Huang Sheng, Piao Chengji, Zhao Zhiying, Beuschel Christine B, Turrel Oriane, Toppe David, Sigrist Stephan J
Institute for Biology/Genetics, Freie Universität Berlin, Berlin, Germany.
NeuroCure Cluster of Excellence, Charité Universitätsmedizin, Berlin, Germany.
PLoS Biol. 2025 Mar 20;23(3):e3003076. doi: 10.1371/journal.pbio.3003076. eCollection 2025 Mar.
Sleep is crucial for cognitive functions and life span across species. While sleep homeostasis and cognitive processes are linked through cellular and synaptic plasticity, the signaling pathways connecting them remain unclear. Here, we show that Drosophila insomniac (inc) short sleep mutants, which lack an adaptor protein for the autism-associated Cullin-3 ubiquitin ligase, exhibited enhanced Pavlovian aversive olfactory learning and memory, unlike other sleep mutants with normal or reduced memory. Through a genetic modifier screen, we found that a mild reduction of Protein Kinase A (PKA) signaling specifically rescued the sleep and longevity phenotypes of inc mutants. However, this reduction further increased their excessive memory and mushroom body overgrowth. Since inc mutants displayed higher PKA signaling, we propose that inc loss-of-function suppresses sleep via increased PKA activity, which also constrains the excessive memory of inc mutants. Our data identify a signaling cascade for balancing sleep and memory functions, and provide a plausible explanation for the sleep phenotypes of inc mutants, suggesting that memory hyperfunction can provoke sleep deficits.
睡眠对于所有物种的认知功能和寿命都至关重要。虽然睡眠稳态和认知过程通过细胞和突触可塑性联系在一起，但连接它们的信号通路仍不清楚。在这里，我们表明，果蝇失眠（inc）短睡眠突变体缺乏与自闭症相关的Cullin-3泛素连接酶的衔接蛋白，与其他记忆正常或减退的睡眠突变体不同，它们表现出增强的巴甫洛夫厌恶性嗅觉学习和记忆。通过基因修饰筛选，我们发现蛋白激酶A（PKA）信号的轻度降低特异性地挽救了inc突变体的睡眠和寿命表型。然而，这种降低进一步增加了它们过度的记忆和蘑菇体过度生长。由于inc突变体显示出更高的PKA信号，我们提出inc功能丧失通过增加PKA活性来抑制睡眠，这也限制了inc突变体的过度记忆。我们的数据确定了一个平衡睡眠和记忆功能的信号级联，并为inc突变体的睡眠表型提供了一个合理的解释，表明记忆功能亢进可引发睡眠缺陷。
