Role of 11β-HSD1 in reference and working memory in ageing: investigating underlying mechanisms and biomarkers of age-associated cognitive decline
Glucocorticoids (GC) have a negative effect on age-associated cognitive decline and the GC metabolising enzyme 11β-hydroxysteroid dehydrogenase Type 1 (11β- HSD1) plays a key role in these effects. Increased glucocorticoids exert detrimental effects on the volume and function of brain regions such as the prefrontal cortex (PFC) and hippocampus that are necessary for cognitive functions such as memory and working memory. Previous research has identified changes in cell populations, metabolite levels and structure within the brain as well as altered levels of inflammation with age, and studies have suggested these biomarkers to be associated with cognitive impairments. Aged mice with a deletion in 11ß-HSD1 (11β-HSD1-/- mice), resulting in lower levels of glucocorticoids within the brain, exhibit attenuated cognitive decline in hippocampal dependent spatial learning and memory with age. However, the mechanisms through which 11β-HSD1 contribute to age-associated cognitive decline remain unknown. However, previous genetic models of 11β-HSD1- /- mice have demonstrated residual 11β-HSD1 activity in the brain which may still exert some effects on cognitive processes. Furthermore, the effect of 11ß-HSD1 on working memory – a more cognitively demanding process essential for everyday decision making - has yet to be determined. This thesis tests the hypothesis that glucocorticoid action mediates age-associated cognitive impairment in spatial learning and memory and spatial working memory through alterations in cell activity, brain metabolite levels and neuroinflammatory processes. Therefore, we aimed to investigate if complete lifelong 11β-HSD1 deficiency would protect against age-associated working memory deficits as well as spatial learning and memory deficits, and its effect on associated neural markers. In particular, we determined changes in hippocampal metabolite levels, cell activity and inflammation as a function of ageing in a longitudinal manner. At 6, 12, 18 and 22 months, male 11β- HSD1-/- and C57BL/6J control mice were cognitively assessed in the Morris Water Maze (MWM) and Radial Arm Water Maze (RAWM) – tests for spatial reference memory and spatial working memory respectively. Magnetic resonance spectroscopy (1H-MRS) was performed to examine the hippocampal metabolite profile in the same mice at 6, 18 and 22 months. Following their final scan, mice were culled and brains dissected for analysis. Results revealed unaltered spatial learning with age in C57BL/6J and 11β-HSD1-/- mice and pointed to a development of alternative strategies for task completion as a result of repeated testing. Spatial memory was more susceptible to age-associated effects with impairments in wild-type mice but not 11β-HSD1-/- mice, though not completely immune from the effects of repeated testing. These impairments were correlated with glutamate/glutamine levels and glial fibrillary acidic protein (GFAP), whilst GFAP was further correlated with 11β-HSD1 protein expression. Working memory was impaired with age in both 11β-HSD1-/- and wild-type mice, suggesting 11β-HSD1 deletion may be detrimental to cognitive processes in the prefrontal cortex. In conclusion, impaired memory with age may be attributed to increased glial reactivity and altered glutamate/glutamine cycling in the hippocampus, and lifelong removal of 11β-HSD1 may alter these processes. However, lifelong removal of 11β-HSD1 may not be as beneficial to working memory processes suggesting that 11β-HSD1 and glucocorticoid action play a key role in working memory processes.