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000268840 037__ $$aDZNE-2024-00344
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000268840 1001_ $$aJovasevic, Vladimir$$b0
000268840 245__ $$aFormation of memory assemblies through the DNA-sensing TLR9 pathway.
000268840 260__ $$aLondon [u.a.]$$bNature Publ. Group$$c2024
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000268840 520__ $$aAs hippocampal neurons respond to diverse types of information1, a subset assembles into microcircuits representing a memory2. Those neurons typically undergo energy-intensive molecular adaptations, occasionally resulting in transient DNA damage3-5. Here we found discrete clusters of excitatory hippocampal CA1 neurons with persistent double-stranded DNA (dsDNA) breaks, nuclear envelope ruptures and perinuclear release of histone and dsDNA fragments hours after learning. Following these early events, some neurons acquired an inflammatory phenotype involving activation of TLR9 signalling and accumulation of centrosomal DNA damage repair complexes6. Neuron-specific knockdown of Tlr9 impaired memory while blunting contextual fear conditioning-induced changes of gene expression in specific clusters of excitatory CA1 neurons. Notably, TLR9 had an essential role in centrosome function, including DNA damage repair, ciliogenesis and build-up of perineuronal nets. We demonstrate a novel cascade of learning-induced molecular events in discrete neuronal clusters undergoing dsDNA damage and TLR9-mediated repair, resulting in their recruitment to memory circuits. With compromised TLR9 function, this fundamental memory mechanism becomes a gateway to genomic instability and cognitive impairments implicated in accelerated senescence, psychiatric disorders and neurodegenerative disorders. Maintaining the integrity of TLR9 inflammatory signalling thus emerges as a promising preventive strategy for neurocognitive deficits.
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000268840 650_7 $$2NLM Chemicals$$aHistones
000268840 650_7 $$2NLM Chemicals$$aTlr9 protein, mouse
000268840 650_7 $$2NLM Chemicals$$aToll-Like Receptor 9
000268840 650_2 $$2MeSH$$aAnimals
000268840 650_2 $$2MeSH$$aFemale
000268840 650_2 $$2MeSH$$aMale
000268840 650_2 $$2MeSH$$aMice
000268840 650_2 $$2MeSH$$aAging: genetics
000268840 650_2 $$2MeSH$$aAging: pathology
000268840 650_2 $$2MeSH$$aCA1 Region, Hippocampal: physiology
000268840 650_2 $$2MeSH$$aCentrosome: metabolism
000268840 650_2 $$2MeSH$$aCognitive Dysfunction: genetics
000268840 650_2 $$2MeSH$$aConditioning, Classical
000268840 650_2 $$2MeSH$$aDNA Breaks, Double-Stranded
000268840 650_2 $$2MeSH$$aDNA Repair
000268840 650_2 $$2MeSH$$aExtracellular Matrix: metabolism
000268840 650_2 $$2MeSH$$aFear
000268840 650_2 $$2MeSH$$aGenomic Instability: genetics
000268840 650_2 $$2MeSH$$aHistones: metabolism
000268840 650_2 $$2MeSH$$aInflammation: genetics
000268840 650_2 $$2MeSH$$aInflammation: immunology
000268840 650_2 $$2MeSH$$aInflammation: metabolism
000268840 650_2 $$2MeSH$$aInflammation: pathology
000268840 650_2 $$2MeSH$$aMemory: physiology
000268840 650_2 $$2MeSH$$aMental Disorders: genetics
000268840 650_2 $$2MeSH$$aNeurodegenerative Diseases: genetics
000268840 650_2 $$2MeSH$$aNeuroinflammatory Diseases: genetics
000268840 650_2 $$2MeSH$$aNeurons: metabolism
000268840 650_2 $$2MeSH$$aNeurons: pathology
000268840 650_2 $$2MeSH$$aNuclear Envelope: pathology
000268840 650_2 $$2MeSH$$aToll-Like Receptor 9: deficiency
000268840 650_2 $$2MeSH$$aToll-Like Receptor 9: genetics
000268840 650_2 $$2MeSH$$aToll-Like Receptor 9: immunology
000268840 650_2 $$2MeSH$$aToll-Like Receptor 9: metabolism
000268840 7001_ $$00000-0002-1708-8091$$aWood, Elizabeth M$$b1
000268840 7001_ $$00000-0002-3560-4491$$aCicvaric, Ana$$b2
000268840 7001_ $$00000-0002-1755-4494$$aZhang, Hui$$b3
000268840 7001_ $$aPetrovic, Zorica$$b4
000268840 7001_ $$aCarboncino, Anna$$b5
000268840 7001_ $$aParker, Kendra K$$b6
000268840 7001_ $$00000-0002-9066-9677$$aBassett, Thomas E$$b7
000268840 7001_ $$aMoltesen, Maria$$b8
000268840 7001_ $$00000-0001-8253-2059$$aYamawaki, Naoki$$b9
000268840 7001_ $$aLogin, Hande$$b10
000268840 7001_ $$aKalucka, Joanna$$b11
000268840 7001_ $$0P:(DE-2719)2811099$$aSananbenesi, Farahnaz$$b12$$udzne
000268840 7001_ $$aZhang, Xusheng$$b13
000268840 7001_ $$0P:(DE-2719)2000047$$aFischer, Andre$$b14$$udzne
000268840 7001_ $$00000-0002-0268-2426$$aRadulovic, Jelena$$b15
000268840 773__ $$0PERI:(DE-600)1413423-8$$a10.1038/s41586-024-07220-7$$gVol. 628, no. 8006, p. 145 - 153$$n8006$$p145 - 153$$tNature$$v628$$x0028-0836$$y2024
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