title: Fetal brain 11β-hydroxysteroid dehydrogenase type 2 selectively determines programming of adult depressive-like behaviors and cognitive function, but not anxiety behaviors in male mice.
abstract: 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.
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom; School of Anatomy, Physiology & Human Biology, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Wyrwoll
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Marianne
authors.initials: M
authors.lastname: Keith
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: June
authors.initials: J
authors.lastname: Noble
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Stevenson
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Bombail
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Sandra
authors.initials: S
authors.lastname: Crombie
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Evans
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: Centre for Cognitive and Neural Systems, University of Edinburgh, EH8 9JZ, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Wood
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.affiliation: UoE/BHF Centre for Cardiovascular Science, University of Edinburgh, EH16 4TJ, United Kingdom. Electronic address: megan.holmes@ed.ac.uk.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Holmes
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism*; D000818:Animals; D001008:Anxiety Disorders / Q000201:enzymology*; D001921:Brain / Q000196:embryology* / Q000201:enzymology*; D003866:Depressive Disorder / Q000201:enzymology*; D004195:Disease Models, Animal; D005260:Female; D047109:Fetal Development; D005938:Glucocorticoids / Q000097:blood / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D012307:Risk Factors; D013312:Stress, Physiological
chemical_list: D005938:Glucocorticoids; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2
keywords: Affective behaviors; Brain 11β-HSD2; Developmental programming; Glucocorticoids