Abstract
Chronic exposure to stress during midlife associates with subsequent age-related cognitive decline and may increase the vulnerability to develop psychiatric conditions. Increased hypothalamic-pituitary-adrenal (HPA) axis activity has been implicated in pathogenesis though any causative role for glucocorticoids is unestablished. This study investigated the contribution of local glucocorticoid regeneration by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), in persisting midlife stress-induced behavioral effects in mice. Middle-aged (10 months old) 11β-HSD1-deficient mice and wild-type congenic controls were randomly assigned to 28 days of chronic unpredictable stress or left undisturbed (non-stressed). All mice underwent behavioral testing at the end of the stress/non-stress period and again 6–7 months later. Chronic stress impaired spatial memory in middle-aged wild-type mice. The effects, involving a wide spectrum of behavioral modalities, persisted for 6–7 months after cessation of stress into early senescence. Enduring effects after midlife stress included impaired spatial memory, enhanced contextual fear memory, impaired fear extinction, heightened anxiety, depressive-like behavior, as well as reduced hippocampal glucocorticoid receptor mRNA expression. In contrast, 11β-HSD1 deficient mice resisted both immediate and enduring effects of chronic stress, despite similar stress-induced increases in systemic glucocorticoid activity during midlife stress. In conclusion, chronic stress in midlife exerts persisting effects leading to cognitive and affective dysfunction in old age via mechanisms that depend, at least in part, on brain glucocorticoids generated locally by 11β-HSD1. This finding supports selective 11β-HSD1 inhibition as a novel therapeutic target to ameliorate the long-term consequences of stress-related psychiatric disorders in midlife.
Highlights
Chronic stress, which activates the HPA axis and increases blood levels of glucocorticoid (GC) stress hormones, causes contemporary cognitive dysfunction and may contribute to the development of depression and anxiety-related disorders (Lupien et al, 2009; Pryce and Fuchs, 2017)
Animal studies show that vulnerability to GC or stress-induced cognitive impairment is greater in middle and old age compared with young adults (Bodnoff et al, 1995; Sandi and Touyarot, 2006)
It is clear that active GCs within specific brain regions are derived from the circulation, and by local regeneration from inert and largely unbound circulating 11-keto forms (11-dehydrocorticosterone). This local regeneration is catalysed by the intracellular enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) which is abundantly expressed in brain regions involved in cognition, anxiety and HPA axis regulation including the hippocampus, cortex and amygdala (Wyrwoll et al, 2011)
Summary
Chronic stress, which activates the HPA axis and increases blood levels of glucocorticoid (GC) stress hormones, causes contemporary cognitive dysfunction and may contribute to the development of depression and anxiety-related disorders (Lupien et al, 2009; Pryce and Fuchs, 2017). It is clear that active GCs (corticosterone in rodents) within specific brain regions are derived from the circulation (only ∼5% of circulating active GCs are unbound and available to penetrate the blood brain barrier), and by local regeneration from inert and largely unbound circulating 11-keto forms (11-dehydrocorticosterone) This local regeneration is catalysed by the intracellular enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) which is abundantly expressed in brain regions involved in cognition, anxiety and HPA axis regulation including the hippocampus, cortex and amygdala (Wyrwoll et al, 2011). We examined if these effects are prevented or attenuated by 11β-HSD1 deficiency
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