Antidepressant drugs reverse the loss of adult neural stem cells following chronic stress.
In rodents, adult neurogenesis occurs in the olfactory bulb and the dentate gyrus of the hippocampus. It has been shown that exposure to psychosocial stress reduces cell proliferation in the dentate gyrus. However, little is known about how stress affects the proliferation kinetics of neural stem cells (NSCs) in the subventricular zone (SVZ), which provide new neurons to the olfactory bulb. We utilized a forced-swim model of stress in the mouse and found that chronic stress decreased the number of NSCs in the SVZ. The reduction of NSC number persisted for weeks after the cessation of stress but was reversed by treatment with the antidepressant drugs fluoxetine and imipramine. We demonstrated by in vitro colony-forming neurosphere assay that corticosterone attenuated neurosphere formation by adult NSCs and, in contrast, that serotonin increased the survival of NSCs. In addition, serotonin expanded the size of the NSC pool in the SVZ when it was infused into the lateral ventricle in vivo. These results suggest that, under chronic stress conditions, the number of NSCs is regulated by the actions of glucocorticoids and serotonin. These data provide insights into the molecular mechanisms underlying the pharmacological actions of antidepressant drugs.
Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Japan. shitoshi@nips.ac.jp
Seiji
S
Hitoshi
Noriko
N
Maruta
Mikito
M
Higashi
Akhilesh
A
Kumar
Nobumasa
N
Kato
Kazuhiro
K
Ikenaka
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001681:Biological Assay; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002908:Chronic Disease; D003345:Corticosterone / Q000009:adverse effects; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D005938:Glucocorticoids / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology; D020547:Lateral Ventricles / Q000166:cytology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D009830:Olfactory Bulb / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D018874:Spheroids, Cellular; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology; D013315:Stress, Psychological / Q000150:complications*; D013550:Swimming / Q000523:psychology; D013687:Telencephalon / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology
D000928:Antidepressive Agents; D003345:Corticosterone; D005473:Fluoxetine; D005938:Glucocorticoids; D007099:Imipramine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors