Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis.

Environmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long-term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long-term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long-term effects of transient ablation of dividing stem cells during adolescence or adulthood, we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.

生命早期（而非青春期或成年期）的环境暴露会导致成年海马齿状回（DG）神经发生持续减少。生命早期暴露导致神经发生长期缺陷的机制仍不清楚。在此，我们研究了在生命早期定向消融分裂的神经干细胞是否足以使DG神经发生长期减少。我们之前发现，在青春期或成年期，干细胞谱系对分裂干细胞的短暂消融的长期影响具有抵抗力，因此我们使用了一种类似的药物遗传学方法，在对环境损伤敏感的生命早期靶向分裂的神经干细胞进行清除。然后我们评估了成年期的巢蛋白干细胞谱系。我们发现，在出生后第一周（此时干细胞高度增殖）进行消融后，成年神经干细胞库会耗尽，但在出生后第三周（此时干细胞更静止）消融则不会。值得注意的是，在出生后第一周或第三周消融增殖的干细胞都会导致成年神经发生减少，且减少程度与干细胞池的变化不成比例，这表明在生命早期干细胞消融后干细胞功能或微环境受到了破坏。这些结果强调出生后的前三周是一系列敏感期，在此期间消融分裂的干细胞会导致成年DG神经发生和干细胞功能的持久改变。这些发现有助于我们理解DG发育与成年神经发生之间的关系，并提出了生命早期经历可能导致成年海马神经发生持久缺陷的一种可能机制。