Depression is a leading cause of disability worldwide, in part because the available treatments are inadequate and do not work for many people. The neurobiology of depression, and the mechanism of action of common antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), is not well understood. One mechanism thought to underlie the effects of these drugs is upregulation of adult hippocampal neurogenesis. Evidence indicates that vesicular zinc is required for modulation of adult hippocampal neurogenesis, at least under some circumstances. Vesicular zinc refers to zinc that is stored in the synaptic vesicles of certain neurons, including in the hippocampus, and released in response to neuronal activity. It can be eliminated from the brain by deletion of zinc transporter 3 (ZnT3), as is the case in ZnT3 knockout mice. Here, we examined the effects of repeated social defeat stress and subsequent chronic treatment with the SSRI fluoxetine on behavior and neurogenesis in ZnT3 knockout mice. We hypothesized that fluoxetine treatment would increase neurogenesis and reverse stress‐induced behavioral symptoms in wild type, but not ZnT3 knockout, mice. As anticipated, stress induced persistent depression‐like effects, including social avoidance and anxiety‐like behavior. Fluoxetine decreased social avoidance, though the effect was not specific to the stressed mice, but did not affect anxiety‐like behavior. Surprisingly, stress increased the survival of neurons born 1 day after the last episode of defeat stress. Fluoxetine treatment also increased cell survival, particularly in wild type mice, though it did not affect proliferation. Our results did not support our hypothesis that vesicular zinc is required for the behavioral benefits of fluoxetine treatment. As to whether vesicular zinc is required for the neurogenic effects of fluoxetine, our results were inconclusive, warranting further investigation into the role of vesicular zinc in adult hippocampal neurogenesis.

中文翻译：

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社会失败压力和氟西汀治疗对缺乏锌转运蛋白 3 (ZnT3) 和囊泡锌的小鼠的神经发生和行为的影响。

抑郁症是世界范围内导致残疾的主要原因，部分原因是可用的治疗方法不充分，对许多人不起作用。抑郁症的神经生物学和常见抗抑郁药物（如选择性 5-羟色胺再摄取抑制剂 (SSRI)）的作用机制尚不清楚。一种被认为是这些药物作用基础的机制是成年海马神经发生的上调。证据表明，至少在某些情况下，调节成人海马神经发生需要泡状锌。囊泡锌是指储存在某些神经元（包括海马体）的突触囊泡中的锌，并响应神经元活动而释放。它可以通过删除锌转运蛋白 3 (ZnT3) 从大脑中消除，就像 ZnT3 基因敲除小鼠的情况一样。这里，我们检查了反复社交失败压力和随后用 SSRI 氟西汀长期治疗对 ZnT3 基因敲除小鼠行为和神经发生的影响。我们假设氟西汀治疗会增加野生型小鼠的神经发生并逆转应激诱导的行为症状，但不会影响 ZnT3 基因敲除小鼠。正如预期的那样，压力会导致持续的抑郁样效应，包括社交回避和焦虑样行为。氟西汀降低了社交回避，虽然这种效果不是针对应激小鼠的，但不影响焦虑样行为。令人惊讶的是，压力增加了在最后一次失败压力发作后 1 天出生的神经元的存活率。氟西汀治疗也增加了细胞存活率，特别是在野生型小鼠中，尽管它不影响增殖。我们的结果不支持我们的假设，即氟西汀治疗的行为益处需要囊泡锌。至于氟西汀的神经源性作用是否需要囊泡锌，我们的结果尚无定论，需要进一步研究囊泡锌在成人海马神经发生中的作用。