Absence of 11b-HSD2 specifically within the fetal brain alter adult ‘depressive’ behaviour. (#183)
Maternal stress and consequent fetal glucocorticoid overexposure increases offspring susceptibility to neuropsychiatric disorders. Fetal brain exposure to glucocorticoids is regulated by 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2) which inactivates glucocorticoids in the placenta and fetal brain. 11b-HSD2-/- offspring generated by heterozygous matings exhibit altered placental function, decreased birth weight, delayed neurodevelopment and increased anxiety and depressive-like behaviour as adults. This raises the question as to whether it is placental or fetal brain 11b-HSD2 that underpins programmed outcomes? A knockout of 11b-HSD2 specifically within the brain during development was created by crossing NestinCre mice with floxed 11b-HSD2 mice to produce 11b-HSD2flx/flx (Con) and NestinCre.11b-HSD2flx/flx (CentralHSD2KO) mice. 11b-HSD2 activity in fetal tissue and placenta was measured, neurodevelopmental landmarks assessed and adult behaviour characterised alongside measurement of HPA axis, serotonin, dopamine and their metabolites and central gene expression. Brain-specific reduction in 11b-HSD2 activity was confirmed in the fetal heads of CentralHSD2KO mice. Birth weight and markers of neurodevelopment were unaltered. Anxiety was assessed in unstressed and acutely stressed adult offspring and was unaltered. However depressive-like behaviour, as assessed by the tail suspension test, was increased in mice with brain-specific deletion of 11b-HSD2 with CentralHSD2KO spending a greater percentage of time hanging in comparison to the Con mice (68 and 53% respectively, P<0.05). Depressive-like behaviour was also exhibited in the novelty-induced hypophagia study with the CentralHSD2KO mice having a reduced latency to feed in comparison to the Con mice (53±8s and 28±4s respectively, P=0.01). Accompanying this altered behaviour was reduced expression of the serotonin receptor 5HT-1a in the hippocampus of CentralHSD2KO mice in comparison to Con (15.0±1.1 grains/cell and 19.3±1.5 grains/cell respectively, P<0.01). Our data suggest that fetal brain 11b-HSD2 impacts specifically on depressive-like behaviours, but that broader anxiety-related and neurodevelopmental effects are likely to relate to indirect effects of 11b-HSD2 in the placenta.