Postnatal Stress Induced by Injection with Valproate Leads to Developing Emotional Disorders Along with Molecular and Cellular Changes in the Hippocampus and Amygdala

Stress derived from an adverse environment during brain development could contribute to psychiatric disorders. To study the influence of stress occurring at birth on behavior development in human, we performed an intraperitoneal injection (i.p.) of valproic acid (VPA; 200 mg/kg), a histone deacetylation inhibitor (HDACi), into male rat pups at the age of postnatal day 7 (P7) that is equivalent to an infant at 36-40 weeks gestation. Our results showed that neuronal differentiation genes, doublecortin (DCX) and NeuroD1, were downregulated in the hippocampus at 24 h post VPA injection. In addition, the cell proliferation was increased in the dentate gyrus and amygdala of rats receiving VPA injection. DCX and NeuN cell population was decreased in the dentate gyrus at 24 h post VPA injection. Moreover, microglial morphological changes in the hippocampus and amygdala were rapidly induced at 24 h after VPA injection. Through a series of behavior tests, we found that rats receiving VPA injection displayed depressive and anxiety-like behaviors at the late postnatal ages, and had impaired social interaction at 8 weeks old. In summary, a single postnatal administration of VPA not only disrupted neural cell differentiation program but also induced anxious, depressive, and impaired social behaviors. Our findings also shed light on early life stress to infants as a significant risk factor with regard to developing emotional disorders in youth, and that these effects may continue into adulthood, possibly due to altered gene expression and neuron-glia interaction occurring in the hippocampus and amygdala at an early age.