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

30 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 language	English (US)
Pages (from-to)	59-70
Number of pages	12
Journal	Psychoneuroendocrinology
Volume	59
DOIs	https://doi.org/10.1016/j.psyneuen.2015.05.003
State	Published - Sep 1 2015
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2015 Published by Elsevier Ltd.

Keywords

Affective behaviors
Brain 11β-HSD2
Developmental programming
Glucocorticoids

Access

10.1016/j.psyneuen.2015.05.003

OpenUrl availability

Full text

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

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, 01.09.2015, p. 59-70.

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

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

@article{7392c83a5b26493f8be8dc58e658fdc4,

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 = "Affective behaviors, Brain 11β-HSD2, Developmental programming, Glucocorticoids",

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.}",

note = "Publisher Copyright: {\textcopyright} 2015 Published by Elsevier Ltd.",

year = "2015",

month = sep,

day = "1",

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

language = "English (US)",

volume = "59",

pages = "59--70",

journal = "Psychoneuroendocrinology",

issn = "0306-4530",

publisher = "Elsevier Limited",

}

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 - 2015/9/1

Y1 - 2015/9/1

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 - Affective behaviors

KW - Brain 11β-HSD2

KW - Developmental programming

KW - Glucocorticoids

UR - http://www.scopus.com/inward/record.url?scp=84937408145&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937408145&partnerID=8YFLogxK

U2 - 10.1016/j.psyneuen.2015.05.003

DO - 10.1016/j.psyneuen.2015.05.003

M3 - Article

C2 - 26036451

AN - SCOPUS:84937408145

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

Bibliographical note

Keywords

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this