Max Planck Institute of Psychiatry, Munich, Germany.
Hippocampus. 2010 Apr;20(4):540-9. doi: 10.1002/hipo.20655.
Age-related cognitive decline is one of the major aspects that impede successful aging in humans. Environmental factors, such as chronic stress, can accelerate or aggravate cognitive deficits during aging. While there is abundant evidence that chronic stress directly affects cognitive performance, the lasting consequences of stress exposures during vulnerable developmental time windows are largely unknown. This is especially true for the adolescent period, which is critical in terms of physical, sexual, and behavioral maturation. Here we used chronic social stress during adolescence in male mice and investigated the consequences of this treatment on cognitive performance during aging. We observed a substantial impairment of spatial memory, but not other memory domains, 12 months after the end of the stress period. This hippocampus-dependent cognitive dysfunction was supported by concomitant impairment in LTP induction in CA1 neurons in 15-month-old animals. Further, we observed a decrease of hippocampal BDNF mRNA and synaptophysin immunoreactivity, suggesting plasticity and structural alterations in formerly stressed mice. Finally, we identified expression changes of specific neurotransmitter subunits critically involved in learning and memory, specifically the NMDA receptor subunit NR2B. Taken together, our results identify possible molecular mechanisms underlying cognitive impairment during aging, demonstrating the detrimental impact of stress during adolescence on hippocampus-dependent cognitive function in aged mice.
年龄相关性认知衰退是阻碍人类成功衰老的主要方面之一。环境因素，如慢性压力，可以加速或加重衰老过程中的认知缺陷。虽然有大量证据表明慢性压力直接影响认知表现，但在脆弱的发育窗口期暴露于压力的持久后果在很大程度上尚不清楚。对于青春期来说尤其如此，因为青春期在身体、性和行为成熟方面是至关重要的。在这里，我们在雄性小鼠的青春期使用慢性社交应激，并研究了这种治疗对衰老期间认知表现的后果。我们观察到，在应激期结束 12 个月后，空间记忆有明显的损伤，但其他记忆领域没有损伤。这种海马依赖的认知功能障碍得到了 15 个月大的动物中海马 CA1 神经元 LTP 诱导同时受损的支持。此外，我们观察到海马 BDNF mRNA 和突触小体免疫反应性降低，提示以前应激的小鼠存在可塑性和结构改变。最后，我们确定了特定神经递质亚基的表达变化，这些亚基在学习和记忆中起着关键作用，特别是 NMDA 受体亚基 NR2B。总之，我们的研究结果确定了衰老期间认知障碍的潜在分子机制，证明了青春期压力对老年小鼠海马依赖认知功能的有害影响。
