or sham-irradiation and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem (S)-MCPG neurogenesis levels. Results: Exposing NHPs to repeated separation stress resulted in depression-like behaviors 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. Conclusion: 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. Citation: Perera TD, Dwork AJ, Keegan KA, Thirumangalakudi L, Lipira CM, et al. Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates. PLoS ONE 6: e17600. doi:10.1371/journal.pone.0017600 Editor: Tadafumi Kato, RIKEN Brain Science Institution, Japan Received November 11, 2010; Accepted February 1, 2011; Published April 15, 2011 Copyright: 2011 Perera et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Funding was provided to Dr. Perera from the National Institute of Mental Health and NARSAD and to Dr. Coplan from NIMH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. E-mail: [email protected] Introduction Major depression is consistently associated with decreased hippocampal volumes and deficits in hippocampus-dependent cognition,. Some of these deficits may reflect structural changes in the hippocampal dentate gyrus. In preclinical studies, factors that predispose to depression, such as social stress,, maternal neglect, and drug abuse decrease rates 21609844 of new neuron formation in the dentate gyrus and cause cell atrophy and death in the CA1/CA3 region of the adult rodent hippocampus. Interventions that ameliorate major depression, including antidepressant medications, electroconvulsive therapy , exercise, and environmental enrichment stimulate dentate gyrus neurogenesis. These findings led to the hypotheses April 2011 | Volume 6 | Issue 4 | e17600 Neurogenesis Necessity for Antidepressants Action that suppression of neurogenesis leads to depression, and that stimulation of neurogenesis is required for treating depression,. Despite generating widespread interest, this hypothesis is based mainly on indirect evidence derived mostly from rodents. A major limitation of 
rodent studies is that the phen