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001     268840
005     20240421003643.0
024 7 _ |a 10.1038/s41586-024-07220-7
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024 7 _ |a 0028-0836
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024 7 _ |a 1476-4687
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037 _ _ |a DZNE-2024-00344
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Jovasevic, Vladimir
|b 0
245 _ _ |a Formation of memory assemblies through the DNA-sensing TLR9 pathway.
260 _ _ |a London [u.a.]
|c 2024
|b Nature Publ. Group
336 7 _ |a article
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520 _ _ |a As 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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650 _ 7 |a Histones
|2 NLM Chemicals
650 _ 7 |a Tlr9 protein, mouse
|2 NLM Chemicals
650 _ 7 |a Toll-Like Receptor 9
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Aging: genetics
|2 MeSH
650 _ 2 |a Aging: pathology
|2 MeSH
650 _ 2 |a CA1 Region, Hippocampal: physiology
|2 MeSH
650 _ 2 |a Centrosome: metabolism
|2 MeSH
650 _ 2 |a Cognitive Dysfunction: genetics
|2 MeSH
650 _ 2 |a Conditioning, Classical
|2 MeSH
650 _ 2 |a DNA Breaks, Double-Stranded
|2 MeSH
650 _ 2 |a DNA Repair
|2 MeSH
650 _ 2 |a Extracellular Matrix: metabolism
|2 MeSH
650 _ 2 |a Fear
|2 MeSH
650 _ 2 |a Genomic Instability: genetics
|2 MeSH
650 _ 2 |a Histones: metabolism
|2 MeSH
650 _ 2 |a Inflammation: genetics
|2 MeSH
650 _ 2 |a Inflammation: immunology
|2 MeSH
650 _ 2 |a Inflammation: metabolism
|2 MeSH
650 _ 2 |a Inflammation: pathology
|2 MeSH
650 _ 2 |a Memory: physiology
|2 MeSH
650 _ 2 |a Mental Disorders: genetics
|2 MeSH
650 _ 2 |a Neurodegenerative Diseases: genetics
|2 MeSH
650 _ 2 |a Neuroinflammatory Diseases: genetics
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Neurons: pathology
|2 MeSH
650 _ 2 |a Nuclear Envelope: pathology
|2 MeSH
650 _ 2 |a Toll-Like Receptor 9: deficiency
|2 MeSH
650 _ 2 |a Toll-Like Receptor 9: genetics
|2 MeSH
650 _ 2 |a Toll-Like Receptor 9: immunology
|2 MeSH
650 _ 2 |a Toll-Like Receptor 9: metabolism
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700 1 _ |a Wood, Elizabeth M
|0 0000-0002-1708-8091
|b 1
700 1 _ |a Cicvaric, Ana
|0 0000-0002-3560-4491
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700 1 _ |a Zhang, Hui
|0 0000-0002-1755-4494
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700 1 _ |a Petrovic, Zorica
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700 1 _ |a Carboncino, Anna
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700 1 _ |a Parker, Kendra K
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700 1 _ |a Bassett, Thomas E
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700 1 _ |a Moltesen, Maria
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700 1 _ |a Yamawaki, Naoki
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700 1 _ |a Login, Hande
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700 1 _ |a Kalucka, Joanna
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700 1 _ |a Sananbenesi, Farahnaz
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700 1 _ |a Zhang, Xusheng
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700 1 _ |a Fischer, Andre
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700 1 _ |a Radulovic, Jelena
|0 0000-0002-0268-2426
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773 _ _ |a 10.1038/s41586-024-07220-7
|g Vol. 628, no. 8006, p. 145 - 153
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