title: Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4.
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.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Jaesuk
authors.initials: J
authors.lastname: Yun
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koike
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ibi
authors.forename: Erika
authors.initials: E
authors.lastname: Toth
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoneyama
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Ogita
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yoneda
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000502:physiology*; D001835:Body Weight; D001921:Brain / Q000378:metabolism*; D002908:Chronic Disease; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D005239:Fear; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008568:Memory; D051379:Mice; D008813:Mice, Inbred ICR; D055495:Neurogenesis; D009929:Organ Size; D012333:RNA, Messenger / Q000096:biosynthesis; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003345:Corticosterone; D012333:RNA, Messenger; C533005:Npas4 protein, mouse