Genetic inactivation of the CRF1 receptor eliminates age‐linked elevation of hippocampal 11β‐hydroxysteroid dehydrogenase type 1 activity in female mice

Abstract

Glucocorticoids are produced through activation of the hypothalamic–pituitary–adrenal (HPA) axis, initiated by the release of corticotropin‐releasing factor (CRF) from the hypothalamus. CRF acts through two receptor subtypes, CRF1 and CRF2. However, the specific contributions of CRF
1
and CRF
2
receptors to age‐related changes in brain glucocorticoid activity remain largely unexplored. In certain tissues, including the hippocampus, glucocorticoid signaling is further amplified by the enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), which regenerates inactive glucocorticoid metabolites into their active form. Notably, prior research investigating the role of hippocampal 11β‐HSD1 in aging has focused exclusively on male subjects. In this study, we used genetic mouse models lacking functional CRF
1
or CRF
2
receptors to investigate their respective roles in regulating hippocampal 11β‐HSD1 activity and glucocorticoid levels across age and sex. Mice of both sexes at 6 and 18 months of age were analyzed. Hippocampal 11β‐HSD1 activity was assessed by measuring the ratio of corticosterone to dehydrocorticosterone using mass spectrometry in tissue extracts from CRF
1
and CRF
2
wild‐type (WT), heterozygous (HET), and knockout (KO) mice. Our results demonstrate that hippocampal 11β‐HSD1 activity increases with age in female CRF
1
WT and HET mice but not in CRF
1
KO females. In contrast, aged males exhibit elevated 11β‐HSD1 activity regardless of CRF
1
genotype. In CRF
1
males, the age‐related increase in hippocampal 11β‐HSD1 activity is associated with higher hippocampal corticosterone levels, whereas in CRF
1
females, it corresponds with a decrease in hippocampal dehydrocorticosterone. CRF
1
deficiency leads to reduced hippocampal levels of both corticosterone and dehydrocorticosterone in males and females at both ages. CRF
1
deficiency is also associated with decreased plasma corticosterone levels in both male and female mice. Male, but not female, CRF
2
mice show an age‐dependent increase in hippocampal 11β‐HSD1 activity, which is not altered by CRF
2
deficiency. Moreover, CRF
2
deficiency results in increased plasma corticosterone in female, but not in male, mice. Overall, our findings reveal that hippocampal 11β‐HSD1 activity increases with age in both sexes. In females, this increase is dependent on the presence of functional CRF
1
receptors. In contrast, males exhibit age‐related increases in 11β‐HSD1 activity independent of CRF
1
function. These findings underscore the importance of considering sex as a biological variable when developing therapeutic strategies targeting 11β‐HSD1 to mitigate age‐related memory decline.

Auteurs Bordeaux Neurocampus