Xiaoyao San intergenerational protects learning-memory ability and neurodevelopment in PPD offspring via the BDNF/mTOR signaling pathway

background As a principal TCM antidepressant intervention, Xiaoyao San (XYS) is extensively applied in postpartum depression (PPD) therapeutics. Nevertheless, fundamental research in this area remains limited, particularly insufficient investigations into the intergenerational effects of XYS on PPD treatment. Methods Female ICR mice received daily corticosterone (CORT) injections (PD1-PD21) to establish a PPD model, with concurrent XYS treatment (45, 30, 15 g/kg) for 21 days. Maternal caring behavior was assessed on PD4 and PD8. On PD22, behavioral tests were conducted, followed by ELISA quantification of serum CORT/ACTH/CRH and HE staining to evaluate hippocampal neuronal damage. Offspring mice underwent morris water maze and Y-maze tests on PD28 to assess cognition, with histological/molecular analyses (HE, immunofluorescence, Golgi staining, western blot) for neurodevelopment. Western blot quantified hippocampal BDNF/mTOR pathway proteins, validated via ANA-12 inhibition. Results XYS enhanced maternal care, reduced anxiety/depression-like behaviors in PPD mice. XYS conferred transgenerational protection of learning and memory functions in offspring mice, as evidenced by: reduced escape latency, increased platform crossings/spontaneous alternation. Besides, XYS treatment attenuated hippocampal neuronal damage in PPD offspring, promoted neurogenesis (increased DCX ⁺ /NeuN ⁺ cells in DG region), dendritic complexity (higher spine density/length), and synaptic protein expression. Maternal XYS administration upregulated BDNF/mTOR pathway. ANA-12 confirmed the pivotal role of BDNF/mTOR pathway in mediating XYS's transgenerational neuroprotective and learning and memory ability. Conclusion XYS alleviated postpartum depression in mice and conferred transgenerational neuroprotection via BDNF/mTOR activation, preserving offspring cognition. This supports XYS's clinical potential for interrupting intergenerational psychiatric disorders.