Transgenerational Transmission of Maternal Stress in Males: MSUS-Induced NSCs Depletion and Adult Hippocampal Neurogenesis Impairment

Postpartum depression (PPD) is driven by chronic stress, and the maternal separation combined with unpredictable maternal stress (MSUS) model can recapitulate key features of PPD in rodents. Anxiety-like and despair-like behaviors are observed in male offspring MSUS-exposed dams, with the most severe manifestations in the directly stressed F0 generation, followed by attenuated but persistent effects in the F1 generation and F2 generation. Correspondingly, immunofluorescence assays reveal significant changes in neural stem cell (NSCs) subpopulations (marked by GFAP, BrdU, and DCX) that persist across the F0 to F2 generations. GFAP quiescent NSCs show a reduction in the reserve pool, BrdU proliferating NSCs exhibit impaired proliferation capacity, and DCX immature neurons display decreased differentiation potential. The declines are associated with the sustained suppression and impairment of adult hippocampal neurogenesis (AHN). RNA sequencing further supports abnormal expression of genes related to neuroinflammation, cell apoptosis and neurogenesis in transgenerational transmission. Collectively, the results suggest that PPD negatively regulates NSCs by disrupting the hypothalamus-pituitary-adrenal axis, leading to reduced AHN and transgenerational transmission of anxiety-like behaviors. This study provides new insights into the understanding the underlying mechanisms and potential prevention strategies for stress-related disorders.