INTRODUCTIONCognitive decline progresses with age, and Nr4a1 has been shown to participate in memory functions. However, the relationship between age‐related Nr4a1 reduction and cognitive decline is undefined.METHODSNr4a1 expressions were evaluated by quantitative PCR and immunochemical approaches. The cognition of mice was examined by multiple behavioral tests. Patch‐clamp experiments were conducted to investigate the synaptic function.RESULTSNR4A1 in peripheral blood mononuclear cells decreased with age in humans. In the mouse brain, age‐dependent Nr4a1 reduction occurred in the hippocampal CA1. Deleting Nr4a1 in CA1 pyramidal neurons (PyrNs) led to the impairment of cognition and excitatory synaptic function. Mechanistically, Nr4a1 enhanced TrkB expression via binding to its promoter. Blocking TrkB compromised the cognitive amelioration with Nr4a1‐overexpression in CA1 PyrNs.DISCUSSIONOur results elucidate the mechanism of Nr4a1‐dependent TrkB regulation in cognition and synaptic function, indicating that Nr4a1 is a target for the treatment of cognitive decline.Highlights Nr4a1 is reduced in PBMCs and CA1 PyrNs with aging. Nr4a1 ablation in CA1 PyrNs impaired cognition and excitatory synaptic function. Nr4a1 overexpression in CA1 PyrNs ameliorated cognitive impairment of aged mice. Nr4a1 bound to TrkB promoter to enhance transcription. Blocking TrkB function compromised Nr4a1‐induced cognitive improvement.

中文翻译：

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核受体 Nr4a1 的逐渐减少介导年龄依赖性认知衰退

简介 认知能力随着年龄的增长而下降，Nr4a1 已被证明参与记忆功能。然而，年龄相关的 Nr4a1 减少与认知能力下降之间的关系尚不清楚。方法通过定量 PCR 和免疫化学方法评估SNr4a1 表达。通过多项行为测试来检查小鼠的认知能力。进行膜片钳实验来研究突触功能。结果人类外周血单个核细胞中的 NR4A1 随着年龄的增长而减少。在小鼠大脑中，海马 CA1 中发生了年龄依赖性 Nr4a1 减少。删除 CA1 锥体神经元 (PyrNs) 中的 Nr4a1 会导致认知和兴奋性突触功能受损。从机制上讲，Nr4a1 通过与其启动子结合来增强 TrkB 的表达。阻断 TrkB 会损害 CA1 PyrNs 中 Nr4a1 过度表达的认知改善。讨论我们的结果阐明了 Nr4a1 依赖性 TrkB 在认知和突触功能中的调节机制，表明 Nr4a1 是治疗认知衰退的靶点。 随着衰老，PBMC 和 CA1 PyrN 中的 Nr4a1 会减少。 CA1 PyrNs 中的 Nr4a1 消融会损害认知和兴奋性突触功能。 CA1 PyrNs 中 Nr4a1 的过度表达可改善老年小鼠的认知障碍。 Nr4a1 与 TrkB 启动子结合以增强转录。 阻断 TrkB 功能会损害 Nr4a1 诱导的认知改善。