Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4.
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.
Yun
Jaesuk
J
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Koike
Hiroyuki
H
Ibi
Daisuke
D
Toth
Erika
E
Mizoguchi
Hiroyuki
H
Nitta
Atsumi
A
Yoneyama
Masanori
M
Ogita
Kiyokazu
K
Yoneda
Yukio
Y
Nabeshima
Toshitaka
T
Nagai
Taku
T
Yamada
Kiyofumi
K
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*
D051792:Basic Helix-Loop-Helix Proteins; D003345:Corticosterone; D012333:RNA, Messenger; C533005:Npas4 protein, mouse