Social isolation reinforces aging-related behavioral inflexibility by promoting neuronal necroptosis in basolateral amygdala.
Social isolation reinforces aging-related behavioral inflexibility by promoting neuronal necroptosis in basolateral amygdala.
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社会隔离通过促进基底外侧杏仁核的神经元坏死而强化与衰老相关的行为僵化
DOI：
10.1038/s41380-022-01694-5
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发表时间：
2022-10
影响因子：
2.8
通讯作者：
Li, Chuanqi
中科院分区：
文献类型：
--
作者：
Zhang, Jiamin;Dias, Daniel;An, Lu;Li, Chuanqi
衰老的特征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偶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，我们报道了坏死性下垂诱导的杏仁基底外侧核(BLA)神经元活性降低在5个月大的SAMP8系小鼠行为不灵活中起着重要作用，SAMP8系是一种成熟的具有年龄相关表型的模型。应用NEC-1S，一种特定的坏死性下垂抑制剂，逆转了SAMP8小鼠行为灵活性的损害。我们进一步观察到糖原合成酶-3α(GSK-3α)的缺失与老年小鼠血乳酸和老年食蟹猴杏仁核中的坏死性下垂密切相关。此外，GSK-3α基因缺失或敲除可导致野生型小鼠坏死性下垂的激活和行为灵活性的降低，而白血球中GSK-3α表达的恢复则阻止了老年小鼠的坏死性下垂和行为不灵活。我们进一步观察到，GSK-3α缺失导致mTORC 1信号的激活，从而促进依赖于RIPK3的坏死性下垂。重要的是，我们发现，社会隔离，一种在老年人中普遍存在的现象，促进了4个月大的SAMP8小鼠的坏死性下垂和行为不灵活。总体而言，我们的研究不仅揭示了老年人行为灵活性障碍的分子机制，而且确定了一个关键的生活方式危险因素和可能的干预策略。
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.
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1080/19648189.2018.1531268
发表时间：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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