Aging is characterized with a progressive decline in many cognitive functions, including behavioral flexibility, an important ability to respond appropriately to changing environmental contingencies. However, the underlying mechanisms of impaired behavioral flexibility in aging are not clear. In this study, we reported that necroptosis-induced reduction of neuronal activity in the basolateral amygdala (BLA) plays an important role in behavioral inflexibility in 5-month-old mice of the senescence-accelerated mice prone-8 (SAMP8) line, a well-established model with age-related phenotypes. Application of Nec-1s, a specific inhibitor of necroptosis, reversed the impairment of behavioral flexibility in SAMP8 mice. We further observed that the loss of glycogen synthase kinase 3α (GSK-3α) was strongly correlated with necroptosis in the BLA of aged mice and the amygdala of aged cynomolgus monkeys (Macaca fascicularis). Moreover, genetic deletion or knockdown of GSK-3α led to the activation of necroptosis and impaired behavioral flexibility in wild-type mice, while the restoration of GSK-3α expression in the BLA arrested necroptosis and behavioral inflexibility in aged mice. We further observed that GSK-3α loss resulted in the activation of mTORC1 signaling to promote RIPK3-dependent necroptosis. Importantly, we discovered that social isolation, a prevalent phenomenon in aged people, facilitated necroptosis and behavioral inflexibility in 4-month-old SAMP8 mice. Overall, our study not only revealed the molecular mechanisms of the dysfunction of behavioral flexibility in aged people but also identified a critical lifestyle risk factor and a possible intervention strategy.

衰老的特点是许多认知功能逐渐下降，包括行为灵活性，这是一种对不断变化的环境突发事件做出适当反应的重要能力。然而，衰老过程中行为灵活性受损的潜在机制尚不清楚。在这项研究中，我们报道了坏死性凋亡诱导的基底外侧杏仁核 (BLA) 神经元活动减少在 5 个月大的衰老加速小鼠 prone-8 (SAMP8) 系小鼠的行为不灵活中起着重要作用，a具有年龄相关表型的成熟模型。Nec-1s（一种坏死性凋亡的特异性抑制剂）的应用逆转了 SAMP8 小鼠行为灵活性的损害。食蟹猴)。此外，GSK-3α 的基因缺失或敲低导致野生型小鼠坏死性凋亡的激活和行为灵活性受损，而 BLA 中 GSK-3α 表达的恢复阻止了老年小鼠的坏死性凋亡和行为不灵活。我们进一步观察到 GSK-3α 缺失导致 mTORC1 信号激活，从而促进 RIPK3 依赖性坏死性凋亡。重要的是，我们发现社交隔离是老年人普遍存在的现象，它促进了 4 个月大的 SAMP8 小鼠的坏死性凋亡和行为不灵活。总的来说，我们的研究不仅揭示了老年人行为灵活性功能障碍的分子机制，而且确定了一个关键的生活方式风险因素和可能的干预策略。