Inhibiting Fear Memory Recall-induced Oligodendrogenesis Rescues PTSD-like Behaviors

The recurrent re-experiencing of traumatic memories is a core symptom of post-traumatic stress disorder (PTSD), and the severity of this symptom has been consistently associated with the clinical course and long-term prognosis of the disorder. Notably, some patients exhibit white matter abnormalities. Myelin, a crucial white matter component, has been shown to regulate the consolidation of remote memory in the adult brain. However, the dynamics of myelin following re-experienced traumatic stressors and their potential significance remain elusive. Here, we developed a repeated fear recall mouse model simulating PTSD re-experiencing symptoms, revealing that fear recalls profoundly reinforce remote fear memory and induce psychotic and social deficits. This pathological reinforcement coincides with region-specific oligodendrogenesis, heightened reactivation of fear recall-associated engram cells, and increased dendritic spine density, as demonstrated by cell-lineage tracing and labeling. We hypothesize that repeated recall-induced oligodendrogenesis may critically reinforce remote fear memories and contribute to these functional impairments. Strikingly, loss-of-function experiments, either inducing apoptosis of new oligodendrocytes or cell-specific Olig2 knockout, effectively relieve the abnormal reinforcement of long-term fear memory and the accompanying social impairments caused by repeated recall. Furthermore, diminished oligodendrogenesis also reduces fear recall-induced neuronal activation and attenuates dendritic spine changes within fear-related brain regions. Crucially, administering rapamycin, a potent oligodendrogenesis inhibitor, during repeated fear recalls phenocopies the beneficial effects of anti-myelination interventions on fear memory-related behavioral defects. In summary, our findings demonstrate that oligodendrogenesis triggered by repeated fear recall is sufficient to drive PTSD-like behavioral progression, likely by modulating neuronal circuits underlying remote fear memories in adults. Medications targeting oligodendrogenesis during recall may prevent pathological reinforcement of long-term fear memories and mitigate psychotic and social deficits in PTSD patients.