Gestational Exposure to Variable Stressors Produces Decrements in Cognitive and Neural Development of Juvenile Male and Female Rats

Gestational stress may have lasting deleterious effects on neuro-cognitive development of offspring. Progesterone (P), and its 5α-reduced metabolites, dihydroprogesterone (DHP) and 5α-pregnan-3α-ol-20-one (3α,5α-THP), maintain pregnancy, and can have effects on cognitive performance and/or neuronal integrity. However, whether some of the deleterious effects of gestational stress on cognitive and neural processes may be related to progestogen formation is not known. Pregnant rat dams were exposed to a regimen of variable stressors (including forced swim, restraint, fasting, social stress, and exposure to cold and light) on gestational days 17-21 or were minimally-handled controls. Male and female offspring were cross-fostered to non-manipulated dams and assessed for motor and cognitive performance between postnatal days 28 and 30. Although the motor behavior of gestationally-stressed offspring did not differ significantly from control, offspring, their cognitive performance in an object recognition task was poorer. Irrespective of sex, dendritic spine density was reduced in dorsal hippocampus of stress-exposed offspring compared to control offspring. Formation of DHP was reduced in medial prefrontal cortex (mPFC) and increased in hippocampus of stressed, compared to control, offspring. Notably, there were sex differences wherein estradiol in mPFC, as well as P and DHP in diencephalon, were increased with stress among females but decreased with stress among males. These data suggest that exposure to variable stress during gestation can perturb cognitive performance, concomitant with dendrite development in hippocampus, and P's 5α-reduction in hippocampus and mPFC. Some sex differences in stress effects on progestogen formation may occur in diencephalon.