Abstract
BackgroundRodent 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/MethodologyAdult 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.ResultsExposing 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.ConclusionWe 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.
Highlights
Major depression is consistently associated with decreased hippocampal volumes and deficits in hippocampus-dependent cognition [1], [2]
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
We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in Nonhuman primate (NHP)
Summary
Major depression is consistently associated with decreased hippocampal volumes and deficits in hippocampus-dependent cognition [1], [2]. Factors that predispose to depression, such as social stress [3], [4], maternal neglect [5], and drug abuse [6] decrease rates of new neuron formation (neurogenesis) 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 (ECT) [7], exercise, and environmental enrichment [8] stimulate dentate gyrus neurogenesis. These findings led to the hypotheses that suppression of neurogenesis leads to depression, and that stimulation of neurogenesis is required for treating depression [9], [10]. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels
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