Genetic inactivation of the <scp> CRF ₁ </scp> receptor eliminates age‐linked elevation of hippocampal 11β‐hydroxysteroid dehydrogenase type 1 activity in female mice

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 CRF₁ and CRF₂ 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 CRF₁ or CRF₂ 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 CRF₁ and CRF₂ wild-type (WT), heterozygous (HET), and knockout (KO) mice. Our results demonstrate that hippocampal 11β-HSD1 activity increases with age in female CRF₁ WT and HET mice but not in CRF₁ KO females. In contrast, aged males exhibit elevated 11β-HSD1 activity regardless of CRF₁ genotype. In CRF₁ males, the age-related increase in hippocampal 11β-HSD1 activity is associated with higher hippocampal corticosterone levels, whereas in CRF₁ females, it corresponds with a decrease in hippocampal dehydrocorticosterone. CRF₁ deficiency leads to reduced hippocampal levels of both corticosterone and dehydrocorticosterone in males and females at both ages. CRF₁ deficiency is also associated with decreased plasma corticosterone levels in both male and female mice. Male, but not female, CRF₂ mice show an age-dependent increase in hippocampal 11β-HSD1 activity, which is not altered by CRF₂ deficiency. Moreover, CRF₂ 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 CRF₁ receptors. In contrast, males exhibit age-related increases in 11β-HSD1 activity independent of CRF₁ 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.