The interactive effect of acute ovarian suppression and the cholinergic system on visuospatial working memory in young women

SummaryWomen have an increased risk of developing Alzheimer's Dementia (AD) compared to men. It has been postulated that this risk may be modulated by a reduction in the neuroprotective effects of estrogen on the brain in the early postmenopausal period. This view is supported by, for example, findings that ovariectomy in younger women (i.e. prior to menopause) significantly increases the risk for the development of memory problems and AD in later life. However, the biological basis underlying these cognitive changes is still poorly understood. Our aim in the current study was to understand the interactive effects of acute, pharmacological-induced menopause (after Gonadotropin Hormone Releasing Hormone agonist (GnRHa) treatment) and scopolamine (a cholinergic antagonist used to model the memory decline associated with aging and AD) on brain functioning. To this end we used fMRI to study encoding during a Delayed Match to Sample (DMTS) (visual working memory) task. We report a relative attenuation in BOLD response brought about by scopolamine in regions that included bilateral prefrontal cortex and the left parahippocampal gyrus. Further, this was greater in women post-GnRHa than in women whose ovaries were functional. Our results also indicate that following pharmacological-induced menopause, cholinergic depletion produces a more significant behavioural deficit in overall memory performance, as manifest by increased response time. These findings suggest that acute loss of ovarian hormones exacerbate the effects of cholinergic depletion on a memory-related, behavioural measure, which is dependent on fronto-temporal brain regions. Overall, our findings point to a neural network by which acute loss of ovarian function may interact to negatively impact encoding.