Project 437794

The increase in cerebral blood flow produced by neural activity (neurovascular coupling), a critical mechanism that matches substrate delivery with energy demands in brain is modulated by circulating immune cells in the blood. Because impaired neurovascular coupling increases the vulnerability of the brain, it is important to understand how changes in vascular tone in response to neural activity may be altered. Our preliminary data showed that a molecule derived from immune cells impairs neurovascular coupling in male only. These data are very exciting since there are very few studies that aimed at studying the effects of the immune system on cerebral blood flow and there no data about sexual differences and menopause on these mechanisms. More importantly, impaired neurovascular coupling increases brain vulnerability to Alzheimer's disease and stroke which incidence is higher in postmenopausal women. Accordingly, the major objective of this research program is to study the effect of sex and menopause on the regulation of neurovascular coupling by immune cells. In particular, we will investigate the effect of proinflammatory components of the adaptive immune system on neurovascular coupling. These studies will be conducted in mice and humanized mice which produces human immune cells in vivo using genetic, biochemical, anatomical and pharmacological approaches. These studies will improve our understanding of the mechanisms underlying the effects of sex differences and menopause on the regulation of neurovascular coupling by pro-inflammatory immune cells. This may provide further therapeutic target to reduce premature disability and death from dysfunctional cerebral blood flow.