Memories are encoded by microcircuits of hippocampal neurons. These cells undergo energy-intensive molecular adaptations during learning that can result in transient DNA damage. Jovasevic et al. show that contextual fear conditioning in mice induces the formation of double-stranded DNA (dsDNA) breaks and gene signatures of inflammation in hippocampal CA1 excitatory neurons. These cells also upregulate TLR9, which can bind dsDNA fragments in endolysosomes and promote DNA damage repair. Hippocampal neuron-specific knockdown of Tlr9 caused genetic instability in these cells and impaired contextual memory formation. Similar observations were made when mice were treated with a TLR9 antagonist, but not with inhibitors of the evolutionary ‘older’ cGAS–STING-mediated pathway of cytosolic dsDNA sensing. Given the association of DNA damage with neurodegeneration, the authors suggest that strategies to maintain the integrity of TLR9 signalling in neurons may have potential for preventing neurocognitive defects.

记忆是由海马神经元的微电路编码的。这些细胞在学习过程中经历能量密集型分子适应，可能导致短暂的 DNA 损伤。约瓦舍维奇等人。研究表明，小鼠的情境恐惧调节会诱导海马 CA1 兴奋性神经元中双链 DNA (dsDNA) 断裂和炎症基因特征的形成。这些细胞还上调 TLR9，TLR9 可以结合内溶酶体中的 dsDNA 片段，促进 DNA 损伤修复。海马神经元特异性敲低Tlr9会导致这些细胞的遗传不稳定，并损害情境记忆的形成。当小鼠接受 TLR9 拮抗剂治疗，但未接受进化“较早”cGAS-STING 介导的胞质 dsDNA 传感途径的抑制剂治疗时，也得到了类似的观察结果。鉴于 DNA 损伤与神经退行性变之间的关联，作者提出维持神经元中 TLR9 信号完整性的策略可能具有预防神经认知缺陷的潜力。