Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan; Center for Precision Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan.
Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
Cell Rep. 2024 Apr 23;43(4):113996. doi: 10.1016/j.celrep.2024.113996. Epub 2024 Mar 24.
Physiological dysfunction confers negative valence to coincidental sensory cues to induce the formation of aversive associative memory. How peripheral tissue stress engages neuromodulatory mechanisms to form aversive memory is poorly understood. Here, we show that in the nematode C. elegans, mitochondrial disruption induces aversive memory through peroxisomal β-oxidation genes in non-neural tissues, including pmp-4/very-long-chain fatty acid transporter, dhs-28/3-hydroxylacyl-CoA dehydrogenase, and daf-22/3-ketoacyl-CoA thiolase. Upregulation of peroxisomal β-oxidation genes under mitochondrial stress requires the nuclear hormone receptor NHR-49. Importantly, the memory-promoting function of peroxisomal β-oxidation is independent of its canonical role in pheromone production. Peripheral signals derived from the peroxisomes target NSM, a critical neuron for memory formation under stress, to upregulate serotonin synthesis and remodel evoked responses to sensory cues. Our genetic, transcriptomic, and metabolomic approaches establish peroxisomal lipid signaling as a crucial mechanism that connects peripheral mitochondrial stress to central serotonin neuromodulation in aversive memory formation.
生理功能障碍赋予偶然感觉线索负效价，从而诱导产生厌恶联想记忆。外周组织应激如何通过神经调质机制形成厌恶记忆，目前还知之甚少。本文中，作者发现在线虫 C. elegans 中，线粒体功能障碍通过非神经组织中的过氧化物酶体β-氧化基因诱导厌恶记忆形成，这些基因包括 pmp-4/长链脂肪酸转运蛋白、dhs-28/3-羟酰基辅酶 A 脱氢酶和 daf-22/3-酮酰基辅酶 A 硫解酶。线粒体应激下过氧化物酶体β-氧化基因的上调需要核激素受体 NHR-49。重要的是，过氧化物酶体β-氧化的促记忆功能与其在信息素产生中的典型作用无关。过氧化物酶体衍生的信号靶向 NSM，即应激下记忆形成的关键神经元，以上调血清素合成并重塑对感觉线索的诱发反应。作者的遗传、转录组和代谢组学方法确立了过氧化物酶体脂质信号作为一种关键机制，将外周线粒体应激与厌恶记忆形成中的中枢 5-羟色胺神经调质联系起来。
