Women experience higher rates of mood disorders. It has been widely reported that prenatal depression is associated with mental health disorders in early childhood. However, the lasting effects of maternal stress before conception on offspring brain development and psychiatric-related behaviors remain unclear.

In a study published in Molecular Psychiatry, a team led by Prof. LIU Xin'an, Prof. CHEN Zuxin and Prof. WANG Liping from the Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences revealed how psychological stress experienced by mothers before conception shape the long-term emotional behaviors of their offspring, and uncovered a brain-body mechanism linking maternal emotional states to adult behavioral outcomes in a sex-specific manner.

Researchers used mice as models. They exposed female mice to chronic unpredictable stress before mating, and assessed their offspring for neurodevelopment, adult behavior, and multi-omics profiles.

Researchers found that maternal premating stress led to delayed neurodevelopment and pronounced sex-specific behavioral abnormalities in adulthood: Female offspring displayed hyperactivity and social deficits, whereas male offspring showed strong anxiety-like behaviors. These behavioral differences were accompanied by marked changes in gut microbiota composition and metabolic profiles, particularly in males.

Lactoferrin is a natural prebiotic widely used in infant nutrition. Researchers administered lactoferrin to the offspring, and found that lactoferrin significantly reduced anxiety-like behaviors in male offspring, but showed minimal improvement in the altered behavioral phenotypes of females, pointing toward sex-dependent microbial and metabolic pathways.

Multi-omics analyses revealed that lactoferrin strengthened microbial network connectivity, enhanced immune-related metabolic pathways, and restored the function of cerebellar Purkinje cells in male offspring, aligning with the behavioral rescue. The intervention strengthened a "microbiota-metabolite-cerebellar molecular factor" network whose improved integration closely paralleled behavioral recovery.

This work underscores the critical role of microbial homeostasis in maintaining brain-body network integrity, and highlights microbiota-targeted strategies as promising avenues for early-life mental health interventions.