophrenia. Reviewed International journal

    Kana Yamamoto, Toshihiko Kuriu, Kensuke Matsumura, Kazuki Nagayasu, Yoshinori Tsurusaki, Noriko Miyake, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Mikiya Fujiwara, Masayuki Baba, Kohei Kitagawa, Tomoya Takemoto, Nanaka Gotoda-Nishimura, Tomohiro Takada, Kaoru Seiriki, Atsuko Hayata-Takano, Atsushi Kasai, Yukio Ago, Satoshi Kida, Kazuhiro Takuma, Fumihito Ono, Naomichi Matsumoto, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa

    Translational Psychiatry   Vol. 11 ( 1 ) page: 548 - 548   2021.10

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    An increasing body of evidence suggests that impaired synapse development and function are associated with schizophrenia; however, the underlying molecular pathophysiological mechanism of the disease remains largely unclear. We conducted a family-based study combined with molecular and cellular analysis using induced pluripotent stem cell (iPSC) technology. We generated iPSCs from patients with familial schizophrenia, differentiated these cells into neurons, and investigated the molecular and cellular phenotypes of the patient's neurons. We identified multiple altered synaptic functions, including increased glutamatergic synaptic transmission, higher synaptic density, and altered splicing of dopamine D2 receptor mRNA in iPSC-derived neurons from patients. We also identified patients' specific genetic mutations using whole-exome sequencing. Our findings support the notion that altered synaptic function may underlie the molecular and cellular pathophysiology of schizophrenia, and that multiple genetic factors cooperatively contribute to the development of schizophrenia.

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  18. Exploring rare cellular activity in more than one million cells by a transscale scope. Reviewed International journal

    T Ichimura, T Kakizuka, K Horikawa, K Seiriki, A Kasai, H Hashimoto, K Fujita, T M Watanabe, T Nagai

    Scientific Reports   Vol. 11 ( 1 ) page: 16539 - 16539   2021.8

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    In many phenomena of biological systems, not a majority, but a minority of cells act on the entire multicellular system causing drastic changes in the system properties. To understand the mechanisms underlying such phenomena, it is essential to observe the spatiotemporal dynamics of a huge population of cells at sub-cellular resolution, which is difficult with conventional tools such as microscopy and flow cytometry. Here, we describe an imaging system named AMATERAS that enables optical imaging with an over-one-centimeter field-of-view and a-few-micrometer spatial resolution. This trans-scale-scope has a simple configuration, composed of a low-power lens for machine vision and a hundred-megapixel image sensor. We demonstrated its high cell-throughput, capable of simultaneously observing more than one million cells. We applied it to dynamic imaging of calcium ions in HeLa cells and cyclic-adenosine-monophosphate in Dictyostelium discoideum, and successfully detected less than 0.01% of rare cells and observed multicellular events induced by these cells.

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  19. Comprehensive characterization of migration profiles of murine cerebral cortical neurons during development using FlashTag labeling. Reviewed International journal

    Satoshi Yoshinaga, Minkyung Shin, Ayako Kitazawa, Kazuhiro Ishii, Masato Tanuma, Atsushi Kasai, Hitoshi Hashimoto, Ken-Ichiro Kubo, Kazunori Nakajima

    iScience   Vol. 24 ( 4 ) page: 102277 - 102277   2021.4

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    In the mammalian cerebral neocortex, different regions have different cytoarchitecture, neuronal birthdates, and functions. In most regions, neuronal migratory profiles are speculated similar based on observations using thymidine analogs. Few reports have investigated regional migratory differences from mitosis at the ventricular surface. In this study, we applied FlashTag technology, in which dyes are injected intraventricularly, to describe migratory profiles. We revealed a mediolateral regional difference in the migratory profiles of neurons that is dependent on developmental stage; for example, neurons labeled at embryonic day 12.5-15.5 reached their destination earlier dorsomedially than dorsolaterally, even where there were underlying ventricular surfaces, reflecting sojourning below the subplate. This difference was hardly recapitulated by thymidine analogs, which visualize neurogenic gradients, suggesting a biological significance different from the neurogenic gradient. These observations advance our understanding of cortical development and the power of FlashTag in studying migration and are thus resources for future neurodevelopmental studies.

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  20. Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder. Reviewed International journal

    Kohei Kitagawa, Kensuke Matsumura, Masayuki Baba, Momoka Kondo, Tomoya Takemoto, Kazuki Nagayasu, Yukio Ago, Kaoru Seiriki, Atsuko Hayata-Takano, Atsushi Kasai, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa

    Molecular Brain   Vol. 14 ( 1 ) page: 56 - 56   2021.3

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    Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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  21. Altered Functional Connectivity of the Orbital Cortex and Striatum Associated with Catalepsy Induced by Dopamine D1 and D2 Antagonists

    Niu Misaki, Kasai Atsushi, Seiriki Kaoru, Hayashida Misuzu, Tanuma Masato, Yokoyama Rei, Hirato Yumi, Hashimoto Hitoshi

    Biological and Pharmaceutical Bulletin   Vol. 44 ( 3 ) page: 442 - 447   2021.3

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    <p>The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166- and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166- and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166- and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.</p>

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  22. Lipocalin-type prostaglandin D synthase regulates light-induced phase advance of the central circadian rhythm in mice. Reviewed International journal

    Chihiro Kawaguchi, Norihito Shintani, Atsuko Hayata-Takano, Michiyoshi Hatanaka, Ai Kuromi, Reiko Nakamura, Yui Yamano, Yusuke Shintani, Katsuya Nagai, Soken Tsuchiya, Yukihiko Sugimoto, Atsushi Ichikawa, Yasushi Okuno, Yoshihiro Urade, Hiroyuki Hirai, Kin-Ya Nagata, Masataka Nakamura, Shuh Narumiya, Takanobu Nakazawa, Atsushi Kasai, Yukio Ago, Kazuhiro Takuma, Akemichi Baba, Hitoshi Hashimoto

    Communications Biology   Vol. 3 ( 1 ) page: 557 - 557   2020.10

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    We previously showed that mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) exhibit attenuated light-induced phase shift. To explore the underlying mechanisms, we performed gene expression analysis of laser capture microdissected suprachiasmatic nuclei (SCNs) and found that lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is involved in the impaired response to light stimulation in the late subjective night in PACAP-deficient mice. L-PGDS-deficient mice also showed impaired light-induced phase advance, but normal phase delay and nonvisual light responses. Then, we examined the receptors involved in the response and observed that mice deficient for type 2 PGD2 receptor DP2/CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) show impaired light-induced phase advance. Concordant results were observed using the selective DP2/CRTH2 antagonist CAY10471. These results indicate that L-PGDS is involved in a mechanism of light-induced phase advance via DP2/CRTH2 signaling.

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  23. (S)-norketamine and (2S,6S)-hydroxynorketamine exert potent antidepressant-like effects in a chronic corticosterone-induced mouse model of depression. Reviewed International journal

    Rei Yokoyama, Momoko Higuchi, Wataru Tanabe, Shinji Tsukada, Megumi Naito, Takumi Yamaguchi, Lu Chen, Atsushi Kasai, Kaoru Seiriki, Takanobu Nakazawa, Shinsaku Nakagawa, Kenji Hashimoto, Hitoshi Hashimoto, Yukio Ago

    Pharmacology, Biochemistry, and Behavior   Vol. 191   page: 172876 - 172876   2020.4

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    Clinical and preclinical studies have shown that the N-methyl-d-aspartate receptor antagonist ketamine exerts rapid and long-lasting antidepressant effects. Although ketamine metabolites might also have potential antidepressant properties, controversial results have been reported for (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) in particular, and there is little information regarding the effects of other ketamine metabolites. Here we aimed to compare the effects of (R)-norketamine ((R)-NK), (S)-NK, (2R,6R)-HNK, and (2S,6S)-HNK in a mouse model of depression induced by chronic corticosterone (CORT) injection. None of the ketamine metabolites at doses up to 20 mg/kg showed antidepressant-like activity in naïve male C57BL6/J mice. Chronic CORT treatment increased immobility in the forced swim test and caused anhedonic-like behaviors in the female encounter test. A single administration of (S)-NK and (2S,6S)-HNK dose-dependently reduced the enhanced immobility at 30 min after injection in chronic CORT-treated mice, while (R)-NK or (2R,6R)-HNK did not. Additionally, (S)-NK and (2S,6S)-HNK, but not (R)-NK or (2R,6R)-HNK, improved chronic CORT-induced anhedonia at 24 h after the injection. These results suggest that (S)-ketamine metabolites (S)-NK and (2S,6S)-HNK have potent acute and sustained antidepressant effects in rodents.

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  24. Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes. Reviewed International journal

    Kensuke Matsumura, Kaoru Seiriki, Shota Okada, Masashi Nagase, Shinya Ayabe, Ikuko Yamada, Tamio Furuse, Hirotoshi Shibuya, Yuka Yasuda, Hidenaga Yamamori, Michiko Fujimoto, Kazuki Nagayasu, Kana Yamamoto, Kohei Kitagawa, Hiroki Miura, Nanaka Gotoda-Nishimura, Hisato Igarashi, Misuzu Hayashida, Masayuki Baba, Momoka Kondo, Shigeru Hasebe, Kosei Ueshima, Atsushi Kasai, Yukio Ago, Atsuko Hayata-Takano, Norihito Shintani, Tokuichi Iguchi, Makoto Sato, Shun Yamaguchi, Masaru Tamura, Shigeharu Wakana, Atsushi Yoshiki, Ayako M Watabe, Hideyuki Okano, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa

    Nature Communications   Vol. 11 ( 1 ) page: 859 - 859   2020.2

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    Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD.

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  25. Autism-associated protein kinase D2 regulates embryonic cortical neuron development. Reviewed International journal

    Kensuke Matsumura, Masayuki Baba, Kazuki Nagayasu, Kana Yamamoto, Momoka Kondo, Kohei Kitagawa, Tomoya Takemoto, Kaoru Seiriki, Atsushi Kasai, Yukio Ago, Atsuko Hayata-Takano, Norihito Shintani, Toshihiko Kuriu, Tokuichi Iguchi, Makoto Sato, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa

    Biochemical and Biophysical Research Communications   Vol. 519 ( 3 ) page: 626 - 632   2019.11

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    Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder, characterized by impaired social interaction, repetitive behavior and restricted interests. Although the molecular etiology of ASD remains largely unknown, recent studies have suggested that de novo mutations are significantly involved in the risk of ASD. We and others recently identified spontaneous de novo mutations in PKD2, a protein kinase D family member, in sporadic ASD cases. However, the biological significance of the de novo PKD2 mutations and the role of PKD2 in brain development remain unclear. Here, we performed functional analysis of PKD2 in cortical neuron development using in utero electroporation. PKD2 is highly expressed in cortical neural stem cells in the developing cortex and regulates cortical neuron development, including the neuronal differentiation of neural stem cells and migration of newborn neurons. Importantly, we determined that the ASD-associated de novo mutations impair the kinase activity of PKD2, suggesting that the de novo PKD2 mutations can be a risk factor for the disease by loss of function of PKD2. Our current findings provide novel insight into the molecular and cellular pathogenesis of ASD.

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  26. Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome. Reviewed International journal

    Masayuki Baba, Kazumasa Yokoyama, Kaoru Seiriki, Yuichiro Naka, Kensuke Matsumura, Momoka Kondo, Kana Yamamoto, Misuzu Hayashida, Atsushi Kasai, Yukio Ago, Kazuki Nagayasu, Atsuko Hayata-Takano, Akinori Takahashi, Shun Yamaguchi, Daisuke Mori, Norio Ozaki, Tadashi Yamamoto, Kazuhiro Takuma, Ryota Hashimoto, Hitoshi Hashimoto, Takanobu Nakazawa

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology   Vol. 44 ( 12 ) page: 2125 - 2135   2019.11

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    3q29 microdeletion, a rare recurrent copy number variant (CNV), greatly confers an increased risk of psychiatric disorders, such as schizophrenia and autism spectrum disorder (ASD), as well as intellectual disability. However, disease-relevant cellular phenotypes of 3q29 deletion syndrome remain to be identified. To reveal the molecular and cellular etiology of 3q29 deletion syndrome, we generated a mouse model of human 3q29 deletion syndrome by chromosome engineering, which achieved construct validity. 3q29 deletion (Df/+) mice showed reduced body weight and brain volume and, more importantly, impaired social interaction and prepulse inhibition. Importantly, the schizophrenia-related impaired prepulse inhibition was reversed by administration of antipsychotics. These findings are reminiscent of the growth defects and neuropsychiatric behavioral phenotypes in patients with 3q29 deletion syndrome and exemplify that the mouse model achieves some part of face validity and predictive validity. Unbiased whole-brain imaging revealed that neuronal hyperactivation after a behavioral task was strikingly exaggerated in a restricted region of the cortex of Df/+ mice. We further elucidated the cellular phenotypes of neuronal hyperactivation and the reduction of parvalbumin expression in the cortex of Df/+ mice. Thus, the 3q29 mouse model provides invaluable insight into the disease-causative molecular and cellular pathology of psychiatric disorders.

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  27. (R)-Ketamine Induces a Greater Increase in Prefrontal 5-HT Release Than (S)-Ketamine and Ketamine Metabolites via an AMPA Receptor-Independent Mechanism. Reviewed International journal

    Yukio Ago, Wataru Tanabe, Momoko Higuchi, Shinji Tsukada, Tatsunori Tanaka, Takumi Yamaguchi, Hisato Igarashi, Rei Yokoyama, Kaoru Seiriki, Atsushi Kasai, Takanobu Nakazawa, Shinsaku Nakagawa, Kenji Hashimoto, Hitoshi Hashimoto

    The International Journal of Neuropsychopharmacology   Vol. 22 ( 10 ) page: 665 - 674   2019.10

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    BACKGROUND: Although recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine's action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine [(R)-NK], (S)-NK, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex of mice. METHODS: The extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis. RESULTS: (R)-Ketamine and (S)-ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of (R)-ketamine was greater than that of (S)-ketamine. In contrast, (S)-ketamine caused a robust increase in dopamine release compared with (R)-ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ. (2R,6R)-HNK caused a slight but significant increase in serotonin and noradrenaline but not dopamine release. (S)-NK increased dopamine and noradrenaline but not serotonin release. Differential effects between (R)-ketamine and (S)-ketamine were also observed in a lipopolysaccharide-induced model of depression. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4- tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), attenuated (S)-ketamine-induced, but not (R)-ketamine-induced serotonin release, whereas NBQX blocked dopamine release induced by both enantiomers. Local application of (R)-ketamine into the prefrontal cortex caused a greater increase in prefrontal serotonin release than that of (S)-ketamine. CONCLUSIONS: (R)-Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism. (S)-Ketamine-induced serotonin and dopamine release was AMPA receptor-dependent. These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites.

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  28. Pituitary Adenylate Cyclase-Activating Polypeptide Modulates Dendritic Spine Maturation and Morphogenesis via MicroRNA-132 Upregulation. Reviewed International journal

    Atsuko Hayata-Takano, Toshihiko Kamo, Harui Kijima, Kaoru Seiriki, Katsuya Ogata, Yukio Ago, Takanobu Nakazawa, Yusuke Shintani, Kosuke Higashino, Kazuki Nagayasu, Norihito Shintani, Atsushi Kasai, James A Waschek, Hitoshi Hashimoto

    The Journal of neuroscience : the official journal of the Society for Neuroscience   Vol. 39 ( 22 ) page: 4208 - 4220   2019.5

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    Alterations in pituitary adenylate cyclase-activating polypeptide (PACAP), a multifunctional neuropeptide, and its receptors have been identified as risk factors for certain psychiatric disorders, including schizophrenia. Increasing evidence from human genetic and animal model studies suggest an association between various psychiatric disorders and altered dendritic spine morphology. In the present study, we investigated the role of exogenous and endogenous PACAP in spine formation and maturation. PACAP modified the density and morphology of PSD-95-positive spines in primary cultured hippocampal neurons. Notably, PACAP increased the levels of microRNA (miR)-132 and decreased expression of corresponding miR-132 target genes and protein expression of p250GAP, a miR-132 effector known to be involved in spine morphology regulation. In corroboration, PSD-95-positive spines were reduced in PACAP-deficient (PACAP-/-) mice versus WT mice. Golgi staining of hippocampal CA1 neurons revealed a reduced spine densities and atypical morphologies in the male PACAP-/- mice. Furthermore, viral miR-132 overexpression reversed the reduction in hippocampal spinal density in the male PACAP-/- mice. These results indicate that PACAP signaling plays a critical role in spine morphogenesis possibly via miR-132. We suggest that dysfunction of PACAP signaling may contribute to the pathogenesis of neuropsychiatric disorders, at least partly through its effects on spine formation.SIGNIFICANCE STATEMENT Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling dysfunction and dendritic spine morphology alterations have recently been suggested as important pathophysiological mechanisms underlying several psychiatric and neurological disorders. In this study, we investigated whether PACAP regulates dendritic spine morphogenesis. In a combination of pharmacological and viral gain- and loss-of-function approaches in vitro and in vivo experiments, we found PACAP to increase the size and density of dendritic spines via miR-132 upregulation. Together, our data suggest that a dysfunction of PACAP signaling may contribute to the pathogenesis of neuropsychiatric disorders, at least partly through abnormal spine formation.

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  29. mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model. Reviewed International journal

    Kawase H, Ago Y, Naito M, Higuchi M, Hara Y, Hasebe S, Tsukada S, Kasai A, Nakazawa T, Mishina T, Kouji H, Takuma K, Hashimoto H

    Pharmacology, biochemistry, and behavior   Vol. 176   page: 1 - 5   2019.1

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    Growing evidence suggests pivotal roles for epigenetic mechanisms in both animal models of and individuals with autism spectrum disorders (ASD). Neuron-restrictive silencer factor (NRSF) binds to neuron-restrictive silencing elements in neuronal genes and recruits co-repressors, such as mSin3, to epigenetically inhibit neuronal gene expression. Because dysregulation of NRSF is related to ASD, here we examined the effects of mS-11, a chemically optimized mimetic of the mSin3-binding helix in NRSF, on the behavioral and morphological abnormalities found in a mouse model of valproic acid (VPA)-induced ASD. Chronic treatment with mS-11 improved prenatal VPA-induced deficits in social interaction. Additionally, we found that NRSF mRNA expression was greater in the somatosensory cortex of VPA-exposed mice than of controls. Agreeing with these behavioral findings, mice that were prenatally exposed to VPA showed lower dendritic spine density in the somatosensory cortex, which was reversed by chronic treatment with mS-11. These findings suggest that mS-11 has the potential for improving ASD-related symptoms through inhibition of mSin3-NRSF binding.

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  30. Whole-brain activity mapping at single-cell resolution

    Kasai Atsushi, Seiriki Kaoru, Hashimoto Hitoshi

    Folia Pharmacologica Japonica   Vol. 153 ( 6 ) page: 278 - 283   2019

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    <p>The neuronal activity forms the basis of functional circuits and brain functions. To understand how the brain operates, recording of neural activity at micro-, meso-, and macro-scales is required. Recently, improved optical microscopic technology helps us to develop a whole-brain imaging system at a single-cell resolution. The combination of a whole-brain imaging system and a reporter system of neuronal activation enables a whole-brain mapping of neuronal activity. In this review, we first describe the high-speed and scalable whole-brain imaging system including our recently developed system, named FAST, and then present the instances of whole-brain mapping of neuronal activity and its analytical methods.</p>

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  31. Saturated excitation microscopy using differential excitation for efficient detection of nonlinear fluorescence signals Reviewed

    Yasunori Nawa, Yasuo Yonemaru, Atsushi Kasai, Ryosuke Oketani, Hitoshi Hashimoto, Nicholas I. Smith, Katsumasa Fujita

    APL Photonics   Vol. 3 ( 8 ) page: 080805 - 080805   2018.8

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  32. β-Arrestin1 and 2 differentially regulate PACAP-induced PAC1 receptor signaling and trafficking. Reviewed International journal

    Yusuke Shintani, Atsuko Hayata-Takano, Keita Moriguchi, Takanobu Nakazawa, Yukio Ago, Atsushi Kasai, Kaoru Seiriki, Norihito Shintani, Hitoshi Hashimoto

    PloS one   Vol. 13 ( 5 ) page: e0196946   2018.5

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    A pituitary adenylate cyclase-activating polypeptide (PACAP)-specific receptor, PAC1R, is coupled with multiple signal transduction pathways including stimulation of adenylate cyclase, phospholipase C and extracellular-signal regulated kinase (ERK)1/2. PAC1R has been shown to exert its long-lasting and potent signals via β-arrestin1 and β-arrestin2. However, the precise roles of the two β-arrestin isoforms in PACAP-PAC1R signaling remain unclear. Here we examined the interaction between the two β-arrestin isoforms and PAC1R, β-arrestin-dependent PAC1R subcellular localization and ERK1/2 activation. Upon PACAP stimulation, although PAC1R similarly interacted with β-arrestin1 and β-arrestin2 in HEK293T cells, the complex of PAC1R and β-arrestin2 was translocated from the cell surface into cytosol, but that of β-arrestin1 remained in the cell surface regions in HeLa cells and mouse primary cultured neurons. Silencing of β-arrestin2 blocked PACAP-induced PAC1R internalization and ERK1/2 phosphorylation, but silencing of β-arrestin1 increased ERK1/2 phosphorylation. These results show that β-arrestin1 and β-arrestin2 exert differential actions on PAC1R internalization and PAC1R-dependent ERK1/2 activation, and suggest that the two β-arrestin isoforms may be involved in fine and precise tuning of the PAC1R signaling pathways.

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  33. Knockdown of the mitochondria-localized protein p13 protects against experimental parkinsonism Reviewed

    Naoki Inoue, Sae Ogura, Atsushi Kasai, Takanobu Nakazawa, Kazuya Ikeda, Shintaro Higashi, Ayako Isotani, Kousuke Baba, Hideki Mochizuki, Harutoshi Fujimura, Yukio Ago, Atsuko Hayata-Takano, Kaoru Seiriki, Yusuke Shintani, Norihito Shintani, Hitoshi Hashimoto

    EMBO Reports   Vol. 19 ( 3 )   2018.3

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    Mitochondrial dysfunction in the nigrostriatal dopaminergic system is a critical hallmark of Parkinson's disease (PD). Mitochondrial toxins produce cellular and behavioural dysfunctions resembling those in patients with PD. Causative gene products for familial PD play important roles in mitochondrial function. Therefore, targeting proteins that regulate mitochondrial integrity could provide convincing strategies for PD therapeutics. We have recently identified a novel 13-kDa protein (p13) that may be involved in mitochondrial oxidative phosphorylation. In the current study, we examine the mitochondrial function of p13 and its involvement in PD pathogenesis using mitochondrial toxin-induced PD models. We show that p13 overexpression induces mitochondrial dysfunction and apoptosis. p13 knockdown attenuates toxin-induced mitochondrial dysfunction and apoptosis in dopaminergic SH-SY5Y cells via the regulation of complex I. Importantly, we generate p13-deficient mice using the CRISPR/Cas9 system and observe that heterozygous p13 knockout prevents toxin-induced motor deficits and the loss of dopaminergic neurons in the substantia nigra. Taken together, our results suggest that manipulating p13 expression may be a promising avenue for therapeutic intervention in PD.

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  34. Unbiased compound screening with a reporter gene assay highlights the role of p13 in the cardiac cellular stress response. Reviewed International journal

    Inoue N, Hirouchi T, Kasai A, Higashi S, Hiraki N, Tanaka S, Nakazawa T, Nunomura K, Lin B, Omori A, Hayata-Takano A, Kim YJ, Doi T, Baba A, Hashimoto H, Shintani N

    Biochemical and biophysical research communications   Vol. 495 ( 2 ) page: 1992 - 1997   2018.1

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    We recently showed that a 13-kDa protein (p13), the homolog protein of formation of mitochondrial complex V assembly factor 1 in yeast, acts as a potential protective factor in pancreatic islets under diabetes. Here, we aimed to identify known compounds regulating p13 mRNA expression to obtain therapeutic insight into the cellular stress response. A luciferase reporter system was developed using the putative promoter region of the human p13 gene. Overexpression of peroxisome proliferator-activated receptor gamma coactivator 1α, a master player regulating mitochondrial metabolism, increased both reporter activity and p13 expression. Following unbiased screening with 2320 known compounds in HeLa cells, 12 pharmacological agents (including 8 cardiotonics and 2 anthracyclines) that elicited >2-fold changes in p13 mRNA expression were identified. Among them, four cardiac glycosides decreased p13 expression and concomitantly elevated cellular oxidative stress. Additional database analyses showed highest p13 expression in heart, with typically decreased expression in cardiac disease. Accordingly, our results illustrate the usefulness of unbiased compound screening as a method for identifying novel functional roles of unfamiliar genes. Our findings also highlight the importance of p13 in the cellular stress response in heart.

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  35. Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells frommonozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine Reviewed

    Takanobu Nakazawa, Masataka Kikuchi, Mitsuru Ishikawa, Hidenaga Yamamori, Kazuki Nagayasu, Takuya Matsumoto, Michiko Fujimoto, Yuka Yasuda, Mikiya Fujiwara, Shota Okada, Kensuke Matsumura, Atsushi Kasai, Atsuko Hayata-Takano, Norihito Shintani, Shusuke Numata, Kazuhiro Takuma, Wado Akamatsu, Hideyuki Okano, Akihiro Nakaya, Hitoshi Hashimoto, Ryota Hashimoto

    SCHIZOPHRENIA RESEARCH   Vol. 181   page: 75 - 82   2017.3

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    Schizophrenia is a chronic psychiatric disorderwith complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair ofmonozygotic twin caseswith treatment-resistant schizophrenia, inwhich one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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  36. ASD-Associated De Novo Mutations in POGZ Impair the DNA-Binding Activity of POGZ Reviewed

    Nakazawa, T; Matsumura, K; Nagayasu, K; Kasai, A; Hayata-Takano, A; Shintani, N; Takuma, K; Yamamori, H; Yasuda, Y; Hashimoto, R; Hashimoto, H

    NEUROPSYCHOPHARMACOLOGY   Vol. 41   page: S347 - S348   2016.12

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  37. Critical involvement of the orbitofrontal cortex in hyperlocomotion induced by NMDA receptor blockade in mice Reviewed

    Kaoru Seiriki, Atsushi Kasai, Takahiro Kuwaki, Takanobu Nakazawa, Shun Yamaguchi, Hitoshi Hashimoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 480 ( 4 ) page: 558 - 563   2016.11

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    Glutamatergic N-methyl-D-aspartate (NMDA) receptors play critical roles in several neurological and psychiatric diseases. Blockade by noncompetitive NMDA receptor antagonist leads to psychotomimetic effects; however, the brain regions responsible for the effects are not well understood. Here, we determined the specific brain regions responsive to MK-801, a noncompetitive NMDA receptor antagonist, by mapping Arc expression as an indicator of neuronal activity using Arc::dVenus reporter mice. MK-801 increased dVenus expression predominantly in the orbitofrontal cortex (OFC) and, as expected, induced a marked hyperlocomotion. Local OFC lesions selectively attenuated the early phase (0-30 min) of MK-801-induced hyperlocomotion. Further, clozapine, an atypical antipsychotic, effectively attenuated both the MK-801-induced dVenus expression in the OFC and hyperlocomotion. These results suggest that the OFC may be critically involved in NMDA receptor-mediated psychotic-like behavioral abnormalities. (C) 2016 Elsevier Inc. All rights reserved.

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  38. Double In situ Hybridization for MicroRNAs and mRNAs in Brain Tissues Reviewed

    Atsushi Kasai, Sora Kakihara, Hiroki Miura, Ryo Okada, Atsuko Hayata-Takano, Keisuke Hazama, Misaki Niu, Norihito Shintani, Takanobu Nakazawa, Hitoshi Hashimoto

    FRONTIERS IN MOLECULAR NEUROSCIENCE   Vol. 9 ( NOV2016 ) page: 126   2016.11

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    MicroRNAs (miRNAs) participate in a variety of functions in the brain. Understanding the in vivo localization of miRNAs is an important step for uncovering their roles in brain function. However, the in situ detection of low-abundance miRNAs in brain tissues remains difficult and requires extensive optimization of in situ hybridization (ISH) protocols in individual laboratories. Thus, detailed information regarding experimental conditions would serve as a useful reference for researchers in this field. Here, we investigated and summarized the effects of adjusting a series of critical steps, including tissue fixation, probe accessibility and hybridization stringency, to standardize the currently used miRNA ISH procedures. As a result, we successfully detected several low-abundance miRNAs by ISH using the following experimental conditions: (1) use of fresh brain tissues, (2) digestion of brain samples with proteinase K, (3) LNA-probe hybridization at a temperature 37 degrees C below the melting temperature of the RNA, (4) performance of high-stringency wash steps using 50% formamide in 1 x standard saline citrate (SSC) buffer. RT-PCR of the punched-out tissues using TaqMan (TM) primers confirmed the ISH results. Finally, double-fluorescence ISH successfully demonstrated the colocalization of miRNAs and mRNAs. Thus, the detailed information regarding the miRNA ISH procedures used in this study may help to resolve the technical hurdles observed in the in vivo localization of miRNAs, and the elucidation of the specific roles of miRNAs.

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  39. Prostaglandin D-2 signaling mediated by the CRTH2 receptor is involved in MK-801-induced cognitive dysfunction Reviewed

    Yusuke Onaka, Norihito Shintani, Takanobu Nakazawa, Takuya Kanoh, Yukio Ago, Toshio Matsuda, Ryota Hashimoto, Kazutaka Ohi, Hiroyuki Hirai, Kin-ya Nagata, Masataka Nakamura, Atsushi Kasai, Atsuko Hayata-Takano, Kazuki Nagayasu, Kazuhiro Takuma, Asao Ogawa, Akemichi Baba, Hitoshi Hashimoto

    BEHAVIOURAL BRAIN RESEARCH   Vol. 314   page: 77 - 86   2016.11

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    Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), which is a second receptor for prostaglandin (PG) D-2, is involved in inflammatory responses in peripheral tissue; however, its role in cognitive function remains unclear. Here, we demonstrate that CRTH2 is involved in cognitive function using a well-established animal model of cognitive dysfunction induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Genetic deletion and pharmacological inhibition of CRTH2 suppressed MK-801-induced cognitive dysfunction. Pharmacological inhibition of cyclooxygenase-1, a rate-limiting enzyme in PG synthesis, also suppressed MK-801-induced cognitive dysfunction. Moreover, an MK-801-induced increase in c-Fos expression in the paraventricular nucleus (PVN) was abolished in the CRTH2-deficient mice. Together, these results suggest that PGD(2)-CRTH2 signaling is involved in both MK-801-induced cognitive dysfunction and neuronal activity regulation in the PVN. Furthermore, genetic association studies suggest that CRTH2 is weakly associated with cognitive function in humans. Our study provides evidence that PGD(2)-CRTH2 signaling is involved in cognitive function and may represent a potential therapeutic target for cognitive dysfunction in patients with psychiatric disorders. (C) 2016 Elsevier B.V. All rights reserved.

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  40. Deletion of JMJD2B in neurons leads to defective spine maturation, hyperactive behavior and memory deficits in mouse Reviewed

    K. Fujiwara, Y. Fujita, A. Kasai, Y. Onaka, H. Hashimoto, H. Okada, T. Yamashita

    TRANSLATIONAL PSYCHIATRY   Vol. 6 ( 3 ) page: e766   2016.3

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    JMJD2B is a histone demethylase enzyme that regulates gene expression through demethylation of H3K9me3. Although mutations of JMJD2B have been suggested to be responsible for neurodevelopmental disorders, the function of JMJD2B in the central nervous system (CNS) remains to be elucidated. Here we show that JMJD2B has a critical role in the development of the CNS. We observed JMJD2B expression, which was especially strong in the hippocampus, throughout the CNS from embryonic periods through adulthood. We generated neuron-specific JMJD2B-deficient mice using the cre-loxP system. We found an increase in total spine number, but a decrease in mature spines, in the CA1 region of the hippocampus. JMJD2B-deficient mice exhibited hyperactive behavior, sustained hyperactivity in a novel environment, deficits in working memory and spontaneous epileptic-like seizures. Together these observations indicate that JMJD2B mutant mice display symptoms reminiscent of neurodevelopmental disorders. Our findings provide evidence for the involvement of histone demethylation in the formation of functional neural networks during development.

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  41. Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder Reviewed

    Ryota Hashimoto, Takanobu Nakazawa, Yoshinori Tsurusaki, Yuka Yasuda, Kazuki Nagayasu, Kensuke Matsumura, Hitoshi Kawashima, Hidenaga Yamamori, Michiko Fujimoto, Kazutaka Ohi, Satomi Umeda-Yano, Masaki Fukunaga, Haruo Fujino, Atsushi Kasai, Atsuko Hayata-Takano, Norihito Shintani, Masatoshi Takeda, Naomichi Matsumoto, Hitoshi Hashimoto

    JOURNAL OF HUMAN GENETICS   Vol. 61 ( 3 ) page: 199 - 206   2016.3

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    Autism spectrum disorder (ASD) is a complex group of clinically heterogeneous neurodevelopmental disorders with unclear etiology and pathogenesis. Genetic studies have identified numerous candidate genetic variants, including de novo mutated ASD-associated genes; however, the function of these de novo mutated genes remains unclear despite extensive bioinformatics resources. Accordingly, it is not easy to assign priorities to numerous candidate ASD-associated genes for further biological analysis. Here we developed a convenient system for identifying an experimental evidence-based annotation of candidate ASD-associated genes. We performed trio-based whole-exome sequencing in 30 sporadic cases of ASD and identified 37 genes with de novo single-nucleotide variations (SNVs). Among them, 5 of those 37 genes, POGZ, PLEKHA4, PCNX, PRKD2 and HERC1, have been previously reported as genes with de novo SNVs in ASD; and consultation with in silico databases showed that only HERC1 might be involved in neural function. To examine whether the identified gene products are involved in neural functions, we performed small hairpin RNA-based assays using neuroblastoma cell lines to assess neurite development. Knockdown of 8 out of the 14 examined genes significantly decreased neurite development (P&lt;0.05, one-way analysis of variance), which was significantly higher than the number expected from gene ontology databases (P= 0.010, Fisher's exact test). Our screening system may be valuable for identifying the neural functions of candidate ASD-associated genes for further analysis and a substantial portion of these genes with de novo SNVs might have roles in neuronal systems, although further detailed analysis might eliminate false positive genes from identified candidate ASD genes.

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  42. Myeloid cell-derived LRG attenuates adverse cardiac remodelling after myocardial infarction Reviewed

    Shohei Kumagai, Hiroyuki Nakayama, Minoru Fujimoto, Hiromi Honda, Satoshi Serada, Hatsue Ishibashi-Ueda, Atsushi Kasai, Masanori Obana, Yasushi Sakata, Yoshiki Sawa, Yasushi Fujio, Tetsuji Naka

    CARDIOVASCULAR RESEARCH   Vol. 109 ( 2 ) page: 272 - 282   2016.2

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    Aims Leucine-rich alpha 2-glycoprotein (LRG) is considered as a biomarker of the clinical activities of chronic inflammatory diseases, including heart failure. However, its pathophysiological roles in cardiac remodelling after myocardial infarction (MI) remain to be clarified. In this study, we have addressed functional roles of LRG in cardiac remodelling after MI.
    Methods and results MI was generated by ligating the left coronary artery in mice. Real-time reverse transcription (RT)-PCR and immunoblot analyses revealed that the expressions of LRG transcript and protein were up-regulated in post-infarct myocardium. LRG protein was produced by heart-infiltrating myeloid cells, such as macrophages and neutrophils. To elucidate functional roles of LRG in cardiac remodelling, we generated MI in wild-type (WT) and LRG-deficient (LRG(-/-)) mice and found that LRG gene ablation aggravated myocardial fibrosis with cardiac dysfunction after MI. Immunohistochemical analyses with anti-CD31 antibody revealed that capillary density decreased at border zone in LRG(-/-) mice compared with WT mice. Consistently, the expression of apelin receptor was reduced in LRG(-/-) mice, implying that the impaired angiogenic activity is associated with adverse cardiac remodelling in LRG(-/-) mice. Moreover, LRG gene ablation suppressed the activation of smad1/5/8, a pro-angiogenic signalling pathway. Finally, the transplantation of WT bone marrow cells into LRG(-/-) mice attenuated cardiac fibrosis with functional improvement after MI, accompanied by restoration of capillary density compared with the bone marrow transplantation from LRG(-/-) mice.
    Conclusion LRG, produced by heart-infiltrating myeloid cells, suppresses adverse cardiac remodelling after MI as a novel cardioprotective factor. LRG signalling could be a therapeutic target against cardiovascular diseases.

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  43. Dopamine inhibits lipopolysaccharide-induced nitric oxide production through the formation of dopamine quinone in murine microglia BV-2 cells Reviewed

    Yasuhiro Yoshioka, Yuta Sugino, Azusa Tozawa, Akiko Yamamuro, Atsushi Kasai, Yuki Ishimaru, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 130 ( 2 ) page: 51 - 59   2016.2

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    Dopamine (DA) has been suggested to modulate functions of glial cells including microglial cells. To reveal the regulatory role of DA in microglial function, in the present study, we investigated the effect of DA on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in murine microglial cell line BV-2. Pretreatment with DA for 24 h concentration-dependently attenuated LPS-induced NO production in BV-2 cells. The inhibitory effect of DA on LPS-induced NO production was not inhibited by SCH-23390 and sulpiride, D-1-like and D-2-like DA receptor antagonists, respectively. In addition, pretreatment with (-)-(6aR, 12bR)-4,6,6a, 7,8,12b-Hexahydro-7-methylindolo[4,3-a]phenanthridin (CY 208-243) and bromocriptine, D-1-like and D-2-like DA receptor agonists, respectively, did not affect the LPS-induced NO production. N-Acetylcysteine, which inhibits DA oxidation, completely inhibited the effect of DA. Tyrosinase, which catalyzes the oxidation of DA to DA quionone (DAQ), accelerated the inhibitory effect of DA on LPS-induced NO production. These results suggest that DA attenuates LPS-induced NO production through the formation of DAQ in BV-2 cells. (C) 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V.

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  44. De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ. Reviewed

    Matsumura K, Nakazawa T, Nagayasu K, Gotoda-Nishimura N, Kasai A, Hayata-Takano A, Shintani N, Yamamori H, Yasuda Y, Hashimoto R, Hashimoto H

    Journal of molecular psychiatry   Vol. 4   page: 1   2016

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  45. Structured line illumination Raman microscopy Reviewed

    Kozue Watanabe, Almar F. Palonpon, Nicholas I. Smith, Liang-da Chiu, Atsushi Kasai, Hitoshi Hashimoto, Satoshi Kawata, Katsumasa Fujita

    NATURE COMMUNICATIONS   Vol. 6   page: 10095   2015.12

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    In the last couple of decades, the spatial resolution in optical microscopy has increased to unprecedented levels by exploiting the fluorescence properties of the probe. At about the same time, Raman imaging techniques have emerged as a way to image inherent chemical information in a sample without using fluorescent probes. However, in many applications, the achievable resolution is limited to about half the wavelength of excitation light. Here we report the use of structured illumination to increase the spatial resolution of label-free spontaneous Raman microscopy, generating highly detailed spatial contrast from the ensemble of molecular information in the sample. Using structured line illumination in slit-scanning Raman microscopy, we demonstrate a marked improvement in spatial resolution and show the applicability to a range of samples, including both biological and inorganic chemical component mapping. This technique is expected to contribute towards greater understanding of chemical component distributions in organic and inorganic materials.

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  46. Comparative gene expression profiles in pancreatic islets associated with agouti yellow mutation and PACAP overexpression in mice Reviewed

    Kazuya Ikeda, Shuhei Tomimoto, Soken Tsuchiya, Ken-Ichi Hamagami, Norihito Shintani, Yukihiko Sugimoto, Atsushi Ichikawa, Atsushi Kasai, Takanobu Nakazawa, Kazuki Nagayasu, Atsuko Hayata-Takano, Akemichi Baba, Hitoshi Hashimoto

    Biochemistry and Biophysics Reports   Vol. 2   page: 179 - 183   2015.7

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    In diabetes mellitus, pituitary adenylate cyclase-activating polypeptide (PACAP) has insulinotropic and glucose-lowering properties. We previously demonstrated that transgenic mice overexpressing PACAP in pancreatic β-cells (PACAP-Tg) show attenuated pancreatic islet hyperplasia and hyperinsulinemia in type 2 diabetic models. To explore the underlying mechanisms, here we crossed PACAP-Tg mice with lethal yellow agouti (KKAy) diabetic mice, and performed gene chip analysis of laser capture microdissected pancreatic islets from four F1 offspring genotypes (wild-type, PACAP-Tg, KKAy, and PACAP-Tg:KKAy). We identified 1371 probes with &gt
    16-fold differences between at least one pair of genotypes, and classified the probes into five clusters with characteristic expression patterns. Gene ontology enrichment analysis showed that genes involved in the terms ribosome and intracellular organelles such as ribonucleoprotein complex, mitochondrion, and chromosome organization were significantly enriched in clusters characterized by up-regulated genes in PACAP-Tg:KKAy mice compared with KKAy mice. These results may provide insight into the mechanisms of diabetes that accompany islet hyperplasia and amelioration by PACAP.

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  47. ATOMOXETINE REVERSES LOCOMOTOR HYPERACTIVITY, IMPAIRED NOVEL OBJECT RECOGNITION, AND PREPULSE INHIBITION IMPAIRMENT IN MICE LACKING PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE Reviewed

    Y. Shibasaki, A. Hayata-Takano, K. Hazama, T. Nakazawa, N. Shintani, A. Kasai, K. Nagayasu, R. Hashimoto, M. Tanida, T. Katayama, S. Matsuzaki, K. Yamada, M. Taniike, Y. Onaka, Y. Ago, J. A. Waschek, K. Koeves, D. Regloedi, A. Tamas, T. Matsuda, A. Baba, H. Hashimoto

    NEUROSCIENCE   Vol. 297   page: 95 - 104   2015.6

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    Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is characterized by attention difficulties, impulsivity, and hyperactivity. A non-stimulant drug, atomoxetine (ATX), which is a selective noradrenaline reuptake inhibitor, is widely used for ADHD because it exhibits fewer adverse effects compared to conventional psychostimulants. However, little is known about the therapeutic mechanisms of ATX. ATX treatment significantly alleviated hyperactivity of pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP(-/-)) mice with C57BL/6J and 129S6/SvEvTac hybrid background. ATX also improved impaired novel object recognition memory and prepulse inhibition in PACAP(-/-) mice with CD1 background. The ATX-induced increases in extracellular noradrenaline and dopamine levels were significantly higher in the prefrontal cortex of PACAP(-/-) mice compared to wild-type mice with C57BL/6J and 129S6/SvEvTac hybrid background. These results suggest that ATX treatment-induced increases in central monoamine metabolism may be involved in the rescue of ADHD-related abnormalities in PACAP(-/-) mice. Our current study suggests that PACAP(-/-) mice are an ideal rodent model with predictive validity for the study of ADHD etiology and drug development. Additionally, the potential effects of differences in genetic background of PACAP(-/-) mice on behaviors are discussed. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

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  48. p13 overexpression in pancreatic beta-cells ameliorates type 2 diabetes in high-fat-fed mice Reviewed

    Shintaro Higashi, Kazuhiko Katagi, Norihito Shintani, Kazuya Ikeda, Yukihiko Sugimoto, Soken Tsuchiya, Naoki Inoue, Shota Tanaka, Mai Koumoto, Atsushi Kasai, Takanobu Nakazawa, Atsuko Hayata-Takano, Ken-Ichi Hamagami, Shuhei Tomimoto, Takuya Yoshida, Tadayasu Ohkubo, Kazuki Nagayasu, Yukio Ago, Yusuke Onaka, Ryota Hashimoto, Atsushi Ichikawa, Akemichi Baba, Hitoshi Hashimoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 461 ( 4 ) page: 612 - 617   2015.6

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    We examined the pancreatic function of p13 encoded by 1110001J03Rik, whose expression is decreased in pancreatic islets in high-fat-fed diabetic mice, by generating transgenic mice overexpressing p13 (p13-Tg) in pancreatic beta-cells. p13-Tg mice showed normal basal glucose metabolism; however, under high-fat feeding, these animals showed augmented glucose-induced first-phase and total insulin secretion, improved glucose disposal, greater islet area and increased mitotic insulin-positive cells. In addition, high-fat diet-induced 4-hydroxynonenal immunoreactivity, a reliable marker and causative agent of lipid peroxidative stress, was significantly decreased in p13-Tg mouse islets. These results indicate that p13 is a novel pancreatic factor exerting multiple beneficial effects against type 2 diabetes. (C) 2015 Elsevier Inc. All rights reserved.

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  49. CRTH2, a prostaglandin D-2 receptor, mediates depression-related behavior in mice Reviewed

    Yusuke Onaka, Norihito Shintani, Takanobu Nakazawa, Ryota Haba, Yukio Ago, Hyper Wang, Takuya Kanoh, Atsuko Hayata-Takano, Hiroyuki Hirai, Kin-ya Nagata, Masataka Nakamura, Ryota Hashimoto, Toshio Matsuda, James A. Waschek, Atsushi Kasai, Kazuki Nagayasu, Akemichi Baba, Hitoshi Hashimoto

    BEHAVIOURAL BRAIN RESEARCH   Vol. 284   page: 131 - 137   2015.5

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    Depression is a complex neuropsychiatric disorder with an unclear molecular etiology. Inflammatory cytokines and molecular intermediates (including prostaglandins) are suggested to be involved in depression; however, the roles of prostaglandins and their respective receptors are largely unknown in depression. Using genetic and pharmacological approaches, we show here that chemoattractant receptorhomologous molecule expressed on T helper type 2 cells (CRTH2), a second receptor for prostaglandin D2 (PGD2), mediates depression-related behavior in mice. CRTH2-deficient (CRTH2(-/-)) mice showed antidepressant-like activity in a chronic corticosterone treatment-induced depression. Consistent with this observation, the pharmacological inhibition of CRTH2 via the clinically available drug ramatroban also rescued abnormal social interaction and depression-related behavior in well-established models, including chronic corticosterone-, lipopolysaccharide-, and tumor-induced pathologically relevant depression models. Importantly, chronic stress via corticosterone treatment increased mRNA levels in PGD2-producing enzymes, such as cyclooxygenase-2 and lipocalin-type PGD2 synthase, in the brain. Furthermore, the activity of the hippocampal noradrenergic system but not the dopaminergic or serotonergic systems was increased in CRTH2(-/-) mice. Together with the observation that untreated CRTH2(-/-) mice showed antidepressant-like activity in the forced swim test, these results provide evidence that central CRTH2-mediated signaling is critically involved in depression-related behavior. (C) 2015 Elsevier B.V. All rights reserved.

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  50. A Mouse Model of Human Primitive Neuroectodermal Tumors Resulting from Microenvironmentally-Driven Malignant Transformation of Orthotopically Transplanted Radial Glial Cells Reviewed

    Sergey Malchenko, Simone Treiger Sredni, Hitoshi Hashimoto, Atsushi Kasai, Kazuki Nagayasu, Jianping Xie, Naira V. Margaryan, Kaoru Seiriki, Rishi R. Lulla, Richard E. B. Seftor, Lauren M. Pachman, Herbert Y. Meltzer, Mary J. C. Hendrix, Marcelo B. Soares

    PLOS ONE   Vol. 10 ( 3 ) page: e0121707   2015.3

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    There is growing evidence and a consensus in the field that most pediatric brain tumors originate from stem cells, of which radial glial cells constitute a subtype. Here we show that orthotopic transplantation of human radial glial (RG) cells to the subventricular zone of the 3rd ventricle - but not to other transplantation sites - of the brain in immunocompromised NOD-SCID mice, gives rise to tumors that have the hallmarks of CNS primitive neuroectodermal tumors (PNETs). The resulting mouse model strikingly recapitulates the phenotype of PNETs. Importantly, the observed tumorigenic transformation was accompanied by aspects of an epithelial to mesenchymal transition (EMT)-like process. It is also noteworthy that the tumors are highly invasive, and that they effectively recruit mouse endothelial cells for angiogenesis. These results are significant for several reasons. First, they show that malignant transformation of radial glial cells can occur in the absence of specific mutations or inherited genomic alterations. Second, they demonstrate that the same radial glial cells may either give rise to brain tumors or differentiate normally depending upon the microenvironment of the specific region of the brain to which the cells are transplanted. In addition to providing a prospect for drug screening and development of new therapeutic strategies, the resulting mouse model of PNETs offers an unprecedented opportunity to identify the cancer driving molecular alterations and the microenvironmental factors that are responsible for committing otherwise normal radial glial cells to a malignant phenotype.

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  51. PACAP Enhances Axon Outgrowth in Cultured Hippocampal Neurons to a Comparable Extent as BDNF Reviewed

    Katsuya Ogata, Norihito Shintani, Atsuko Hayata-Takano, Toshihiko Kamo, Shintaro Higashi, Kaoru Seiriki, Hisae Momosaki, David Vaudry, Hubert Vaudry, Ludovic Galas, Atsushi Kasai, Kazuki Nagayasu, Takanobu Nakazawa, Ryota Hashimoto, Yukio Ago, Toshio Matsuda, Akemichi Baba, Hitoshi Hashimoto

    PLOS ONE   Vol. 10 ( 3 ) page: e0120526   2015.3

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    Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activities including modulation of synaptic plasticity and memory, hippocampal neurogenesis, and neuroprotection, most of which are shared with brain-derived neurotrophic factor (BDNF). Therefore, the aim of this study was to compare morphological effects of PACAP and BDNF on primary cultured hippocampal neurons. At days in vitro (DIV) 3, PACAP increased neurite length and number to similar levels by BDNF, but vasoactive intestinal polypeptide showed much lower effects. In addition, PACAP increased axon, but not dendrite, length, and soma size at DIV 3 similarly to BDNF. The PACAP antagonist PACAP6-38 completely blocked the PACAP-induced increase in axon, but not dendrite, length. Interestingly, the BDNF-induced increase in axon length was also inhibited by PACAP6-38, suggesting a mechanism involving PACAP signaling. K252a, a TrkB receptor inhibitor, inhibited axon outgrowth induced by PACAP and BDNF without affecting dendrite length. These results indicate that in primary cultured hippocampal neurons, PACAP shows morphological actions via its cognate receptor PAC1, stimulating neurite length and number, and soma size to a comparable extent as BDNF, and that the increase in total neurite length is ascribed to axon outgrowth.

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  52. Simultaneous neuron- and astrocyte-specific fluorescent marking Reviewed

    Wiebke Schulze, Atsuko Hayata-Takano, Toshihiko Kamo, Takanobu Nakazawa, Kazuki Nagayasu, Atsushi Kasai, Kaoru Seiriki, Norihito Shintani, Yukio Ago, Camille Farfan, Ryota Hashimoto, Akemichi Baba, Hitoshi Hashimoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 459 ( 1 ) page: 81 - 86   2015.3

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    Systematic and simultaneous analysis of multiple cell types in the brain is becoming important, but such tools have not yet been adequately developed. Here, we aimed to generate a method for the specific fluorescent labeling of neurons and astrocytes, two major cell types in the brain, and we have developed lentiviral vectors to express the red fluorescent protein tdTomato in neurons and the enhanced green fluorescent protein (EGFP) in astrocytes. Importantly, both fluorescent proteins are fused to histone 2B protein (H2B) to confer nuclear localization to distinguish between single cells. We also constructed several expression constructs, including a tandem alignment of the neuron- and astrocyte-expression cassettes for simultaneous labeling. Introducing these vectors and constructs in vitro and in vivo resulted in cell type-specific and nuclear-localized fluorescence signals enabling easy detection and distinguishability of neurons and astrocytes. This tool is expected to be utilized for the simultaneous analysis of changes in neurons and astrocytes in healthy and diseased brains. (C) 2015 Elsevier Inc. All rights reserved.

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  53. Identification of the role of bone morphogenetic protein (BMP) and transforming growth factor-beta (TGF-beta) signaling in the trajectory of serotonergic differentiation in a rapid assay in mouse embryonic stem cells in vitro Reviewed

    Atsushi Yamasaki, Atsushi Kasai, Akihiro Toi, Maki Kurita, Saki Kimoto, Atsuko Hayata-Takano, Takanobu Nakazawa, Kazuki Nagayasu, Norihito Shintani, Ryota Hashimoto, Akira Ito, Herbert Y. Meltzer, Yukio Ago, James A. Waschek, Yusuke Onaka, Toshio Matsuda, Akemichi Baba, Hitoshi Hashimoto

    JOURNAL OF NEUROCHEMISTRY   Vol. 132 ( 4 ) page: 418 - 428   2015.2

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    The mechanism by which extracellular molecules control serotonergic cell fate remains elusive. Recently, we showed that noggin, which inactivates bone morphogenetic proteins (BMPs), induces serotonergic differentiation of mouse embryonic (ES) and induced pluripotent stem cells with coordinated gene expression along the serotonergic lineage. Here, we created a rapid assay for serotonergic induction by generating knock-in ES cells expressing a naturally secreted Gaussia luciferase driven by the enhancer of Pet-1Fev, a landmark of serotonergic differentiation. Using these cells, we performed candidate-based screening and identified BMP type I receptor kinase inhibitors LDN-193189 and DMH1 as activators of luciferase. LDN-193189 induced ES cells to express the genes encoding Pet-1, tryptophan hydroxylase 2, and the serotonin transporter, and increased serotonin release without altering dopamine release. In contrast, TGF-beta receptor inhibitor SB-431542 selectively inhibited serotonergic differentiation, without changing overall neuronal differentiation. LDN-193189 inhibited expression of the BMP signaling target gene Id, and induced the TGF-beta target gene Lefty, whereas the opposite effect was observed with SB-431542. This study thus provides a new tool to investigate serotonergic differentiation and suggests that inhibition of BMP type I receptors and concomitant activation of TGF-b receptor signaling are implicated in serotonergic differentiation.

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  54. Enhancement of the lateral resolution of Raman microscopy by use of structured illumination Reviewed

    Almar F. Palonpon, Kozue Watanabe, Nicholas I. Smith, Liang Da Chiu, Atsushi Kasai, Hitoshi Hashimoto, Satoshi Kawata, Katsumasa Fujita

    Optics InfoBase Conference Papers   Vol. Part F132-JSAP 2019   2015

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  55. Increased Behavioral and Neuronal Responses to a Hallucinogenic Drug in PACAP Heterozygous Mutant Mice Reviewed

    Keisuke Hazama, Atsuko Hayata-Takano, Kazuki Uetsuki, Atsushi Kasai, Naoki Encho, Norihito Shintani, Kazuki Nagayasu, Ryota Hashimoto, Dora Reglodi, Tsuyoshi Miyakawa, Takanobu Nakazawa, Akemichi Baba, Hitoshi Hashimoto

    PLOS ONE   Vol. 9 ( 2 ) page: e89153   2014.2

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    Accumulating evidence from human genetic studies implicates the pituitary adenylate cyclase-activating polypeptide (PACAP) gene as a risk factor for psychiatric disorders, including schizophrenia and stress-related diseases. Mice with homozygous disruption of the PACAP gene display profound behavioral and neurological abnormalities that are ameliorated with the atypical antipsychotic and dopamine D-2 and serotonin (5-HT)(2) antagonist risperidone and the 5-HT2 receptor antagonist ritanserin; however, the underlying mechanisms remain unknown. Here, we investigated if PACAP heterozygous mutant (PACAP+/2) mice, which appear behaviorally normal, are vulnerable to aversive stimuli. PACAP+/2 mice were administered a 5-HT2 receptor agonist, (6)-2,5-dimethoxy-4-iodoamphetamine (DOI), a hallucinogenic drug, and their responses were compared with the littermate wild-type mice. After DOI injection, PACAP+/2 mice showed increased head-twitch responses, while their behavior was normal after saline. DOI induced deficits in sensorimotor gating, as determined by prepulse inhibition, specifically in PACAP+/2 mice. However, other 5-HT2 receptor-dependent responses, such as corticosterone release and hypothermia, were similarly observed in PACAP+/2 and wild-type mice. c-Fos expression analysis, performed in various brain regions, revealed that the DOI-induced increase in the number of c-Fos-positive cells was more pronounced in 5-HT(2)A receptor-negative cells in the somatosensory cortex in PACAP+/2 mice compared with wild-type mice. These results indicate that PACAP+/2 mice exhibit specific vulnerability to DOI-induced deficits in cortical sensory function, such as exaggerated head-twitch responses and sensorimotor gating deficits. Our findings provide insight into the neural mechanisms underlying impaired behavioral responses in which 5-HT2 receptors are implicated.

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  56. Central CRTH2, a Second Prostaglandin D-2 Receptor, Mediates Emotional Impairment in the Lipopolysaccharide and Tumor-Induced Sickness Behavior Model Reviewed

    Ryota Haba, Norihito Shintani, Yusuke Onaka, Takuya Kanoh, Hyper Wang, Risa Takenaga, Atsuko Hayata, Hiroyuki Hirai, Kin-ya Nagata, Masataka Nakamura, Atsushi Kasai, Ryota Hashimoto, Kazuki Nagayasu, Takanobu Nakazawa, Hitoshi Hashimoto, Akemichi Baba

    JOURNAL OF NEUROSCIENCE   Vol. 34 ( 7 ) page: 2514 - 2523   2014.2

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    Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) is a second prostaglandin D-2 receptor involved in mediating the allergic response; however, its central function is not yet known. Here, we demonstrate that central CRTH2 mediates emotional impairment. Lipopolysaccharide (LPS)-induced decreases in social interaction and novel exploratory behavior were observed in wild-type (CRTH2(+/+)) mice but not CRTH2-deficient (CRTH2(-/-)) mice, but both genotypes showed hypolocomotion and anorexia following LPS injection. Tumor (colon 26) inoculation, a more pathologically relevant model, induced decreases in social interaction and novel exploratory behavior in CRTH2(+/+), but not CRTH2(-/-) mice. In addition, the CRTH2 antagonists including clinically available ramatroban reversed impaired social interaction and novel exploratory behavior after either LPS or tumor inoculation in CRTH2(+/+) mice. Finally, LPS-induced c-Fos expression in the hypothalamic paraventricular nucleus (PVN) and central amygdala (CeA) was selectively abolished in CRTH2(-/-) mice. These results show that CRTH2 participates in LPS-induced emotional changes and activation in the PVN and CeA. Our study provides the first evidence that central CRTH2 regulates specific emotional behaviors, and that CRTH2 antagonism has potential as a therapeutic target for behavioral symptoms associated with tumors and infectious diseases.

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  57. Targeted STAT3 disruption in myeloid cells alters immunosuppressor cell abundance in a murine model of spontaneous medulloblastoma Reviewed

    Catalina Abad, Hiroko Nobuta, Jiaxi Li, Atsushi Kasai, William H. Yong, James A. Waschek

    JOURNAL OF LEUKOCYTE BIOLOGY   Vol. 95 ( 2 ) page: 357 - 367   2014.2

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    Targeted mutation of STAT3 in myeloid cells dramatically altered the relative abundance of specific immune cell types within tumors, with no impact on tumor incidence. Although the immune system may provide early protection against cancer, tumors may exploit the healing arm of the immune system to enhance their growth and metastasis. For example, myeloid derived suppressor cells (MDSCs) are thought to promote tumor growth by several mechanisms, including the suppression of T cell activity. It has been suggested that STAT3 activation in myeloid cells modulates multiple aspects of MDSC physiology, including their expansion and activity. Whereas most animal studies investigating tumor immunology have used tumor implants, we used transgenic mice (Smo*) that spontaneously develop medulloblastoma brain tumors to investigate the temporal accumulation of MDSCs within tumors and how myeloid STAT3 disruption affects MDSC and other immune cell types. We found distinct populations of MDSC in medulloblastoma tumors, with a high prevalence of CD11b(+)Ly6G(+)Ly6C(low/-) cells, described previously by others as G-MDSCs. These were found early in tumor development, in premalignant lesions located on the surface of the cerebellum of 28-day-old mice. In fully developed tumors, pSTAT3 was found in the majority of these cells. Conditional STAT3 gene disruption in myeloid cells resulted in an enhanced proinflammatory phenotype of macrophages in Smo* mice. Moreover, a significant reduction in the abundance of G-MDSCs and Tregs was observed within tumors along with an increased presence of CD4(+) and CD8(+) cells. Despite these alterations in immune cells induced by myeloid STAT3 disruption, we found no effect on tumor incidence in Smo* mice with this deletion.

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  58. Inhibition of apelin expression switches endothelial cells from proliferative to mature state in pathological retinal angiogenesis Reviewed

    Atsushi Kasai, Yuki Ishimaru, Kosuke Higashino, Kohei Kobayashi, Akiko Yamamuro, Yasuhiro Yoshioka, Sadaaki Maeda

    Angiogenesis   Vol. 16 ( 3 ) page: 723 - 734   2013.7

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    The recruitment of mural cells such as pericytes to patent vessels with an endothelial lumen is a key factor for the maturation of blood vessels and the prevention of hemorrhage in pathological angiogenesis. To date, our understanding of the specific trigger underlying the transition from cell growth to the maturation phase remains incomplete. Since rapid endothelial cell growth causes pericyte loss, we hypothesized that suppression of endothelial growth factors would both promote pericyte recruitment, in addition to inhibiting pathological angiogenesis. Here, we demonstrate that targeted knockdown of apelin in endothelial cells using siRNA induced the expression of monocyte chemoattractant protein-1 (MCP-1) through activation of Smad3, via suppression of the PI3K/Akt pathway. The conditioned medium of endothelial cells treated with apelin siRNA enhanced the migration of vascular smooth muscle cells, through MCP-1 and its receptor pathway. Moreover, in vivo delivery of siRNA targeting apelin, which causes exuberant endothelial cell proliferation and pathological angiogenesis through its receptor APJ, led to increased pericyte coverage and suppressed pathological angiogenesis in an oxygen-induced retinopathy model. These data demonstrate that apelin is not only a potent endothelial growth factor, but also restricts pericyte recruitment, establishing a new connection between endothelial cell proliferation signaling and a trigger of mural recruitment. © 2013 The Author(s).

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  59. Laser-Induced Choroidal Neovascularization in Mice Attenuated by Deficiency in the Apelin-APJ System Reviewed

    Chikako Hara, Atsushi Kasai, Fumi Gomi, Tatsuya Satooka, Susumu Sakimoto, Kei Nakai, Yasuhiro Yoshioka, Akiko Yamamuro, Sadaaki Maeda, Kohji Nishida

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   Vol. 54 ( 6 ) page: 4321 - 4329   2013.6

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    PURPOSE. To investigate the role of the apelin-APJ system in the development of choroidal neovascularization (CNV).
    METHODS. Experimental CNV was induced by laser photocoagulation in wild-type (WT), apelin-deficient (apelin-KO), and apelin receptor (APJ)-deficient (APJ-KO) mice. The gene expression levels of angiogenic or inflammatory factors were determined by quantitative real-time reverse transcription-polymerase chain reaction. APJ expression in CNV lesions was examined by immunohistochemistry. The sizes of the CNV lesions in the three mouse models were measured and compared histologically using isolectin B4 staining. Macrophage recruitment was measured by flow cytometric analysis. Proliferation of endothelial cells was determined using the alamar Blue assay.
    RESULTS. Laser photocoagulation significantly increased expression of apelin and APJ in the retina-retinal pigment epithelium (RPE) complex. APJ immunoreactive cells were found in the CNV lesions and colocalized with platelet endothelial cell adhesion molecule-1, an endothelial cell marker. The sizes of the CNV lesions in apelin-KO or APJ-KO mice decreased significantly compared with those in the WT mice. Macrophages in the RPE complex of the apelin-KO mice, in which gene expression of the inflammatory factors was almost equal to that in WT mice, were recruited as a result of laser photocoagulation to the same degree as in WT mice. In addition, apelin small and interfering RNA (siRNA) suppressed proliferation of endothelial cells independently of vascular endothelial growth factor (VEGF) receptor 2 signaling, while VEGF increased expression of apelin and APJ in human umbilical vein endothelial cells.
    CONCLUSIONS. The results suggested that the apelin-APJ system contributes to CNV development partially independent of the VEGF pathway.

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  60. [Apelin-APJ system: from discovery to therapeutic target]. Reviewed

    Kasai A

    Nihon yakurigaku zasshi. Folia pharmacologica Japonica   Vol. 139 ( 5 ) page: 198 - 202   2012.5

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  61. Performance of cell-penetrating peptide-linked polymers physically mixed with poorly membrane-permeable molecules on cell membranes Reviewed

    Shinji Sakuma, Masaya Suita, Takafumi Yamamoto, Yoshie Masaoka, Makoto Kataoka, Shinji Yamashita, Noriko Nakajima, Norihiro Shinkai, Hitoshi Yamauchi, Ken-ichiro Hiwatari, Akio Hashizume, Hiroyuki Tachikawa, Ryoji Kimura, Yuki Ishimaru, Atsushi Kasai, Sadaaki Maeda

    EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS   Vol. 81 ( 1 ) page: 64 - 73   2012.5

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    We are investigating a new class of penetration enhancers that enable poorly membrane-permeable molecules physically mixed with them to effectively penetrate cell membranes without their concomitant cellular uptake. Since we previously revealed that poly(N-vinylacetamide-co-acrylic acid) modified with D-octaarginine, which is a typical cell-penetrating peptide, significantly enhanced the nasal absorption of insulin, we examined the performance of the polymers on cell membranes. When Caco-2 cells were incubated with 5(6)-carboxyfluorescein (CF) for 30 min, approximately 0.1% of applied CF was internalized into the cells. This poor membrane permeability was dramatically enhanced by D-octaarginine-linked polymers; a 25-fold increase in the cellular uptake of CF was observed when the polymer concentration was adjusted to 0.2 mg/mL. None of the individual components, for example, D-octaarginine, had any influence on CF uptake, demonstrating that only D-octaarginine anchored chemically to the polymeric platform enhanced the membrane permeation of CF. The polymer-induced CF uptake was consistently high even when the incubation time was extended to 120 min. Confocal laser scanning microphotographs of cells incubated with D-octaarginine-linked polymers bearing rhodamine red demonstrated that the cell outline was stained with red fluorescence. The polymer-induced CF uptake was significantly suppressed by 5-(N-ethyl-N-isopropyl)amiloride, which is an inhibitor of macropinocytosis. Results indicated that D-octaarginine-linked polymers remained on the cell membrane and poorly membrane-permeable CF was continuously internalized into cells mainly via macropinocytosis repeated for the individual peptidyl branches in the polymer backbone. (C) 2012 Elsevier B.V. All rights reserved.

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  62. レーザー誘発性脈絡膜新生血管におけるapelin/APJシグナルの関与 Reviewed

    上野 千佳子, 笠井 淳司, 五味 文, 里岡 達哉, 中井 慶, 山室 晶子, 西田 幸二

    日本眼科学会雑誌   Vol. 116 ( 臨増 ) page: 340 - 340   2012.3

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  63. Apelin Deficiency Accelerates the Progression of Amyotrophic Lateral Sclerosis Reviewed

    Atsushi Kasai, Toshihiko Kinjo, Rie Ishihara, Ikumi Sakai, Yuki Ishimaru, Yasuhiro Yoshioka, Akiko Yamamuro, Kumiko Ishige, Yoshihisa Ito, Sadaaki Maeda

    PLOS ONE   Vol. 6 ( 8 ) page: e23968   2011.8

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    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Recent studies have implicated that chronic hypoxia and insufficient vascular endothelial growth factor (VEGF)-dependent neuroprotection may lead to the degeneration of motor neurons in ALS. Expression of apelin, an endogenous ligand for the G protein-coupled receptor APJ, is regulated by hypoxia. In addition, recent reports suggest that apelin protects neurons against glutamate-induced excitotoxicity. Here, we examined whether apelin is an endogenous neuroprotective factor using SOD1(G93A) mouse model of ALS. In mouse CNS tissues, the highest expressions of both apelin and APJ mRNAs were detected in spinal cord. APJ immunoreactivity was observed in neuronal cell bodies located in gray matter of spinal cord. Although apelin mRNA expression in the spinal cord of wild-type mice was not changed from 4 to 18 weeks age, that of SOD1(G93A) mice was reduced along with the paralytic phenotype. In addition, double mutant apelin-deficient and SOD1(G93A) displayed the disease phenotypes earlier than SOD1(G93A) littermates. Immunohistochemical observation revealed that the number of motor neurons was decreased and microglia were activated in the spinal cord of the double mutant mice, indicating that apelin deficiency pathologically accelerated the progression of ALS. Furthermore, we showed that apelin enhanced the protective effect of VEGF on H2O2-induced neuronal death in primary neurons. These results suggest that apelin/APJ system in the spinal cord has a neuroprotective effect against the pathogenesis of ALS.

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  64. Pathological Role of Apelin in Angiogenic Eye Disease Reviewed

    Atsushi Kasai

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN   Vol. 131 ( 8 ) page: 1201 - 1206   2011.8

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    Progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis mainly induced by vascular endothelial growth factor (VEGF). Anti-angiogenic therapy using anti-VEGF antibodies is effective in treating diabetic retinopathy, even though its efficacy is not long-lasting. Since many factors are involved in angiogenesis, it is reasonable to seek new therapeutic target molecules in pathological retinal angiogenesis. We have found that apelin/APJ system is involved in not only physiological but also pathological retinal angiogenesis using a mouse model of oxygen-induced retinopathy (OIR). Oxygen-induced vessel loss in the retinas of OIR model leads to a significant increase in the capillary density accompanied by abnormal vessel growth, similar to aneurysms, which are hardly detected in the retinas of control mice. Compared with age-matched control mice, retinal apelin expression was dramatically increased during retinal angiogenesis in OIR model. Immunostaining for APJ, apelin receptor, in retinal from OIR model revealed that APJ was localized in proliferating endothelial cells in the retinal vascular plexus. Retinal angiogenesis in the OIR model was rarely observed in apelin deficient mice, although temporal expression pattern of VEGF was similar to that of wild-type OIR model. In addition, clinical study showed that vitreous concentrations of apelin were significantly higher in the proliferative diabetic retinopathy group than in the control group. Taken together, these findings clearly suggest that apelin/APJ system may be a crucial factor for pathological retinal angiogenesis. Inhibition of this system could offer new therapeutic opportunities against ischemic retinopathy.

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  65. Caspase-4 Directly Activates Caspase-9 in Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells Reviewed

    Akiko Yamamuro, Takashi Kishino, Yu Ohshima, Yasuhiro Yoshioka, Tomoki Kimura, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 115 ( 2 ) page: 239 - 243   2011.2

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    The present study investigated the function of caspase-4 in endoplasmic reticulum (ER) stress-induced apoptosis in human neuronal cell line SH-SY5Y. Tunicamycin, which is known to induce ER stress, activated both caspase-9 and caspase-4, and the activation of caspase-4 preceded that of caspase-9. The caspase-4 inhibitor LEVD-CHO suppressed both the apoptosis and caspase-9 activation. In addition, human recombinant active caspase-4 cleaved wild type and D330A mutant substituted Asp-330 for alanine of human recombinant procaspase-9, but did not cleave D315A mutant substituted Asp-315 for alanine. These results suggest that caspase-4 directly activates caspase-9 by the processing of procaspase-9 at Asp-315 in ER stress induced neuronal apoptosis.

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  66. Phenotypic Characterization of Transgenic Mice Overexpressing Neuregulin-1 Reviewed

    Taisuke Kato, Atsushi Kasai, Makoto Mizuno, Liang Fengyi, Norihito Shintani, Sadaaki Maeda, Minesuke Yokoyama, Miwako Ozaki, Hiroyuki Nawa

    PLOS ONE   Vol. 5 ( 12 ) page: e14185   2010.12

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    Background: Neuregulin-1 (NRG1) is one of the susceptibility genes for schizophrenia and implicated in the neurotrophic regulation of GABAergic and dopaminergic neurons, myelination, and NMDA receptor function. Postmortem studies often indicate a pathologic association of increased NRG1 expression or signaling with this illness. However, the psychobehavioral implication of NRG1 signaling has mainly been investigated using hypomorphic mutant mice for individual NRG1 splice variants.
    Methodology/Principal Findings: To assess the behavioral impact of hyper NRG1 signaling, we generated and analyzed two independent mouse transgenic (Tg) lines carrying the transgene of green fluorescent protein (GFP)-tagged type-1 NRG1 cDNA. The promoter of elongation-factor 1 alpha gene drove ubiquitous expression of GFP-tagged NRG1 in the whole brain. As compared to control littermates, both heterozygous NRG1-Tg lines showed increased locomotor activity, a nonsignificant trend toward decreasing prepulse inhibition, and decreased context-dependent fear learning but exhibited normal levels of tone-dependent learning. In addition, social interaction scores in both Tg lines were reduced in an isolation-induced resident-intruder test. There were also phenotypic increases in a GABAergic marker (parvalbumin) as well as in myelination markers (myelin basic protein and 2&apos;,3&apos;-cyclic nucleotide 3&apos;-phosphodiesterase) in their frontal cortex, indicating the authenticity of NRG1 hyper-signaling, although there were marked decreases in tyrosine hydroxylase levels and dopamine content in the hippocampus.
    Conclusions: These findings suggest that aberrant hyper-signals of NRG1 also disrupt various cognitive and behavioral processes. Thus, neuropathological implication of hyper NRG1 signaling in psychiatric diseases should be evaluated with further experimentation.

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  67. Apelin Is a Crucial Factor for Hypoxia-Induced Retinal Angiogenesis Reviewed

    Atsushi Kasai, Yuki Ishimaru, Toshihiko Kinjo, Tatsuya Satooka, Nao Matsumoto, Yasuhiro Yoshioka, Akiko Yamamuro, Fumi Gomi, Norihito Shintani, Akemichi Baba, Sadaaki Maeda

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY   Vol. 30 ( 11 ) page: 2182 - U361   2010.11

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    Objective-To investigate the role of endogenous apelin in pathological retinal angiogenesis.
    Methods and Results-The progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis, mainly induced by vascular endothelial growth factor (VEGF) and erythropoietin. Although antiangiogenic therapies using anti-VEGF drugs are effective in treating retinal neovascularization, they show a transient efficacy and cause general adverse effects. New therapeutic target molecules are needed to resolve these issues. It was recently demonstrated that the apelin/APJ system, a newly deorphanized G protein-coupled receptor system, is involved in physiological retinal vascularization. Retinal angiography and mRNA expression were examined during hypoxia-induced retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Compared with age-matched control mice, retinal apelin expression was dramatically increased during the hypoxic phase in oxygen-induced retinopathy model mice. APJ was colocalized in proliferative cells, which were probably endothelial cells of the ectopic vessels in the vitreous body. Apelin deficiency hardly induced hypoxia-induced retinal angiogenesis despite the upregulation of VEGF and erythropoietin mRNA in oxygen-induced retinopathy model mice. Apelin small and interfering RNA suppressed the proliferation of endothelial cells independent of the VEGF/VEGF receptor 2 signaling pathway.
    Conclusion-These results suggest that apelin is a prerequisite factor for hypoxia-induced retinal angiogenesis. (Arterioscler Thromb Vasc Biol. 2010; 30: 2182-2187.)

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  68. Nitric Oxide Inhibits Lipopolysaccharide-Induced Inducible Nitric Oxide Synthase Expression and Its Own Production Through the cGMP Signaling Pathway in Murine Microglia BV-2 Cells Reviewed

    Yasuhiro Yoshioka, Nobuo Takeda, Akiko Yamamuro, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 113 ( 2 ) page: 153 - 160   2010.6

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    The present study examined the effect of the nitric oxide (NO) donor NOC18 on lipopolysaccharide (LPS)-induced NO production to investigate a regulation mechanism of NO production by microglial cells. LPS increased the levels of NO and inducible NO synthase (iNOS) protein in BV-2 murine microglial cells in a concentration-dependent manner. Pretreatment with NOC18 for 24 h concentration-dependently attenuated the LPS-induced iNOS protein expression and NO production. The inhibitory effect of NOC18 on LPS-induced NO production was partially blocked by LY83583, a soluble guanylate cyclase inhibitor. Pretreatment with dibutyryl guanosine-3',5'-cyclic monophosphate (DBcGMP), a cell-permeable cGMP analogue, for 24 h attenuated partially LPS-induced iNOS protein expression and NO production. Furthermore, the effects of LPS on iNOS and NO production were inhibited by the c-Jun N-terminal kinase (JNK) inhibitor SP600125, and LPS-induced phosphorylation of JNK and c-Jun was inhibited by NOC18 and DBcGMP. These results suggest that NO production by microglial cells is controlled by a negative feedback mechanism via the NO/cGMP signaling pathway.

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  69. Apelin is a crucial factor for hypoxia-induced retinal angiogenesis Reviewed

    笠井 淳司

    Arteriosclerosis, Thrombosis, and Vascular Biology   Vol. 30   page: 2182 - 2187   2010

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  70. Retardation of retinal vascular development in apelin-deficient mice Reviewed

    Atsushi Kasai, Norihito Shintani, Hideaki Kato, Satoshi Matsuda, Fumi Gomi, Ryota Haba, Hitoshi Hashimoto, Michiya Kakuda, Yasuo Tano, Akemichi Baba

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY   Vol. 28 ( 10 ) page: 1717 - 1722   2008.10

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    Objective -Apelin is an endogenous ligand for the G protein -coupled receptor, APJ, and participates in multiple physiological processes. To identify the roles of endogenous apelin, we investigated the phenotype of apelin-deficient (apelin-KO) mice.
    Methods and Results -Apelin-KO mice showed impaired retinal vascularization and ocular development, which were analyzed by histology, immunohistochemistry, real-time polymerase chain reaction, and the mouse corneal micropocket assay. Apelin-KO mice showed significantly impaired retinal vascularization in the early postnatal period. Retinal apelin/ APJ mRNAs were transiently upregulated during the first 2 postnatal weeks but were undetectable in adults. There were no differences in VEGF or FGF2 mRNA expression, or in the morphology and localization of GFAP-positive astrocytes, in the apelin-KO retinas at P5. The corneal pocket assay showed that angiogenic responses to VEGF and FGF2 were remarkably decreased in apelin-KO mice. The reduced responses to VEGF and FGF2 in apelin-KO mice were partially restored by apelin, but apelin alone did not induce angiogenesis.
    Conclusions -Our results suggest that spatiotemporally regulated apelin/ APJ signaling participates in retinal vascularization in a cooperative manner with VEGF or FGF2, and contributes to normal ocular development.

    DOI: 10.1161/ATVBAHA.108.163402

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  71. [First screening for behavioral phenotype of gene-engineered mice]. Reviewed

    Kasai A, Shintani N

    Nihon yakurigaku zasshi. Folia pharmacologica Japonica   Vol. 130 ( 4 ) page: 281 - 285   2007.10

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MISC 42

  1. Trans-scale-scope to find rare cellular activity in sub-million cells

    Taro Ichimura, Taishi Kakizuka, Kazuki Horikawa, Kaoru Seiriki, Atsushi Kasai, Hitoshi Hashimoto, Katsumasa Fujita, Tomonobu M. Watanabe, Takeharu Nagai

        2020.6

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    <title>Abstract</title>There are many phenomena in biological systems where less than 1% of rare cells trigger entire multicellular systems. In order to scientifically understand the mechanisms of these rare cell-driven systems, simultaneous observation of huge populations of cells is essential. It has been difficult to observe the dynamics of such phenomena with conventional microscopes. In this study, we propose a novel type of imager, trans-scale-scope, which allows us to observe cell dynamics with sub-cell resolution in a field of view greater than a centimeter. The imaging system is mainly composed of a hundred-megapixel image sensor and a macro-lens for full-size sensor. This method, which is the basement of the future imaging system named AMATERAS (A Multi-scale/modal Analytical Tool for Every Rare Activity in Singularity), realized observation of sub-million cells at the same time. By observing the macroscale-pattern formation process of <italic>Dictyostelium discoideum</italic>, a model organism for studying fundamental aspects of cell-cell communication and chemotaxis, we have shown that the 0.1 % of rare cells triggered a stream of collective cell migration.

    DOI: 10.1101/2020.06.29.179044

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  2. High-resolution imaging of primate brains using FAST

    Hashimoto H, Seiriki K, Kasai A, Nakazawa T, Inoue K, Takada M

    International Workshop "Monitoring and manipulating brain function in non-human primates"(2018/7/31, 千葉市)     2018.7

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  3. Whole-brain imaging analysis of animal models of neuropsychiatric disorders Invited

    Kaoru Seiriki, Atsushi Kasai, Hitoshi Hashimoto

    Japanese Journal of Biological Psychiatry   Vol. 29 ( 1 ) page: 22 - 26   2018.3

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  4. FAST, High-speed serial-sectioning imaging for whole brain analysis with high scalability.

    Kasai A, Seiriki K, Hashimoto T, Niu M, Yamaguchi S, Naka Y, Igarashi H, Tamura M, Nakazawa T, Inoue K, Takada M, Fujita K, Hashimoto H

    Neuroscience 2017(2017/11/13,Washington, DC, USA)     2017.11

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  5. 全脳マッピングと神経活動操作による情動行動制御機構の解明

    笠井 淳司, 丹生 光咲, 勢力 薫, 五十嵐 久人, 桑木 崇宏, 田沼 将人, 中澤 敬信, 山口 瞬, 山中 章弘, 橋本 均

    日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集   Vol. 39回・47回   page: 173 - 173   2017.9

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  6. Saturated Excitation Microscopy Using Image Subtraction (光・量子デバイス研究会・International Symposium on Biomedical Optics (バイオメディカルフォトニクス応用))

    Nawa Yasunori, Yonemaru Yasuo, Kasai Atsushi, Smith Nicholas, Hashimoto Hitoshi, Kawata Satoshi, Fujita Katsumasa

    電気学会研究会資料. OQD = The papers of technical meeting on optical and quantum devices, IEE Japan   Vol. 2017 ( 1 ) page: 17 - 20   2017.3

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  7. Studies on the molecular mechanism of clozapine action with iPSC technology Reviewed

    Fujiwara Mikiya, Kikuchi Masataka, Nagayasu Kazuki, Nakazawa Takanobu, Yamamori Hidenaga, Kasai Atsushi, Hayata-Takano Atsuko, Shintani Norihito, Fujimoto Michiko, Yasuda Yuka, Ishikawa Mitsuru, Akamatsu Wado, Okano Hideyuki, Nakaya Akihiro, Hashimoto Hitoshi, Hashimoto Ryota

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 130 ( 3 ) page: S254   2016.3

  8. Whole-brain activity mapping after restraint stress and analysis of neuronal innervation of the activated nucleus Reviewed

    Niu Misaki, Kasai Atsushi, Seiriki Kaoru, Yamaguchi Shun, Yamanaka Akihiro, Nakazawa Takanobu, Hashimoto Hiroshi

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 130 ( 3 ) page: S164   2016.3

  9. Myeloid Cell Derived Leucine Rich alpha 2 Glycoprotein Attenuates Adverse Cardiac Remodeling After Myocardial Infarction

    Shohei Kumagai, Hiroyuki Nakayama, Minoru Fujimoto, Hiromi Honda, Satoshi Serada, Atsushi Kasai, Masanori Obana, Yasushi Sakata, Yoshiki Sawa, Tetsuji Naka, Yasushi Fujio

    CIRCULATION   Vol. 132   2015.11

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  10. A new imaging system to detect whole brain structural and functional alterations at cellular and subcellular levels Reviewed

    Seiriki Kaoru, Kasai Atsushi, Niu Misaki, Yamaguchi Shun, Hashimoto Takeshi, Hashimoto Hitoshi

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 128 ( 3 ) page: S93   2015.7

  11. PACAPシグナルによる精神神経機能調節におけるセロトニン2A受容体シグナルの関与

    早田敦子, 狭間啓佑, 森口啓太, 吾郷由希夫, 円丁直樹, 中澤敬信, 永安一樹, 笠井淳司, 尾中勇祐, 新谷紀人, 馬場明道, 橋本均

    日本神経精神薬理学雑誌   Vol. 35   page: 55 - 56   2015

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  12. 「脳の科学Up Date」 最近の全脳三次元解析の現状と展望

    笠井 淳司, 橋本 均

    脳21   Vol. 17 ( 4 ) page: 115 - 119   2014.10

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  13. Altered expression of PACAP in the mPFC in depression-like states induced by chronic social defeat stress

    Keisuke Hazama, Atsushi Kasai, Sumiaki Ogawa, Atsuko Hayata, Norihito Shintani, Akemiti Baba, Hitoshi Hashimoto

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 124   page: 187P - 187P   2014

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  14. The balance between BMP and TGF-beta signaling at an early stage steers serotonergic differentiation from ES cells

    Atsushi Yamasaki, Atsushi Kasai, Akihiro Toi, Maki Kurita, Atsuko Hayata-Takano, Kazuki Nagayasu, Norihito Shintani, Akemichi Baba, Hitoshi Hashimoto

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 124   page: 181P - 181P   2014

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  15. ANALYSIS OF PACAP SIGNALING-MEDIATED RECEPTOR INTERNALIZATION USING THE HALOTAG SYSTEM

    A. Hayata, N. Encho, K. Moriguchi, T. Fujino, N. Shintani, A. Kasai, A. Baba, H. Hashimoto

    JOURNAL OF MOLECULAR NEUROSCIENCE   Vol. 51   page: S203 - S203   2013.11

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  16. PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) PLAYS SIGNIFICANT ROLES IN DENDRITIC SPINE FORMATION AND MORPHOLOGY

    S. Higashi, K. Seiriki, A. Hayata, K. Ogata, N. Shintani, A. Kasai, D. Vaudry, A. Baba, H. Hashimoto

    JOURNAL OF MOLECULAR NEUROSCIENCE   Vol. 51   page: S226 - S226   2013.11

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  17. 核酸医薬品開発に向けた現状と展望 Invited

    笠井 淳司

    脳21   Vol. 16   page: 89 - 94   2013

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  18. Effect of apelin siRNA on the maturation of blood vessels

    Yuki Ishimaru, Nao Matsumoto, Kosuke Higashino, Akihide Sumino, Atsushi Kasai, Yasuhiro Yoshioka, Akiko Yamamuro, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 118   page: 160P - 160P   2012

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  19. siRNA targeting apelin prevents the increase in capillary density and abnormal vessels in retina induced by hypoxia

    Yuki Ishimaru, Atsushi Kasai, Kosuke Higashino, Yasuhiro Yoshioka, Akiko Yamamuro, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 118   page: 96P - 96P   2012

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  20. Dopamine attenuates LPS-induced cytokine expression in microglial cells

    Yasuhiro Yoshioka, Yuta Sugino, Kazuya Nishimoto, Takuma Nishizawa, Akiko Yamamuro, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 115   page: 188P - 188P   2011

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  21. Noradrenaline protects astrocytes from H2O2-induced cell death via beta(3)-receptor stimulation

    Yasuhiro Yoshioka, Toshiki Motegi, Rie Tsujimoto, Ami Morishita, Chiharu Shirasu, Akiko Yamamuro, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 115   page: 243P - 243P   2011

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  22. 眼内血管新生性疾患におけるアペリンの役割 Invited

    笠井 淳司

    日本薬理学雑誌   Vol. 131 ( 8 ) page: 1201 - 1206   2011

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    DOI: 10.1248/yakushi.131.1201

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  23. Suppression of pathological retinal angiogenesis by siRNA targeting apelin

    Atsushi Kasai, Yuki Ishimaru, Fumi Gomi, Yasuhiro Yoshioka, Akiko Yamamuro, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 115   page: 64P - 64P   2011

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  24. Proteasome inhibitor induces apoptosis through ROS generation by NOX5

    Akiko Yamamuro, Maya Nakagawa, Kei Hasegawa, Aya Katoh, Yasuhiro Yoshioka, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 115   page: 189P - 189P   2011

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  25. Apelin is involved in the progression of amyotrophic lateral sclerosis

    Atsushi Kasai, Toshihiko Kinjo, Yasuhiro Yoshioka, Akiko Yamamuro, Kumiko Ishige, Yoshihisa Ito, Sadaaki Maeda

    NEUROSCIENCE RESEARCH   Vol. 68   page: E197 - E198   2010

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    DOI: 10.1016/j.neures.2010.07.2446

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  26. Apelin promotes endothelial cell growth during hypoxia-induced retinal angiogenesis

    Yuki Ishimaru, Atsushi Kasai, Toshihiko Kinjo, Yasuhiro Yoshioka, Akiko Yamamuro, Norihito Shintani, Akemichi Baba, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 112   page: 68P - 68P   2010

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  27. Dopamine protects neurons from LPS-induced cell death in co-culture of neurons and microglial cells

    Tadahiro Kitamoto, Yasuhiro Yoshioka, Akiko Yamamuro, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 112   page: 140P - 140P   2010

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  28. Noradrenaline protects neurons from H2O2-induced cell death by increasing the release of glutathione from astrocytes via beta-adrenoreceptor stimulation

    Yasuhiro Yoshioka, Toshiki Motegi, Akiko Yamamuro, Atsushi Kasai, Sadaaki Maeda

    NEUROSCIENCE RESEARCH   Vol. 68   page: E347 - E347   2010

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    DOI: 10.1016/j.neures.2010.07.1538

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  29. 生理活性ペプチド: Apelin

    笠井 淳司

      Vol. 13   page: 89 - 93   2010

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  30. マウス表現型の網羅的解析法

    笠井 淳司

    実践行動薬理学     page: 20 - 26   2010

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  31. Noradrenaline protects neurons from hydrogen peroxide-induced cell death by increasing the release of glutathione from astrocytes

    Toshiki Motegi, Yasuhiro Yoshioka, Akiko Yamamuro, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 112   page: 141P - 141P   2010

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  32. Apelin is required for the development of oxygen-induced retinopathy

    Atsushi Kasai, Toshihiko Kinjo, Yasuhiro Yoshioka, Akiko Yamamuro, Norihito Shintani, Hitoshi Hashimoto, Akemichi Baba, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 109   page: 201P - 201P   2009

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  33. Dopamine inhibits NO production by LPS-activated microglia through the formation of quinoprotein

    Yasuhiro Yoshioka, Azusa Tozawa, Tadahiro Kitamoto, Akiko Yamamuro, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 109   page: 128P - 128P   2009

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  34. Dysfunction of ubiquitin-proteasome syetem induces neuronal cell death through an activation of NADPH oxidase

    Akiko Yamamuro, Takumi Iyama, Yasuhiro Yoshioka, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 109   page: 153P - 153P   2009

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  35. Noradrenaline attenuates hydrogen peroxide-induced cell death of astrocyte through the increase in the level of intracellular glutathione

    Hisatsugu Kadoi, Yasuhiro Yoshioka, Akiko Yamamuro, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 109   page: 129P - 129P   2009

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  36. Research to develop therapy for ischemic disease: from basic research to translational research

    Journal of the Pharmaceutical Society of Japan   Vol. 128   page: 45 - 48   2008.9

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  37. Caspase-9 is a substrate of caspase-4

    Akiko Yamamuro, Yu Ohshima, Yasuhiro Yoshioka, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 106   page: 234P - 234P   2008

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  38. Dopamine inhibits NO production by LPS-activated microglia

    Azusa Tozawa, Yasuhiro Yoshioka, Akiko Yamamuro, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 106   page: 128P - 128P   2008

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  39. Negative feedback regulation of NO production in LPS-stimulated microglia

    Nobuo Takeda, Yasuhiro Yoshioka, Akiko Yarriamuro, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 106   page: 128P - 128P   2008

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  40. Proteasome inhibitor induces cell death via production of reactive oxygen species in human neuroblastoma SH-SY5Y cells

    Yu Ohshima, Akiko Yamamuro, Yasuhiro Yoshioka, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 106   page: 232P - 232P   2008

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  41. Noradrenaline and adrenaline attenuate hydrogen peroxide-induced cell death in astrocyte

    Hisatsugu Kadoi, Yasuhiro Yoshioka, Akiko Yarnamuro, Atsushi Kasai, Sadaaki Maeda

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 106   page: 185P - 185P   2008

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  42. Lack of apelin results in retardation of retinal vascular development

    Atsushi Kasai, Norihito Shintani, Hideaki Kato, Satoshi Matsuda, Fumi Gomi, Hitoshi Hashimoto, Michiya Kakuda, Yasuo Tano, Akemichi Baba

    JOURNAL OF PHARMACOLOGICAL SCIENCES   Vol. 103   page: 63P - 63P   2007

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Presentations 9

  1. サポートベクターマシーンを用いたストレス応答制御機構の解明

    笠井淳司

    第2回脳科学サロン「脳とAI」  2020.10.10 

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  2. 脳機能解明に向けた全脳多色蛍光標識法の開発 Invited

    笠井淳司

    第67回日本実験動物学会総会  2020.5.24 

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  3. Apelin is involved in the progression of amyotrophic lateral sclerosis

    Kasai Atsushi

    2010.9 

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  4. レーザー誘発脈絡膜血管新生におけるapelin-APJ systemの役割

    笠井 淳司

    次世代を担う創薬・医療薬理シンポジウム2012  2012.9.1 

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  5. PACAP欠損マウスにおける慢性的な社会的敗北ストレス誘発うつ様症状の消失

    笠井 淳司

    日本薬学会第133年会  2013.3 

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  6. Inhibition of the apelin-APJ signal switches endothelial cells from proliferative to mature state in pathological retinal angiogenesis

    笠井 淳司

    第21回日本血管生物医学会総会学術集会  2013.9 

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  7. Hypoxia induced apelin mRNA expression in astrocytes International conference

    Kasai Atsushi

    The IXth World Conference on Clinical Pharmacology and Therapeutics  2008.7.29 

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  8. Apelin is a crucial factor for hypoxia-induced retinal angiogenesis International conference

    Kasai Atsushi

    WorldPharma2010  2010.7 

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  9. Apelin is a crucial factor for hypoxia-induced retinal angiogenesis International conference

    笠井 淳司

    第18回日本血管生物医学会学術集会/8th Korea-Japan Joint Symposium on Vascular Biology  2010.12 

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KAKENHI (Grants-in-Aid for Scientific Research) 30

  1. The science of envy: Bio-Robotics integration for understanding social emotions and achieving an inclusive society

    Grant number:22B306  2022.5 - 2025.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Transformative Research Areas (B)  Grant-in-Aid for Transformative Research Areas (B)

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  2. Mechanisms of neurodevelopmental disorders

    2021.4 - 2024.3

    JST  Fusion Oriented REsearch for disruptive Science and Technology  Fusion Oriented REsearch for disruptive Science and Technology

    Atsushi Kasai

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  3. 全脳細胞解析による不安制御に関わる神経基盤の解明と創薬研究への応用

    Grant number:20H03391  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    笠井 淳司

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    Grant amount:\17680000 ( Direct Cost: \13600000 、 Indirect Cost:\4080000 )

    近年、不安障害の患者数は急増しており、認知症患者数よりも多く、社会負担が甚大なが
    ら、成因・病態機構や治療機序が未解明で新規治療薬の開発も長年失敗している。本研究では、それを打開するため、応募者らが最近開発した方法論を駆使し、従来研究では見逃されていた病態の詳細な分子・神経基盤の解明を通じ、新たな治療法の確立に貢献する。具体的には、最新の高精細全脳イメージング法および単一細胞トランスクリプトーム解析法を組み合わせ、強い精神的ストレスに暴露された脳を、全脳細胞レベルで解析し、ストレス誘発不安様行動を制御する神経基盤を明らかにする。
    近年、不安障害の患者数は急増しており、認知症患者数よりも多く、社会負担が甚大ながら、成因・病態機構や治療機序が未解明で新規治療薬の開発も長年失敗している。本研究では、それを打開するため、応募者らが最近開発した方法論を駆使し、従来研究では見逃されていた病態の詳細な分子・神経基盤の解明を通じ、新たな治療法の確立に貢献する。具体的には、最新の高精細全脳イメージング法および単一細胞トランスクリプトーム解析法を組み合わせ、強い精神的ストレスに暴露された脳を、全脳細胞レベルで解析し、ストレス誘発不安様行動を制御する神経基盤を明らかにすることを目指している。本年度は、mRNAの発現を二重蛍光標識in situ hybridization法により明らかにし、ストレス応答性神経細胞のマーカー分子を同定した。また、同定したマーカー分子の発現細胞特異的にCreリコンビナーゼを発現するマウスを作成し、アデノ随伴ウイルスベクターを用いて、特異性を確認した。
    今後は、ストレス応答発現細胞の神経活動を計測し、その挙動から不安関連行動との関係性を詳細に明らかにすることを目指す。
    計画通り進捗し、ストレス応答候補分子のCreリコンビナーゼ特異的なマウスの作出に成功したため。
    神経細胞種特異的な活動操作や活動計測を行い、不安関連行動との関係性をより詳細に明らかにする。

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  4. A novel mechanism for the development of stress-related psychiatric disorders

    Grant number:17H05054  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)  Grant-in-Aid for Young Scientists (A)

    Kasai Atsushi

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    Authorship:Principal investigator 

    Grant amount:\24700000 ( Direct Cost: \19000000 、 Indirect Cost:\5700000 )

    Although mental stress can cause the onset of psychiatric disorders such as depression, the pathogenesis of these disorders remains unclear. Here, we combined whole-brain activation mapping and data-driven analysis by support vector machine to identify a new population of neurons involved in the stress response and subsequent development of depression-like behavior. We have clarified the neuronal connectivity of the cell population to stress circuits at the whole brain level, and showed that specific neural manipulation of the cell population can mediate bidirectional and reversible control of stress-induced anxiety-related behavior and the onset of depressive-like behaviors. These results suggest that the cell population can be a therapeutic target for stress-related psychiatric disorders.

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  5. ストレスによる睡眠障害の発症機序解明と治療標的分子の探索

    Grant number:23K27331  2024.2 - 2026.3

    科学研究費助成事業  基盤研究(B)

    笠井 淳司

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    Authorship:Principal investigator 

    Grant amount:\11310000 ( Direct Cost: \8700000 、 Indirect Cost:\2610000 )

  6. ストレスによる睡眠障害の発症機序解明と治療標的分子の探索

    Grant number:23H02640  2023.4 - 2026.3

    科学研究費助成事業  基盤研究(B)

    笠井 淳司, 林 悠

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    Grant amount:\18850000 ( Direct Cost: \14500000 、 Indirect Cost:\4350000 )

    日本人の約20%が睡眠障害を抱えており、その半数がストレスに起因するとされている。しかし、不眠症の発症メカニズムは未だ不明であり、結果として睡眠/覚醒サイクルを強制的にコントロールしているのが現状である。本研究では、現状を打開するため、応募者らが最近得た知見を基に、独自の方法論を駆使して睡眠障害の詳細な分子・神経基盤を解明し、新たな治療法の確立に貢献する。

  7. レジリエンスを獲得させる新たなストレス関連障害治療戦略

    Grant number:22K19378  2022.6 - 2024.3

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    笠井 淳司

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    Authorship:Principal investigator 

    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

    高精細な高速全脳イメージングシステムFASTと、脳内空間情報を保持したシングル細胞トランスクリプトーム解析法を組み合わせ、ストレスレジリエンスを高める神経細胞のシングル細胞発現解析、薬理学的介入による神経活動への影響評価、行動薬理学的な検証を行う。
    ストレスは、ヒトの心身に悪影響を及ぼし、様々な精神疾患の原因になると考えられている。近年世界中で精神疾患患者数が増加しており、特に、気分障害やストレス関連障害の患者数の増加率は高い。最近ではCOVID-19感染の回復後に、約3割の患者が心的外傷後ストレス障害を発症するとの報告もある。また患者の約3割が治療抵抗性を示すことや寛解期からの再発リスクが高いことなど、既存のストレス関連障害の治療満足度は低い。既存の精神療法と薬物療法の治療法では、症状が改善した寛解期に患者自身でストレス要因に対処する力をつける必要がある。従って、患者自身の個々の力や環境に依存せず、ストレスレジリエンス(回復力)を高めれば、治療抵抗性や再発リスクを軽減できることに繋がり、有益な新規治療戦略になると考えられる。しかしながら、このストレスレジリエンスの生物学的なメカニズムは未だほとんど明らかにされていない。そこで本課題では、ストレスレジリエンスを高める神経細胞の遺伝的特性を同定し、その特性に基づき薬理学的に介入し、レリエンスを高める新規のストレス関連障害治療戦略を動物実験で実証することを目指している。本年度は、社会的敗北ストレス応答性神経細胞のシングル細胞発現解析、薬理学的介入による神経活動への影響評価を実施した。
    計画通り進捗し、シングル細胞トランスクリプトーム解析を終了し、薬理学的介入試験を開始できたため。
    行動薬理学的な介入の例数を重ね、レジリエンス獲得に向けた評価を試みる。

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  8. げっ歯類の嫉妬:全脳活動計測による嫉妬の生成モジュールの探索

    Grant number:22H05080  2022.5 - 2025.3

    日本学術振興会  科学研究費助成事業 学術変革領域研究(B)  学術変革領域研究(B)

    笠井 淳司, 野村 洋, 野村 洋

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    Authorship:Principal investigator 

    Grant amount:\56290000 ( Direct Cost: \43300000 、 Indirect Cost:\12990000 )

    社会的情動の一つである嫉妬(不公平嫌悪)は、時空間的に動的な脳活動によって処理さ
    れるため、静的な神経回路地図を描いてきた従来の研究戦略からの変革が必要である。そこで独自の技術を組み合わせ嫉妬に関わるミクロ・マクロ制御のダイナミックな活動連関を明らかにする。さらに大規模な活動計測・詳細な活動操作・嫉妬表出の観察を通して、社会的情動モデルの機能モジュールの仮説を実証し、本領域で作成するヒト共生ロボットの開発に貢献し、共生社会への応用を目指す。

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  9. 嫉妬の科学推進のための戦略的研究推進支援

    Grant number:22H05079  2022.5 - 2025.3

    日本学術振興会  科学研究費助成事業 学術変革領域研究(B)  学術変革領域研究(B)

    笠井 淳司, 田中 宏和, 野村 洋, 揚妻 正和, 日永田 智絵, 則武 厚, 田中 宏和, 野村 洋, 揚妻 正和, 日永田 智絵, 則武 厚

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    Authorship:Principal investigator 

    Grant amount:\5070000 ( Direct Cost: \3900000 、 Indirect Cost:\1170000 )

    本総括班では、「嫉妬」を神経科学とロボティクスの手法を融合して解明するため、各計画班の緊密な領域内連携を促し、各計画班の研究支援を実施する。また、積極的に研究成果の発信、領域外研究者への技術共有や国際共同研究の基盤構築を実施し、嫉妬の科学を周知することを目指している。本年度は、キックオフミーティング、数理解析サマーセミナー、ロボティクス研究セミナーを開催し、領域内・外の研究者の理解度向上とともに交流を促した。また、第100回日本生理学会大会にて、共催シンポジウムを開催し、本領域の成果を発信し、関係学会の会員に周知を図った。また、ホームページを開設し、本領域についての成果や研究方針等の情報を発信する基盤を構築した。

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  10. Mechanism of drug addiction based on multi-scale analysis

    2021.7 - 2025.3

    AMED 

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  11. Identity and circuit functions of glia engrams

    Grant number:21H02588  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

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  12. マルチスケール解析によるストレス性精神疾患の構成的理解

    Grant number:21H00200  2021.4 - 2023.3

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    笠井 淳司

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    Authorship:Principal investigator 

    Grant amount:\6110000 ( Direct Cost: \4700000 、 Indirect Cost:\1410000 )

    本課題では、分子、個々の神経活動、領野レベルの神経活動、行動レベルの多階層の統合的な解析を通じて、脳内のストレス応答性神経細胞が、どのようにして不安様行動やうつ様行動の発現制御に関わるのかを詳細に明らかにすることを目指している。本年度は、シングル細胞RNA-seq解析により、ストレス応答性神経細胞の分子特性を明らかにし、マーカー分子となる遺伝子の脳内局在をin situ hybridization法により確認した。さらに、そのマーカー分子発現細胞特異的にCreリコンビナーゼを発現するマウスの作製に着手した。

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  13. Elucidation of the etiology of neurodevelopmental disorders through multi-scale omics analysis

    Grant number:20K21479  2020.7 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    Kasai Atsushi

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    Authorship:Principal investigator 

    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

    The etiology of neurodevelopmental disorders, such as autism spectrum disorders, remains unclear, and the current interventions are severely limited. In this study, we aimed to elucidate the etiology of developmental disorders by combining birthdate tagging techniques during the cortical development period with whole-brain imaging to identify abnormal cell populations. Our findings revealed that heterogeneity in the distribution of neurons differentiating at E13.5 within the cerebral cortex, attributed to epigenetic changes. Additionally, we observed significant alterations in the distribution of inhibitory neurons compared to excitatory neurons. These findings contribute to future drug discovery research therapeutic target for neurodevelomental disorders.

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  14. 脳疾患の解明と創薬へ向けた疾患モデル脳のマルチスケールデータ解析

    Grant number:20H00492  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    橋本 均, 笠井 淳司, 勢力 薫, 笠井 淳司, 勢力 薫

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    Authorship:Coinvestigator(s) 

    本研究は、脳疾患と脳神経機能の発現機構の解析に貢献する観察・操作技術横断的な研究を推進するため、広範な空間分解能イメージングと細胞標識レポーターを用いた高精細・脳領域・細胞アトラスの構築を行い、正常脳と病態脳をアンバイアスに比較解析する方法を構築することを目的にしている。
    本年度は、高精細全脳イメージング装置FASTを改良し、シナプス構造である樹状突起スパイン等を観察するための超解像ユニットを導入すると共に、z方向の位置精度の向上、さらに高・低倍の対物レンズの併用・自動切り替え装置の開発を行った。
    また、多機能アトラスに統合するデータとして、保有する3q29欠失マウスや薬物投与マウスの全脳活動マップのデータを取得した。

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  15. 負の情動行動を制御する脳領域間情報動態の解明

    Grant number:20H05065  2020.4 - 2022.3

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    笠井 淳司

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    Authorship:Principal investigator 

    Grant amount:\5720000 ( Direct Cost: \4400000 、 Indirect Cost:\1320000 )

    負の情動行動制御におけるストレス情報のベクトルの向きや重みなど多領野の活動連関の制御機構を明らかにする。さらに、複数脳領域の活動パターンによる脳機能制御など脳特有の性質(Emergent properties)の理解を目指す。
    精神的ストレスは、ストレス応答機構としての不快情動を惹起し、不安などの情動行動を引き起こす。情動行動は、複数の脳情報の並列処理や同期的活動など、複数の脳領域の活動連関により制御されると考えられる。しかしながら、その詳細は不明である。そこで本課題では、多領野の活動を制御する脳領域のカルシウムイメージングを行った。観察した約20%の細胞の神経活動だけが、不安関連行動の直後に上昇することを見出した。この結果は、不安関連行動の制御に新たな細胞集団が関与する可能性を示しており、探索行動、覚醒レベル、情報処理などの不安応答プロセスにおいて、新たな神経メカニズムの一端を明らかにすることに成功した。
    令和3年度が最終年度であるため、記入しない。
    令和3年度が最終年度であるため、記入しない。

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  16. 中枢疾患創薬を加速する全脳細胞解析による不安障害の標的分子の探索

    2020.4 - 2022.3

    蓬庵社  令和2年度(第25回)特別研究助成 

    笠井淳司

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  17. 母体免疫活性と胎仔脳の相互作用に起因する社会性行動の異常に関わる全脳活動変化と分子基盤の解明

    2019.6 - 2021.3

    旭硝子財団  2019年度研究助成金 

    笠井 淳司

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    Authorship:Principal investigator  Grant type:Competitive

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  18. トランスオミックス解析によるストレス性精神疾患の構成的理解

    Grant number:19H05217  2019.4 - 2021.3

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    笠井 淳司

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    Authorship:Principal investigator 

    Grant amount:\6110000 ( Direct Cost: \4700000 、 Indirect Cost:\1410000 )

    本課題では、強い精神的ストレスにより惹起される不安様行動に関わる神経基盤の構成的要素を明らかにする。具体的には、全脳神経活動、神経回路網、遺伝子発現のトランスオミックス解析により、ストレス応答に特に重要な神経細胞の特性を、明らかにする。その特性を用いて各階層を操作し、自由行動下神経活動、行動(行動薬理学)の変化を解析し、ストレス性精神疾患の病態を創出する最小パーツを理解する。
    本課題は、精神的ストレスを暴露された脳内の多階層オミックス解析を実施し、ストレス性精神疾患病態の構成的な理解を目指している。昨年度までに、ストレス応答性前障神経細胞のシングル細胞トランスクリプトーム解析を実施し、複数の細胞群に分類した。これらの細胞群の役割を明らかにするため、各細胞の回路情報を全脳イメージングにより明らかにした。特にストレスや恐怖に応答することが知られている扁桃体基底外側核からの入力があることを見出した。また、扁桃体から前障に投射する神経終末を活性化させることにより不安様行動が惹起されることを見出し、ストレス誘発不安様行動に重要な神経回路であることを示した。さらに、前障ストレス応答性神経細胞の分子特性として、高発現する4つの遺伝子を同定することに成功した。今後は、これらの分子の発現制御がストレス性精神疾患の発症に関与するのかについて詳細に解析することにより、ストレス性精神疾患の病態を創出する最小パーツの理解に貢献したい。
    令和2年度が最終年度であるため、記入しない。
    令和2年度が最終年度であるため、記入しない。

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  19. Development of a single-cell RNA sequencing method linked to spatio-temporal cellular characteristics

    Grant number:18K19399  2018.6 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Challenging Research (Exploratory)  Challenging Research (Exploratory)

    Kasai Atsushi

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    Authorship:Principal investigator 

    Grant amount:\6240000 ( Direct Cost: \4800000 、 Indirect Cost:\1440000 )

    Drug discovery for psychiatric disorders including depression and post-traumatic stress disorder has not been successful for many years. One of the reasons for this is thought to be the problem of omics research method, which is hypothesis-based analysis of local brain regions. Here, to identify therapeutic targets for psychiatric disorders, we established a methodology combining data-driven analysis of brain-wide activation mapping with single-cell transcriptome analysis linking the spatial information. Using this methodology, we revealed the molecular characteristics of an ensemble that are important for stress response, and found new candidate therapeutic target molecules for stress-induced mental disorders.

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  20. 高精細全脳イメージングを用いた負の情動行動制御における多領野連関解析

    Grant number:18H05132  2018.4 - 2020.3

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    笠井 淳司

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    Authorship:Principal investigator 

    Grant amount:\5720000 ( Direct Cost: \4400000 、 Indirect Cost:\1320000 )

    本研究は、前障のストレス応答神経細胞の活動を回路特異的に操作し、最新光学イメージング法FASTによる全脳活動マッピングを実施し、負の情動行動制御機構における多領野連関の解読を目指している。本年度は、以下の成果を得た。
    1)前障のストレス応答性神経細胞の活動操作による行動変化
    ストレスにより活性化する前障の神経細胞を特異的に活動操作するため、2種類のアデノ随伴ウイルスベクター(AAV)を用いて、ストレス刺激特異的に応答する神経細胞にDREADD受容体を発現させ、活動操作した。その結果、オープンフィールド試験および高架式十字迷路試験において不安様行動を誘発することを見出した。
    2)多領野神経活動に与える影響
    1)と同様にストレスに応答した細胞のみを再度活性化させた際に前頭前皮質や扁桃体を含む多領野の神経活動が活性化する結果を得た。

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  21. 脳機能解明に資する細胞種特異的な多色蛍光標識マウスの開発

    2018

    株式会社ケー・エー・シー  創立40周年記念研究助成 

    笠井 淳司

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\1000000 ( Direct Cost: \1000000 )

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  22. Whole brain activity mapping and analysis of neuronal innervation in a stress model

    Grant number:15K14964  2015.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    Kasai Atsushi, HASHIMOTO Hitoshi, YAMANAKA Akihiro, YAMAGUCHI Shun, HASHIMOTO Takeshi, HASHIMOTO Hitoshi, YAMANAKA Akihiro, YAMAGUCHI Shun, HASHIMOTO Takeshi

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    Authorship:Principal investigator 

    Grant amount:\3770000 ( Direct Cost: \2900000 、 Indirect Cost:\870000 )

    In order to understand the pathogenic mechanisms of stress-related mental disorders, it is needed to systemically identify brain functional alterations in stress exposure. We recently developed an automated imaging system with high speed at subcellular resolution, named FAST. Here, to reveal spatial patterns of stress-related neuronal activation, we performed whole-brain imaging of stressed Arc-dVenus reporter mice which expressed destabilized Venus in activated neurons, and compared of the number and distribution of dVenus-positive cells among control and stressors by FAST system. Mental stress increased the number of dVenus positive-cells in several brain regions. Moreover, we found stress-related neuronal circuitries including these nuclei by anatomical investigation of projections using anterograde and retrograde tracing. These results lead to a better understanding of anatomo-functional neuronal networks related with stress-induced psychiatric disorders.

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  23. Functional analyses of mitochondrial fusion inhibition in the regulation of neuronal cells

    Grant number:25670038  2013.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    SHINTANI NORIHITO, KASAI ATSUSHI, BABA AKEMICHI, KASAI ATSUSHI, BABA AKEMICHI

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    Authorship:Coinvestigator(s) 

    Recently, much attention has been gathered on the mitochondrial fusion and division machinery as a novel drug targets for neurodegenerative diseases. In this study, we performed functional analyses of the novel factor MIFI (mitochondrial fusion inhibitor) in the neuronal development and cell death. The obtained results suggested that MIFI functions in the neuronal cells possibly from early development, is associated with oxidative stress status, and shows stimulatory effects in the insult-induced cell death of neuroblastoma SH-SY5Y cells. In addition, this study developed essential research tools for the further functional analyses of MIFI, such as chemical compounds regulating MIFI expression and mice lacking MIFI.

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  24. Neural stem cells have directivity characteristics in the cell fate decision.

    Grant number:25670037  2013.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    KASAI Atsushi

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    Authorship:Principal investigator 

    Grant amount:\3900000 ( Direct Cost: \3000000 、 Indirect Cost:\900000 )

    Neural stem cells have pluripotency to differentiate into a variety of neural cells, such as neuron and glia cells. Here, we showed that noggin treatment to embryonic stem cells changed miRNA expression patterns in neural stem cells differentiated by diverse methods and increased serotonin neuronal differentiation. These findings suggest that pluripotency of neural stem cells may be already assigned the directional differentiation.

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  25. Involvement of Apelin/APJ system in intraocular neovascularizatio

    Grant number:22591942  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    GOMI Fumi, OSHIMA Yusuke, SUZUKI Mihoko, IKUNO Yasushi, SAWA Miki, BABA Akemichii, KASAI Atushi, OSHIMA Yusuke, SUZUKI Mihoko, IKUNO Yasushi, SAWA Miki, BABA Akemichii, KASAI Atushi

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Competitive

    Apelin induces the hypoxia-induced retinal angiogenesisindependent of the VEGF/VEGF receptor 2 signaling pathway. Apelin is also involved in the development of choroidal neovascularization. Therefore, a therapy targeting of apelin possibly rescues nonresponders for anti-VEGF treatment.

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  26. Research on the onset and progression of amyotrophic lateral sclerosis using genetically modified animals

    Grant number:21590110  2009 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    MAEDA Sadaaki, YOSHIOKA Yasuhiro, YAMAMURO Akiko, ISHIMARU Yuki, KASAI Atsushi, YOSHIOKA Yasuhiro, YAMAMURO Akiko, ISHIMARU Yuki, KASAI Atsushi

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Competitive

    We examined whether apelin is an endogenous neuroprotective factor using SOD1(G93A) mouse model of ALS. Double mutant apelin-deficient and SOD1(G93A) displayed the disease phenotypes earlier than SOD1(G93A) littermates. In addition, the number of motor neurons was decreased in the spinal cord of the double mutant mice. Furthermore, we showed that apelin enhanced the protective effect of VEGF on hydrogen peroxide-induced neuronal death in primary neurons. These results suggest that apelin/APJ system in the spinal cord has a neuroprotective effect against the pathogenesis of ALS, and that apelin may be a useful therapeutic target for ALS.

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  27. Possibility of apelin in ischemic retinal disease as a new target for drug development

    Grant number:21790098  2009 - 2010

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    KASAI Atsushi

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    Pathological angiogenesis in patients with ischemic retinal diseases such as diabetic retinopathy results in visual loss and blindness, because the newly formed vessels are quite leaky and can cause vitreous hemorrhage. We previously reported that a dramatic upregulation of apelin expression cause exuberant endothelial cell proliferation and pathological angiogenesis in retinas of oxygen-induced retinopathy model. Here, we demonstrate that in vivo delivery of apelin siRNA to retina resulted in suppression of pathological angiogenesis in oxygen-induced retinopathy model.

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  28. オーファンGPCRリガンドapelinの神経保護作用に関する神経薬理学的研究

    2009

    日本科学協会  笹川科学研究助成 

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    Grant type:Competitive

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  29. 筋萎縮性側索硬化症モデルマウスを用いた新規創薬標的分子の探索

    2008 - 2010

    内藤記念科学振興財団  内藤記念科学奨励金・研究助成 

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    Grant type:Competitive

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  30. Involvement of apelin, an endogenous ligand for GPCR APJ, in the development of ischemic retinopathy

    Grant number:19890247  2007 - 2008

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (Start-up)  Grant-in-Aid for Young Scientists (Start-up)

    KASAI Atsushi

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3075000 ( Direct Cost: \2670000 、 Indirect Cost:\405000 )

    糖尿病網膜症などの虚血性網膜症の病態進行に病的な血管新生が深く関与していることが知られている。今回,新規生理活性物質apelinが,虚血性血管新生に関与するのか否かを検討した。その結果,マウス虚血性網膜症(ROP)モデルの網膜において, apelin発現が劇的に上昇していることを明らかにした。また, apelin遺伝子欠損マウスを用いたROPモデルにおいて,野生型マウスと比較して有意に網膜血管量が低下していた。これらの結果から,内因性apelinは,病的な虚血性血管新生に対し,促進的に作用する因子であることを明らかにした。

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