Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4

Authors

  • Jaesuk Yun,

    1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
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    • These authors contributed equally to this study.

  • Hiroyuki Koike,

    1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
    2. Laboratory of Molecular Pharmacology, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan
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    • These authors contributed equally to this study.

  • Daisuke Ibi,

    1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
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  • Erika Toth,

    1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
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  • Hiroyuki Mizoguchi,

    1. Futuristic Environmental Simulation Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
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  • Atsumi Nitta,

    1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
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  • Masanori Yoneyama,

    1. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
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  • Kiyokazu Ogita,

    1. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan
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  • Yukio Yoneda,

    1. Laboratory of Molecular Pharmacology, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan
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  • Toshitaka Nabeshima,

    1. Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan
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  • Taku Nagai,

    1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
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  • Kiyofumi Yamada

    1. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
    2. CREST, JST, Nagoya, Japan
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Address correspondence and reprint requests to Dr Kiyofumi Yamada, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan. E-mail: kyamada@med.nagoya-u.ac.jp

Abstract

J. Neurochem. (2010) 114, 1840–1851.

Abstract

Neurogenesis in the hippocampus occurs throughout life in a wide range of species and could be associated with hippocampus-dependent learning and memory. Stress is well established to seriously perturb physiological/psychological homeostasis and affect hippocampal function. In the present study, to investigate the effect of chronic restraint stress in early life on hippocampal neurogenesis and hippocampus-dependent memory, 3-week-old mice were subjected to restraint stress 6 days a week for 4 weeks. The chronic restraint stress significantly decreased the hippocampal volume by 6.3% and impaired hippocampal neurogenesis as indicated by the reduced number of Ki67-, 5-bromo-2′-deoxyuridine- and doublecortin-positive cells in the dentate gyrus. The chronic restraint stress severely impaired hippocampus-dependent contextual fear memory without affecting hippocampus-independent fear memory. The expression level of brain-specific transcription factor neuronal PAS domain protein 4 (Npas4) mRNA in the hippocampus was down-regulated by the restraint stress or by acute corticosterone treatment. Npas4 immunoreactivity was detected in progenitors, immature and mature neurons of the dentate gyrus in control and stressed mice. Our findings suggest that the chronic restraint stress decreases hippocampal neurogenesis, leading to an impairment of hippocampus-dependent fear memory in mice. Corticosterone-induced down-regulation of Npas4 expression may play a role in stress-induced impairment of hippocampal function.

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