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 damage^3,4,5. 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.

当海马神经元对不同类型的信息做出反应¹时，一个子集就会组装成代表记忆^{2 的}微电路。这些神经元通常会经历能量密集型分子适应，偶尔会导致短暂的 DNA 损伤^3,4,5。在这里，我们发现了离散的兴奋性海马 CA1 神经元簇，在学习后数小时内出现持续的双链 DNA (dsDNA) 断裂、核膜破裂以及组蛋白和 dsDNA 片段的核周释放。在这些早期事件之后，一些神经元获得了炎症表型，涉及 TLR9 信号传导的激活和中心体 DNA 损伤修复复合物的积累⁶。Tlr9的神经元特异性敲低会损害记忆，同时减弱情境恐惧条件诱导的特定兴奋性 CA1 神经元簇中基因表达的变化。值得注意的是，TLR9 在中心体功能中发挥着重要作用，包括 DNA 损伤修复、纤毛发生和神经周围网的构建。我们展示了离散神经元簇中学习诱导分子事件的新型级联，这些事件经历了 dsDNA 损伤和 TLR9 介导的修复，从而导致它们被招募到记忆回路中。由于 TLR9 功能受损，这种基本记忆机制成为基因组不稳定和认知障碍的门户，这些障碍与加速衰老、精神疾病和神经退行性疾病有关。因此，维持 TLR9 炎症信号的完整性成为神经认知缺陷的一种有前途的预防策略。