Stress or elevated glucocorticoids during sensitive windows of fetal development increase the risk of neuropsychiatric disorders in adult rodents and humans, a phenomenon known as glucocorticoid programming. 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2), which catalyses rapid inactivation of glucocorticoids in the placenta, controls access of maternal glucocorticoids to the fetal compartment, placing it in a key position to modulate glucocorticoid programming of behavior. However, the importance of the high expression of 11β-HSD2 within the midgestational fetal brain is unknown. To examine this, a brain-specific knockout of 11β-HSD2 (HSD2BKO) was generated and compared to wild-type littermates. HSD2BKO have markedly diminished fetal brain 11β-HSD2, but intact fetal body and placental 11β-HSD2 and normal fetal and placental growth. Despite normal fetal plasma corticosterone, HSD2BKO exhibit elevated fetal brain corticosterone levels at midgestation. As adults, HSD2BKO show depressive-like behavior and have cognitive impairments. However, unlike complete feto-placental deficiency, HSD2BKO show no anxiety-like behavioral deficits. The clear mechanistic separation of the programmed components of depression and cognition from anxiety implies distinct mechanisms of pathogenesis, affording potential opportunities for stratified interventions.
Bibliographical noteFunding Information:
We acknowledge Wellcome Trust project grant ( WT079009 ) and EU FP7 collaborative grant Developmental origins of healthy and unhealthy ageing (DORIAN) to MCH and JRS. The work was supported by a PhD studentship (SC) from The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704). Funding from the Biotechnology and Biological Sciences Research Council (BBSRC) , Engineering and Physical Sciences Research Council (EPSRC) , Economic and Social Research Council (ESRC) , and Medical Research Council (MRC) is gratefully acknowledged.
© 2015 Published by Elsevier Ltd.
- Affective behaviors
- Brain 11β-HSD2
- Developmental programming