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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1
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Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1

机译：缺乏热休克因子1的小鼠海马自旋和神经发生受损以及情感行为改变

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摘要

Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and patho-physiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1~(-/-)) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1~(-/-) mice. In addition, HSF1~(-/-) mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. fuerthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid-neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1~(-/-) mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.
机译：大脑中异常的转录调节被认为是神经精神疾病的发病机理和病理生理的关键组成部分之一。热休克因子（HSF）通过控制基因表达来调节细胞稳态。但是，HSF在脑功能中的作用尚未完全阐明。在本研究中，我们试图阐明使用HSF1缺陷（HSF1〜（-/-））小鼠的HSF1介导的基因调控在神经元和行为发育中的作用。我们在HSF1〜（-/-）小鼠的齿状回中发现异常形态的颗粒神经元和受损的神经发生。此外，HSF1〜（-/-）小鼠表现出异常的情感行为，包括减少的焦虑和社交能力，但增加了抑郁样行为和攻击性。此外，HSF1缺乏症增加了反复暴露于约束压力下的行为脆弱性。重要的是，抢救新生儿中的HSF1缺乏症而不是成年海马体可以逆转异常的焦虑和抑郁样行为。这些结果表明海马HSF1在神经元和行为发展中的关键作用。分子机制分析表明，HSF1直接调节多唾液酸转移酶基因的表达，然后调节海马中的多唾液酸-神经细胞粘附分子（PSA-NCAM）水平。酶从新生儿海马中去除PSA会导致成年期间的异常行为，类似于在HSF1〜（-/-）小鼠中观察到的行为。因此，这些结果表明，HSF1的一个作用是通过聚唾液酸转移酶的转录调控来控制海马PSA-NCAM的水平，这一过程可能与小鼠的神经元和行为发育有关。

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  • 作者

    Shusaku Uchida; Kumiko Hara; Ayumi Kobayashi; Mitsuaki Fujimoto; Koji Otsuki; Hirotaka Yamagata; Teruyuki Hobara; Naoko Abe; Fumihiro Higuchi; Tomohiko Shibata; Shunsuke Hasegawa; Satoshi Kida; Akira Nakai; Yoshifumi Watanabe;

  • 作者单位

    Division of Neuropsychiatry, Department of Neuroscience, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Division of Neuropsychiatry, Department of Neuroscience, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Division of Neuropsychiatry, Department of Neuroscience, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Department of Biochemistry and Molecular Biology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Division of Neuropsychiatry, Department of Neuroscience, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Division of Neuropsychiatry, Department of Neuroscience, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Division of Neuropsychiatry, Department of Neuroscience, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Division of Neuropsychiatry, Department of Neuroscience, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Division of Neuropsychiatry, Department of Neuroscience, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Division of Neuropsychiatry, Department of Neuroscience, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan;

    Department of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan;

    Department of Biochemistry and Molecular Biology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

    Division of Neuropsychiatry, Department of Neuroscience, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    emotion; spine density; neuronal maturation; polysialylation;

    机译：情感;脊柱密度;神经元成熟;多唾液酸化;

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