Modulation of dendritic development by the neuronal hemoglobin: Role of beta-hemoglobin deficit in mediating prenatal stress-related affective disorders.

Beta-hemoglobin (HBB) is expressed in neurons, though its function remains incompletely understood. Prenatal stress (PS) is a well-established risk factor for neuropsychiatric disorders; however, the molecular mechanisms underlying its long-term effects are still unclear. In this study, we demonstrated that PS induces persistent anxiety- and depression-like behaviors in adult rat offspring, along with a significant downregulation of HBB in prefrontal cortical neurons. Deficiency of HBB resulted in neuronal hypoxia, impairing dendritic development, synaptic function, and neuronal connectivity; whereas overexpression of HBB rescued these behavioral and neuronal deficits. In healthy control rat offspring, knockdown of HBB in prefrontal cortical neurons recapitulated the phenotypes induced by PS. To intervene in these pathogenic processes, we found that early-life hyperbaric oxygen therapy (HBOT) restored HBB expression, alleviated neuronal hypoxia, and prevented the development of affective disorders in adulthood. Our findings identify cortical HBB as a key mediator linking PS to neurodevelopmental impairments and suggest hyperbaric oxygen therapy as a potential therapeutic strategy for stress-related psychiatric disorders.