Research Area
Our research focuses on understanding how environmental stress regulates behaviour and brain ageing in health and disease. The goal is to identify new targets for the treatment of cognitive dysfunction associated with ageing and stress-related disorders.
Cognitive impairment occurs in a substantial segment of the elderly population. Risk factors include age, genetics and other health conditions such as diabetes, obesity, and depression. However, the central mechanisms that underlie mild cognitive impairment (MCI) which can lead to dementia remains unclear. One environmental influence of particular interest is brain exposure to increased levels of stress glucocorticoid (GC) hormones over the lifespan.
Brain GC metabolism and cognitive function: Whereas only ~5% of circulating GCs are free to enter tissues, intracellular steroid metabolising enzymes make a significant contribution to the local pool of GCs. Our preclinical research has demonstrated that 11ß-HSD1, an enzyme that generates active GCs within specific target tissues including brain, directly contributes to age-related cognitive decline. Thus, a transgenic deficiency of 11ß-HSD1 prevents memory impairments in old age; and treatment with 11ß-HSD1 inhibitors reversed age-related memory deficits. These findings underscore the importance of reducing GC action in the brain to maintain cognitive function in old age and supports 11ß-HSD1 as a therapeutic target for cognitive enhancement.
Midlife stress and brain ageing: Chronic stress compromises the health of both the brain and body, increasing the risk of anxiety and depression and cardiovascular disease. We have shown in our preclinical models that chronic stress during middle-age causes impaired memory, anxiety and depression-like behaviours that remained evident 6 months after stress cessation. Importantly, a deficiency of 11ß-HSD1 prevents the midlife stress effects on behaviour. We investigate brain mechanisms that underpin these changes and whether the impact of stress in midlife can be reversed or accelerated with other genetic or environmental factors.
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