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

Caitlin Wyrwoll, Marianne Keith, June Noble, Paula L. Stevenson, Vincent Bombail, Sandra Crombie, Louise C. Evans, Matthew A. Bailey, Emma Wood, Jonathan R. Seckl, Megan C. Holmes

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)59-70
Number of pages12
JournalPsychoneuroendocrinology
Volume59
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

Keywords

  • Affective behaviors
  • Brain 11β-HSD2
  • Developmental programming
  • Glucocorticoids

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