Prenatal stress is associated with an increased vulnerability to neurodevelopmental disorders, including autism and schizophrenia. To determine the critical time window when fetal antecedents may induce a disease predisposition, we examined behavioral responses in offspring exposed to stress during early, mid, and late gestation. We found that male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity, anhedonia, and an increased sensitivity to selective serotonin reuptake inhibitor treatment. Long-term alterations in central corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, as well as increased hypothalamic-pituitary-adrenal (HPA) axis responsivity, were present in these mice and likely contributed to an elevated stress sensitivity. Changes in CRF and GR gene methylation correlated with altered gene expression, providing important evidence of epigenetic programming during early prenatal stress. In addition, we found the core mechanism underlying male vulnerability may involve sex-specific placenta responsivity, where stress early in pregnancy significantly increased expression of PPAR␣ (peroxisome proliferator-activated receptor ␣), IGFBP-1 (insulin-like growth factor binding protein 1), HIF3␣ (hypoxia-inducible factor 3a), and GLUT4 (glucose transporter 4) in male placentas but not females. Examination of placental epigenetic machinery revealed basal sex differences, providing further evidence that sex-specific programming begins very early in pregnancy, and may contribute to the timing and vulnerability of the developing fetus to maternal perturbations. Overall, these results indicate that stress experience early in pregnancy may contribute to male neurodevelopmental disorders through impacts on placental function and fetal development.

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To examine the long-term effects of stress experienced early in gestation on the programming of offspring feeding behaviors and energy balance, pregnant mice were exposed to stress during early pregnancy (days 1–7) and adult offspring examined on chow and high fat diets for long-term outcomes. Placental 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and insulin-like growth factor 2 (IGF-2) expression was measured to determine the possible sex-specific contribution of prenatal stress (PNS) on fetal programming of embryo growth and development during early pregnancy. PNS mice showed a basal hyperphagia when on chow diet. Prenatal treatment differences were ameliorated when adult mice were on a high fat diet. Interestingly, PNS male mice also had significantly reduced body weights compared to control males on both chow and high fat diets. Body composition analyses revealed reduced body fat and increased lean mass in PNS mice on the high fat diet, but no differences were detected in plasma leptin or insulin-like growth factor 1 (IGF-1) levels. Mechanistic examination of gene expression in embryonic day 12 placentas found that early PNS was associated with increased IGF-2 expression and sex-dependent effects of stress on 11 β-HSD2, supporting specific aspects of early pregnancy. These studies suggest that the long-term effects of stress during pregnancy on programming of feeding behavior and energy homeostasis begin much earlier in development than previously thought.

Adding a vision-based performance measure to cognitive and balance testing enhances the detection capabilities of current sideline concussion assessment. This observation in patients with mild traumatic brain injury reflects the common involvement and widespread distribution of brain pathways dedicated to vision.