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<p>Recurrent re-experiencing traumatic memory is known as a common symptom in post-traumatic stress disorder (PTSD) patients, and its severity is closely related to the progression and prognosis of PTSD. Notably, some individuals with PTSD exhibit white matter abnormalities. Myelin constitutes a critical structure within white matter, and myelination in the adult brain has been demonstrated to actively regulate the consolidation of remote memories. However, the dynamics of myelin after re-experiencing traumatic stressors and their functional significance remain largely unexplored. Here, we developed a repeated fear recall mouse model to mimic re-experiencing symptoms in PTSD patients, and found that repeated fear recall can reinforce remote fear memory while cause anxiety-like behaviors and social preference deficits. This coincides with region-specific oligodendrogenesis, heightened reactivation of fear recall-associated engram cells, and an increase in dendritic spine density, demonstrated through cell-lineage tracing and labeling. We hypothesize that oligodendrogenesis driven by repeated fear recall is sufficient to regulate remote fear memory and behavioral abnormalities. Loss-of-function experiments, either inducing apoptosis of new oligodendrocytes (OLs) or cell-type-specific knocking out (cKO) oligodendroglial transcription factor 2 (Olig2), significantly attenuated the abnormal reinforcement of remote fear memory and ameliorated social deficits induced by repeated fear recall. Moreover, inhibiting oligodendrogenesis through Olig2 cKO relieved anxiety-like behavior. Notably, diminished newly formed OLs also decreases fear recall-induced neuronal activation and dendritic spine density in fear-related brain regions. More importantly, administering rapamycin, a potent inhibitor of oligodendrogenesis, during repeated fear recalls phenocopies the effects of anti-myelination on fear memory-related behavioral defects. In summary, our findings demonstrate that oligodendrogenesis induced by repeated fear recall is sufficient to drive the progression of PTSD-like behaviors, likely by modulating neuronal activity and dendritic spine density within the adult fear circuitry. Pharmacological treatments that inhibiting oligodendrogenesis during the recall phase represent a promising therapeutic strategy for preventing the pathological reinforcement of long-term fear memories, thereby averting the emergence of anxiety-like behaviors and social preference deficits in individuals with PTSD.</p><p></p>

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Inhibiting fear memory recall-induced oligodendrogenesis rescues PTSD-like behaviors

  • 期刊论文

  • 发表日期：

    2026年6月16日

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  • Jie Feng,
  • Nan-xin Huang,
  • Kun Liu,
  • Yu-chen Fan,
  • Jing-fei Chen,
  • Yi-bei Zhao,
  • Bin Yu,
  • Qian-feng Fu,
  • Feng Mei,
  • Fei Wang,
  • Lan Xiao

摘要

Recurrent re-experiencing traumatic memory is known as a common symptom in post-traumatic stress disorder (PTSD) patients, and its severity is closely related to the progression and prognosis of PTSD. Notably, some individuals with PTSD exhibit white matter abnormalities. Myelin constitutes a critical structure within white matter, and myelination in the adult brain has been demonstrated to actively regulate the consolidation of remote memories. However, the dynamics of myelin after re-experiencing traumatic stressors and their functional significance remain largely unexplored. Here, we developed a repeated fear recall mouse model to mimic re-experiencing symptoms in PTSD patients, and found that repeated fear recall can reinforce remote fear memory while cause anxiety-like behaviors and social preference deficits. This coincides with region-specific oligodendrogenesis, heightened reactivation of fear recall-associated engram cells, and an increase in dendritic spine density, demonstrated through cell-lineage tracing and labeling. We hypothesize that oligodendrogenesis driven by repeated fear recall is sufficient to regulate remote fear memory and behavioral abnormalities. Loss-of-function experiments, either inducing apoptosis of new oligodendrocytes (OLs) or cell-type-specific knocking out (cKO) oligodendroglial transcription factor 2 (Olig2), significantly attenuated the abnormal reinforcement of remote fear memory and ameliorated social deficits induced by repeated fear recall. Moreover, inhibiting oligodendrogenesis through Olig2 cKO relieved anxiety-like behavior. Notably, diminished newly formed OLs also decreases fear recall-induced neuronal activation and dendritic spine density in fear-related brain regions. More importantly, administering rapamycin, a potent inhibitor of oligodendrogenesis, during repeated fear recalls phenocopies the effects of anti-myelination on fear memory-related behavioral defects. In summary, our findings demonstrate that oligodendrogenesis induced by repeated fear recall is sufficient to drive the progression of PTSD-like behaviors, likely by modulating neuronal activity and dendritic spine density within the adult fear circuitry. Pharmacological treatments that inhibiting oligodendrogenesis during the recall phase represent a promising therapeutic strategy for preventing the pathological reinforcement of long-term fear memories, thereby averting the emergence of anxiety-like behaviors and social preference deficits in individuals with PTSD.