中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (7): 3073-3082.doi: 10.4103/NRR.NRR-D-24-01026

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

齿状回整体内在兴奋性和自噬蛋白调控的恐惧泛化

  

  • 出版日期:2026-07-15 发布日期:2026-03-31

The intrinsic excitability of and autophagy protein expression levels in dentate gyrus ensembles regulate fear generalization

Qing Lin1, 2, #, Tao Jin1, 2, #, Yang Yang1, 2, Xutian Hou1, 2, Ruyan Chen1, 2, Lan Ma1, 2, Xing Liu1, 2, Feifei Wang1, 2, *   

  1. 1School of Basic Medicine Sciences, State Key Laboratory of Brain Function and Disease, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of neurology, Pharmacology Research Center, Huashan Hospital, Fudan University, Shanghai, China;  2Research Unit of Addition Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai, China
  • Online:2026-07-15 Published:2026-03-31
  • Contact: Feifei Wang, PhD, ffwang@fudan.edu.cn.
  • Supported by:
    This work was supported by grants from the STI2030-Major Projects, Nos. 2021ZD0203500 (to FW), 2021ZD0202100 (to XL); the National Natural Science Foundation of China, Nos. 32222033 (to FW), 32330041 (to LM) and 82021002 (to LM), 32171041 (to XL) and 32450102 (to XL); and the CAMS Innovation Fund for Medical Sciences, No. 2021-I2M-5-009 (to LM and XL).

摘要:

恐惧的过度泛化与精神障碍和认知能力下降有关。最近的研究表明,背侧齿状回中的记忆印迹细胞被整合成功能异质的集合体,分别参与情境恐惧记忆的泛化和辨别。然而,促进恐惧泛化的细胞内信号仍有待全面阐明。实验利用神经元活性依赖的标记(RAM)系统标记并操纵了背侧齿状回中由情境恐惧条件激活的c-Fos+和Npas4+集合。结果显示,通过过表达 NaChBac 增加 Fos依赖的神经元集合的兴奋性,或通过过表达Kir2.1降低Npas4依赖的的神经元集合的兴奋性,都能促进恐惧记忆的泛化。此外,CRISPR介导的背侧齿状回神经元中自噬蛋白Atg5或Atg7的下调抑制了c-Fos的激活,但没有抑制Npas4。在Fos依赖的或Npas4依赖的的神经元集合中敲除Atg5或Atg7会导致神经元兴奋性的增加和棘突密度的降低。然而,在Fos依赖的神经元集合中敲除Atg7会促进记忆泛化,而在Npas4依赖的的神经元集合中敲除Atg5或Atg7会增加焦虑水平。这些结果有助于理解记忆印迹的不同可塑性是如何参与调节恐惧记忆泛化和焦虑的。


https://orcid.org/0000-0002-2351-6873 (Feifei Wang)

关键词: 焦虑, ATG7/5, c-Fos, 树突棘, 齿状回, 内在兴奋性, 记忆泛化, Npas4

Abstract:

The overgeneralization of fear is associated with psychiatric disorders and cognitive decline. Recent studies have shown that engram cells in the dorsal dentate gyrus are integrated into functionally heterogeneous ensembles that are involved in contextual fear memory generalization and discrimination. However, the intracellular signals that promote fear generalization remain to be fully elucidated. In this study, we labeled and manipulated the c-Fos+ and Npas4+ ensembles in the dorsal dentate gyrus that are activated by contextual fear conditioning using a robust activity marking system. The results showed that increasing the excitability of Fos-dependent robust activity marking by overexpressing NaChBac or decreasing the excitability of Npas4-dependent robust activity marking by overexpressing Kir2.1 promoted fear memory generalization. Furthermore, CRISPR-mediated downregulation of the autophagy-related Atg5 or Atg7 genes in dorsal dentate gyrus neurons inhibited activation of c-Fos, but not Npas4. Knockdown of Atg5 or Atg7 in the Fos-dependent robust activity marking or Npas4-dependent robust activity marking ensemble led to an increase in neuronal excitability and a decrease in spine density in both ensembles. However, Atg7 knockdown in the Fos-dependent robust activity marking ensemble promoted memory generalization, while knockdown of Atg5 or Atg7 in the Npas4-dependent robust activity marking ensemble increased anxiety levels. These results contribute to our understanding of how the varying plasticity of memory engrams is involved in regulating fear memory generalization and anxiety.

Key words: anxiety, ATG7/5, c-Fos, dendritic spine, dentate gyrus, intrinsic excitability, memory generalization, Npas4