Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Neuron. 2018 May 2;98(3):562-574.e5. doi: 10.1016/j.neuron.2018.03.039. Epub 2018 Apr 12.
Perhaps the most devastating decline with age is the loss of memory. Therefore, identifying mechanisms to restore memory function with age is critical. Using C. elegans associative learning and memory assays, we identified a gain-of-function G signaling pathway mutant that forms a long-term (cAMP response element binding protein [CREB]-dependent) memory following one conditioned stimulus-unconditioned stimulus (CS-US) pairing, which usually requires seven CS-US pairings. Increased CREB activity in AIM interneurons reduces the threshold for memory consolidation through transcription of a set of previously identified "long-term memory" genes. Enhanced G signaling in the AWC sensory neuron is both necessary and sufficient for improved memory and increased AIM CREB activity, and activation of G specifically in aged animals rescues the ability to form memory. Activation of G in AWC sensory neurons non-cell autonomously induces consolidation after one CS-US pairing, enabling both cognitive function maintenance with age and restoration of memory function in animals with impaired memory performance without decreased longevity.
随着年龄的增长，记忆力下降可能是最具破坏性的。因此，识别恢复与年龄相关的记忆功能的机制至关重要。使用秀丽隐杆线虫的联想学习和记忆测定法，我们发现一种功能获得的 G 信号通路突变体，在一次条件刺激-非条件刺激（CS-US）配对后形成长期（cAMP 反应元件结合蛋白 [CREB] 依赖性）记忆，而通常需要七次 CS-US 配对。AIM 中间神经元中 CREB 活性的增加通过一组先前鉴定的“长时记忆”基因的转录降低了记忆巩固的阈值。AWC 感觉神经元中增强的 G 信号对于改善记忆和增加 AIM CREB 活性是必要且充分的，并且在年老动物中特异性激活 G 可以挽救形成记忆的能力。AWC 感觉神经元中 G 的激活非细胞自主地诱导 CS-US 配对后的巩固，使动物的认知功能随着年龄的增长得以维持，并在记忆功能受损的动物中恢复记忆功能，而不会降低寿命。
