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.
PLoS One. 2011 Apr 15;6(4):e17600. doi: 10.1371/journal.pone.0017600.
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.
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.
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.
啮齿动物研究表明，神经发生对于介导抗抑郁药的有益作用是必要的。非人类灵长类动物（NHP）研究可能会将重要的啮齿动物发现与临床领域联系起来，因为 NHP 抑郁症与人类抑郁症具有显著的同源性，并且灵长类动物的神经发生动力学与啮齿动物不同。在证明抗抑郁药可以刺激 NHP 的神经发生之后，我们目前的研究检查了神经发生是否是 NHP 抗抑郁药疗效所必需的。
材料/方法：成年雌性凤头猕猴被随机分配到三个社会围栏（每组 6 只）。围栏 1 的动物接受了 15 周的对照条件，其中一半接受了抗抑郁药氟西汀，另一半接受了生理盐水安慰剂。围栏 2 的动物接受了 15 周的分离应激，其中一半接受了氟西汀，另一半接受了安慰剂。围栏 3 的动物 2 周接受辐照（N=4）或假辐照（N=2），然后暴露于 15 周的应激和氟西汀中。依赖测量是每周的行为观察和死后神经发生水平。
反复分离应激使 NHP 产生类似抑郁症的行为（快感缺失和从属），同时减少了海马神经发生。氟西汀治疗刺激了神经发生并预防了类似抑郁症的行为的出现。用辐照消除神经发生会消除氟西汀的治疗效果。未受压力的对照动物具有正常行为，尽管氟西汀治疗的对照动物具有更高的神经发生率。在所有组中，类似抑郁症的行为与神经发生率降低有关，但这种负相关仅对前齿状回即将完成成熟的新神经元具有统计学意义。
我们提供的证据表明，神经发生的诱导是氟西汀在 NHP 中治疗效果的必要组成部分。鉴于猴子和人类之间的相似性，海马神经发生可能在治疗临床抑郁症中发挥类似的作用。未来的研究将研究几个悬而未决的问题，例如神经抑制是否足以产生抑郁症，以及氟西汀的治疗性神经可塑性作用是否特定于抗抑郁药。
