Toll-like receptor 9 (TLR9) is an innate immune sensor that recognizes intracellular double-stranded DNA (dsDNA). In Nature, Jovasevic et al. show that TLR9–NF-κB signaling in specific hippocampal neurons is required for the generation of learning-induced memory formation in mice. Using models of contextual fear conditioning (CFC), the authors show that nuclear non-coding dsDNA fragments appear within hours after stimulation, accumulating at perinuclear regions adjacent to the endoplasmic reticulum. After 96 hours, stimulated hippocampal neurons show increased expression of TLR9 and activated DNA-damage response pathways, as indicated by the appearance of γH2AX histone foci and the DNA repair protein 53BP1. TLR9 signaling is required for genomic DNA repair and memory formation, as conditional depletion or knockdown of hippocampal Tlr9 or Rela blunted DNA repair as well as the memory response. Importantly, neuronal TLR9 expression is required, as conditional Tlr9 deletion in either astrocytes or microglia did not blunt the CFC response; similarly, the cGAS-STING pathway (another intracellular DNA sensor) or type I interferon signaling is not required. Single-nuclei RNA-sequencing analysis also indicated TLR9-dependent upregulation of IL-6 production in response to CFC stimulation, but its role remains unclear. How contextual fear stimulation specifically triggers nuclear dsDNA breaks in hippocampal neurons remains unknown; however, what is clear is that these neurons have co-opted the innate TLR9 DNA-sensing pathway to promote their genomic stability and induce contextual long-term memory responses.

Original reference: Nature 628, 145–153 (2024)

Toll 样受体 9 (TLR9​​) 是一种识别细胞内双链 DNA (dsDNA) 的先天免疫传感器。在《自然》杂志上，约瓦塞维奇等人。研究表明，特定海马神经元中的 TLR9–NF-κB 信号传导对于小鼠学习诱导的记忆形成是必需的。作者利用情境恐惧条件反射 (CFC) 模型表明，核非编码 dsDNA 片段在刺激后数小时内出现，并积累在邻近内质网的核周区域。 96 小时后，受刺激的海马神经元显示 TLR9 表达增加，并激活 DNA 损伤反应途径，如 γH2AX 组蛋白灶和 DNA 修复蛋白 53BP1 的出现所示。 TLR9 信号传导是基因组 DNA 修复和记忆形成所必需的，因为海马Tlr9或Rela的条件性消耗或敲低会削弱 DNA 修复和记忆反应。重要的是，神经元 TLR9 表达是必需的，因为星形胶质细胞或小胶质细胞中条件性TLR9缺失不会减弱 CFC 反应；类似地，不需要 cGAS-STING 通路（另一种细胞内 DNA 传感器）或 I 型干扰素信号传导。单核 RNA 测序分析还表明，CFC 刺激导致 TLR9 依赖性 IL-6 产生上调，但其作用仍不清楚。情境恐惧刺激如何特异性触发海马神经元核 dsDNA 断裂仍然未知。然而，显而易见的是，这些神经元已经选择了先天的 TLR9 DNA 传感通路来促进其基因组稳定性并诱导上下文长期记忆反应。

原始参考文献： Nature 628 , 145–153 (2024)