Source Paper
Sex-Specific Programming of Offspring Emotionality after Stress Early in Pregnancy
Bridget R. Mueller, Tracy L. Bale
Journal of Neuroscience • 2008
View Abstract
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 PPARα (peroxisome proliferator-activated receptor α), IGFBP-1 (insulin-like growth factor binding protein 1), HIF3α (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.
Behavioral Stress Responsivity Testing
Objective: Assessment of maladaptive behavioral stress responsivity and anhedonia in offspring exposed to prenatal stress at different gestational periods (early, mid, and late gestation)
Protocol Steps
Prenatal Stress Exposure
Pregnant dams exposed to stress during early, mid, or late gestation periods
Note: Three different gestational time windows examined to determine critical period for fetal antecedents inducing disease predisposition
View evidence from paper
“examined behavioral responses in offspring exposed to stress during early, mid, and late gestation”
Behavioral Stress Responsivity Testing
Assessment of maladaptive behavioral stress responsivity in offspring
Note: Male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity
View evidence from paper
“male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity”
Anhedonia Assessment
Evaluation of anhedonia in offspring
Note: Anhedonia was measured as an outcome in offspring exposed to early prenatal stress
View evidence from paper
“male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity, anhedonia”
SSRI Treatment Sensitivity Testing
Assessment of sensitivity to selective serotonin reuptake inhibitor treatment
Note: Increased sensitivity to SSRI treatment observed in male offspring exposed to early prenatal stress
View evidence from paper
“increased sensitivity to selective serotonin reuptake inhibitor treatment”