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Background: Disruptions to neurodevelopment is known to be linked to behavioural disorders in childhood and into adulthood. The fetal brain is extremely vulnerable to stimuli that alter inhibitory GABAergic pathways and critical myelination processes programming long-term neurobehavioural disruption. The maturation of the GABAergic system into the major inhibitory pathway in the brain, and the development of oligodendrocytes into mature cells capable of producing myelin are integral components of optimal neurodevelopment. The current study aimed to elucidate prenatal stress-induced mechanisms that disrupt these processes, and to delineate the role of placental pathways in these adverse outcomes. Methods: Pregnant guinea pig dams were exposed prenatal stress with strobe light exposure for 2hrs/day on gestational age (GA) 35, 40, 45, 50, 55, 60 and 65, and groups of fetuses and placentae were collected after the stress exposure on GA40, GA50, GA60 and GA69 (term). Fetal plasma, placental and brain tissue were collected for allopregnanolone and cortisol quantification with ELISA. Relative mRNA expression of genes of specific pathways of interest were examined with real-time PCR in placental and hippocampal tissue, and myelin basic protein (MBP) was quantified immunohistochemically in the hippocampus and surrounding regions for assessment of mature myelin. Results: Prenatal stress in mid-late gestation resulted in disruptions to the translational machinery responsible for the production of myelin, and decreased myelin coverage in the hippocampus and surrounding regions. The male placenta showed an initial protective increase in allopregnanolone concentrations in response to maternal psychosocial stress. The male and female placentae had a sex-dependent increase in neurosteroidogenic enzymes at term following prenatal stress. Independent from exposure to prenatal stress, at gestational day 60 - a critical period for myelin development, the placentae of female fetuses had increased capability of preventing cortisol transfer to the fetus through expression of 11-beta-hydroxysteroid dehydrogenase type 1 and 2. Conclusion: The deficits early in the process of maturation of myelination indicates that the reduced myelination observed at childhood equivalence in previous studies begins in fetal life. This negative programming persists into childhood potentially due to dysregulation of MBP translation processes. Expression patterns of neurosteroidogenic enzymes in the placenta at term following stress may identify at-risk fetuses that have been exposed to a stressful in utero environment. 

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