Effect and mechanism of maternal prolactin levels on depressive-like behavior in prenatally stressed offspring.

Prenatal stress (PS) has an adverse impact on the neurodevelopment of the fetus and increases the risk of depression in offspring. Prolactin (PRL), a polypeptide hormone released by the pituitary gland, has a promising neuroprotective effect. However, it is not clear whether the decline in PRL levels during gestation is related to the depressive-like behavior of offspring caused by PS. This study aimed to assess the role and mechanism of PRL during gestation on depressive-like behavior in PS offspring rats. We found that PS led to a marked decrease in serum PRL levels of the maternal rats, accompanied by depressive-like behavior in offspring rats. Exogenous PRL supplementation during pregnancy significantly mitigated depressive-like behavior, ameliorated neuronal damage and neuroinflammation, and restored synaptic plasticity in the medial prefrontal cortex (mPFC) of PS offspring rats. Further investigation confirmed that PRL exerted a neuroprotective effect by activating the cAMP signaling in the mPFC of PS offspring rats. Single cell RNA (scRNA) sequencing revealed that PRL administration during pregnancy resulted in the alterations of immune cell proportions, such as microglia, granulocytes, and B cells. Further analysis of microglia found that the differentially expressed genes (DEGs) in microglia were involved in multiple immune-related signaling pathways. Meanwhile, PRL intervention switched microglial polarization toward the M2 phenotype in PS offspring rats. Additionally, PRL administration during pregnancy effectively ameliorated gut microbiota disturbances in PS offspring rats. Our findings proposed that PRL administration during pregnancy could significantly mitigate depressive-like behavior in PS offspring rats by modulating cAMP signaling-mediated synaptic plasticity, facilitating microglial M2 polarization, and ameliorating gut microbiota dysbiosis.