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

doi:10.1016/j.psyneuen.2015.05.003

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 journal › Article › peer-review

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 language	English
Pages (from-to)	59–70
Number of pages	12
Journal	Psychoneuroendocrinology
Volume	59
DOIs	https://doi.org/10.1016/j.psyneuen.2015.05.003
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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10.1016/j.psyneuen.2015.05.003

Fetal brain 11β-hydroxysteroid dehydrogenase type 2 selectively determines programming
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Final published version, 732 KBLicence: Creative Commons: Attribution (CC-BY)

http://www.sciencedirect.com/science/article/pii/S0306453015001833

MRC Centenary Awards
Deary, I. (Principal Investigator)
MRC
1/06/12 → 30/09/13
Project: Research
DEVELOPMENT ORIGINS OF HEALTH AND UNHEALTHY AGEING :THE ROLE OF MATERNAL OBESITY DORIAN
Seckl, J. (Principal Investigator)
EU government bodies
1/01/12 → 31/12/14
Project: Research
MRC Centre for Cognitive Ageing and Cognitive Epidemiology
Deary, I. (Principal Investigator), Holmes, M. (Co-investigator), Logie, P. (Co-investigator), McCulloch, J. (Co-investigator), Porteous, D. (Co-investigator), Roberts, N. (Co-investigator), Seckl, J. (Co-investigator), Starr, J. (Co-investigator) & Wardlaw, J. (Co-investigator)
MRC
1/09/08 → 31/08/13
Project: Research

Cite this

Wyrwoll, C., Keith, M., Noble, J., Stevenson, P. L., Bombail, V., Crombie, S., Evans, L. C., Bailey, M. A., Wood, E., Seckl, J. R., & Holmes, M. C. (2015). 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. Psychoneuroendocrinology, 59, 59–70. https://doi.org/10.1016/j.psyneuen.2015.05.003

@article{ead7ac1a32814ede83d6fdb1af3fd2cf,

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.",

keywords = "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",

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

year = "2015",

month = sep,

doi = "10.1016/j.psyneuen.2015.05.003",

language = "English",

volume = "59",

pages = "59–70",

journal = "Psychoneuroendocrinology",

issn = "0306-4530",

publisher = "Elsevier",

}

Wyrwoll, C, Keith, M, Noble, J, Stevenson, PL, Bombail, V, Crombie, S, Evans, LC, Bailey, MA , Wood, E, Seckl, JR & Holmes, MC 2015, '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', Psychoneuroendocrinology, vol. 59, pp. 59–70. https://doi.org/10.1016/j.psyneuen.2015.05.003

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. / Wyrwoll, Caitlin; Keith, Marianne; Noble, June et al.
In: Psychoneuroendocrinology, Vol. 59, 09.2015, p. 59–70.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Wyrwoll, Caitlin

AU - Keith, Marianne

AU - Noble, June

AU - Stevenson, Paula L.

AU - Bombail, Vincent

AU - Crombie, Sandra

AU - Evans, Louise C

AU - Bailey, Matthew A.

AU - Wood, Emma

AU - Seckl, Jonathan R.

AU - Holmes, Megan C.

PY - 2015/9

Y1 - 2015/9

N2 - 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.

AB - 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.

KW - Glucocorticoids

KW - Developmental programming

KW - Affective behaviors

KW - Brain 11 beta-HSD2

KW - BETA-HYDROXYSTEROID DEHYDROGENASE

KW - SEROTONIN(1A) RECEPTOR-BINDING

KW - POSITRON-EMISSION-TOMOGRAPHY

KW - MESSENGER-RNA EXPRESSION

KW - PRENATAL STRESS

KW - 5-HT1A RECEPTOR

KW - MINERALOCORTICOID RECEPTOR

KW - ANTIDEPRESSANT-TREATMENT

KW - GLUCOCORTICOID EXPOSURE

KW - PLACENTAL 11-BETA-HSD2

U2 - 10.1016/j.psyneuen.2015.05.003

DO - 10.1016/j.psyneuen.2015.05.003

M3 - Article

SN - 0306-4530

VL - 59

SP - 59

EP - 70

JO - Psychoneuroendocrinology

JF - Psychoneuroendocrinology

ER -

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

Keywords / Materials (for Non-textual outputs)

Access to Document

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Projects

MRC Centenary Awards

DEVELOPMENT ORIGINS OF HEALTH AND UNHEALTHY AGEING :THE ROLE OF MATERNAL OBESITY DORIAN

MRC Centre for Cognitive Ageing and Cognitive Epidemiology

Cite this