Impact of hypertension and high-fat diet on estradiol’s role in cortical synaptic plasticity
The overall hypothesis of Project 2 is that cardiometabolic disease prior to menopause impedes the beneficial cognitive effects of hormone therapy by blunting neurovascular coupling via endothelial nitric oxide synthase uncoupling, thus impairing the local network activity and synaptic plasticity required to preserve functional cortical circuits and therefore for cognition.
Hypothesized model by which effects of estrogens on cortical synaptic plasticity and neurovascular coupling diverge in healthy and unhealthy females. Memory and learning are dependent on proper synaptic plasticity mechanisms, which are directly and indirectly determined, among other mechanisms, by neuronal activity and metabolism, mechanisms mutually dependent on each other too. In turn, neurovascular coupling (NVC) depends and has effects on neuronal activity and metabolism and relies on the proper function of endothelial cells of the brain vasculature. Cessation of endogenous circulating estrogens in healthy conditions has detrimental effects on NVC, neuronal activity, and synaptic plasticity (blue thunderbolts) that are ultimately responsible for overall impaired cognition. While hormone therapy early after menopause prevents or reverts many of those deficits (green blunt arrows), it is unknown whether the neuroprotective effect of estrogens therapy is able to overcome the presence of prior history of cardiovascular or metabolic disease in unhealthy aging conditions at menopause (red thunderbolts).
