Projects per year
Abstract / Description of output
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 language | English |
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Pages (from-to) | 59–70 |
Number of pages | 12 |
Journal | Psychoneuroendocrinology |
Volume | 59 |
DOIs | |
Publication status | Published - Sept 2015 |
Keywords / Materials (for Non-textual outputs)
- Glucocorticoids
- Developmental programming
- Affective behaviors
- Brain 11 beta-HSD2
- BETA-HYDROXYSTEROID DEHYDROGENASE
- SEROTONIN(1A) RECEPTOR-BINDING
- POSITRON-EMISSION-TOMOGRAPHY
- MESSENGER-RNA EXPRESSION
- PRENATAL STRESS
- 5-HT1A RECEPTOR
- MINERALOCORTICOID RECEPTOR
- ANTIDEPRESSANT-TREATMENT
- GLUCOCORTICOID EXPOSURE
- PLACENTAL 11-BETA-HSD2
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- 4 Finished
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DEVELOPMENT ORIGINS OF HEALTH AND UNHEALTHY AGEING :THE ROLE OF MATERNAL OBESITY DORIAN
1/01/12 → 31/12/14
Project: Research
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MRC Centre for Cognitive Ageing and Cognitive Epidemiology
Deary, I., Holmes, M., Logie, P., McCulloch, J., Porteous, D., Roberts, N., Seckl, J., Starr, J. & Wardlaw, J.
1/09/08 → 31/08/13
Project: Research