Advance in the mechanisms underlying prenatal stress-induced depressive-like behavior in offspring

Prenatal stress (PS) represents a critical environmental factor that causes developmental disruptions in offspring, characterized by multisystemic vulnerabilities across neuropsychiatric, cardiovascular, metabolic, and immunological domains. Through intricate embryonic reprogramming mechanisms, PS alters brain developmental trajectories and physiological regulatory networks, resulting in increased long-term risks for neurodevelopmental disorders, particularly depressive-like behavior. PS causes dysregulation in multiple physiological processes, including hypothalamic-pituitary-adrenal (HPA) axis activation, epigenetic modifications, neurotransmitter systems, brain-derived neurotrophic factor (BDNF), gut microbiota, and neuroimmune responses. Additionally, genetic factors, sex specificity, and critical developmental windows further complicate the PS-mediated onset of depressive-like behavior. Here, we review clinical and animal studies and analyze how the multiple mechanisms form complex regulatory networks during intrauterine development, leading to long-lasting psychopathological effects in offspring.