title: Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates.
abstract: BACKGROUND
  Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels.
  
  
  RESULTS
  Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation.
  
  
  CONCLUSIONS
  We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.
authors.affiliation: Department of Psychiatry, College of Physicians and Surgeons, Columbia University Medical Center and New York State Psychiatric Institute, New York, New York, United States of America. tp119@columbia.edu
authors.forename: Tarique D
authors.initials: TD
authors.lastname: Perera
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dwork
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Keegan
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Thirumangalakudi
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lipira
authors.forename: Niamh
authors.initials: N
authors.lastname: Joyce
authors.forename: Christopher
authors.initials: C
authors.lastname: Lange
authors.forename: J Dee
authors.initials: JD
authors.lastname: Higley
authors.forename: Gorazd
authors.initials: G
authors.lastname: Rosoklija
authors.forename: Rene
authors.initials: R
authors.lastname: Hen
authors.forename: Harold A
authors.initials: HA
authors.lastname: Sackeim
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Coplan
mesh_terms: D000375:Aging / Q000187:drug effects*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000089622:Doublecortin Domain Proteins; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D011323:Primates / Q000502:physiology*
chemical_list: D000928:Antidepressive Agents; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides