Perinatal Programming of Neurodevelopment

María Eugenia Pallarés, Marta C. Antonelli

Marta C. Antonelli

Our laboratory has a long-standing interest in the effects of prenatal stress (PS) on various neurotransmitter pathways and the morphology of the developing brain as well as in behavioural aspects of the offspring. Employing a commonly used PS paradigm in which the dams were subjected to restraint stress during the last week of gestation, we observed that several of these pathways were altered in the offspring brain. In this chapter, we will summarize and discuss the results obtained with the main catecholaminergic pathways, namely dopamine (DA) and norepinephrine (NE). In our hands, PS produces an increase in dopamine D2-type receptors in limbic areas, a decreased DA release after amphetamine stimulation in prefrontal cortex (PFC) and an increase in NE release in the same area of the adult offspring brain. In addition, DA uptake is altered at prepubertal stages that persist through adulthood. However, the expression of the step-limiting enzyme of the DA synthesis, tyrosine hydroxylase (TH), is only impaired at early stages of development after PS in the neuronal bodies. At the nuclear regulation level, dopaminergic transcription factors Nurr1 and Ptx3 showed a high vulnerability to PS showing changes along the lifespan. It was striking to observe that many impairments observed in most of these pathways differed depending on whether they were tested before or after puberty indicating a particular sensitivity of the systems to variations in gonadal hormones peaks. In fact, we observed that PS induced long-term effects on the male offspring reproductive system and spermatogenesis development, particularly by inducing a long-term imbalance of circulating sexual hormone levels. Our findings suggest that PS exerts long-term effects on various neurotransmitter pathways altering the normal connectivity between brain areas. Since the developing forebrain was shown to be influenced by androgen exposure, and PS was shown to disrupt prenatal testosterone surges, our results suggest that prenatal insults might be affecting the organizational role of androgens during brain development and differentially modulating their activational role during pubertal brain maturation.