11β-HSD Types 1 and 2 in the Songbird Brain

Abstract

Glucocorticoid (GC) hormones act on the brain to regulate diverse functions, from behavior and homeostasis to the activity of the hypothalamic–pituitary–adrenal axis. Local regeneration and metabolism of GCs can occur in target tissues through the actions of the 11β-hydroxysteroid dehydrogenases [11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 11 beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2), respectively] to regulate access to GC receptors. Songbirds have become especially important model organisms for studies of stress hormone action; however, there has been little focus on neural GC metabolism. Therefore, we tested the hypothesis that 11β-HSD1 and 11β-HSD2 are expressed in GC-sensitive regions of the songbird brain. Localization of 11β-HSD expression in these regions could provide precise temporal and spatial control over GC actions. We quantified GC sensitivity in zebra finch (Taeniopygia guttata) brain by measuring glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression across six regions, followed by quantification of 11β-HSD1 and 11β-HSD2 expression. We detected GR, MR, and 11β-HSD2 mRNA expression throughout the adult brain. Whereas 11β-HSD1 expression was undetectable in the adult brain, we detected low levels of expression in the brain of developing finches. Across several adult brain regions, expression of 11β-HSD2 covaried with GR and MR, with the exception of the cerebellum and hippocampus. It is possible that receptors in these latter two regions require direct access to systemic GC levels. Overall, these results suggest that 11β-HSD2 expression protects the adult songbird brain by rapid metabolism of GCs in a context and region-specific manner.

The stressed brain: regional and stress‐related corticosterone and stress‐regulated gene expression in the adult zebra finch (Taeniopygia guttata)

“…CORT treatment mimicking acute stress levels should up‐regulate expression of all three genes, with the greatest degree of up‐regulation in those regions expressing the most GR, namely the CER and cTEL, based on our previous work 22 . However, these regions also express the most 11βHSD2, which would in theory prevent CORT access to GR and subsequent downstream signalling 22 . Therefore, we predicted that CORT treatment would more potently increase downstream gene expression in those regions with lower 11βHSD2, albeit with lower GR (HYP and HP).…”

“…Although previous work failed to identify 11βHSD2 in the chicken brain, 28 this enzyme is expressed and actively metabolises CORT in the zebra finch brain, 29 suggesting a potentially important role in songbirds. Moreover, we recently documented regional variation in 11βHSD2 expression in the adult zebra finch brain, with relatively higher levels in CER than in DIEN or HP 22 . If 11βHSD2 regulates CORT in the zebra finch brain, we predicted that brain CORT levels would be highest in regions expressing the least amounts of the enzyme, DIEN and HP, and lowest in CER, which expresses relatively higher levels of 11βHSD2 22 .…”

“…Moreover, we recently documented regional variation in 11βHSD2 expression in the adult zebra finch brain, with relatively higher levels in CER than in DIEN or HP 22 . If 11βHSD2 regulates CORT in the zebra finch brain, we predicted that brain CORT levels would be highest in regions expressing the least amounts of the enzyme, DIEN and HP, and lowest in CER, which expresses relatively higher levels of 11βHSD2 22 .…”

“…In addition, we know of no studies in songbirds that investigate the downstream effects of central CORT binding, nor do we appreciate how genes are regulated by CORT in discrete brain regions. Although much of the CORT regulatory machinery is highly conserved, there are important differences in patterns of CORT‐metabolic enzyme expression, 22 ligand specificity of CBGs, 23 and the abundance and ligand specificity of MR between birds and mammals 24 . Because the songbird is a useful model for exploring the dynamics of neurogenesis, vocal learning and cognition, which are processes that are all sensitive to CORT, these are pressing questions to address.…”

“…We used an ex vivo slice culture technique to expose microdissected sections of adult zebra finch brain (CER, HP, caudal telencephalon [cTEL] and hypothalamus [HYP]) to physiological stress levels of CORT, then quantified expression of FKBP5, GILZ and SGK1, three CORT‐regulated genes in mammals 30‐32 . CORT treatment mimicking acute stress levels should up‐regulate expression of all three genes, with the greatest degree of up‐regulation in those regions expressing the most GR, namely the CER and cTEL, based on our previous work 22 . However, these regions also express the most 11βHSD2, which would in theory prevent CORT access to GR and subsequent downstream signalling 22 .…”