Project 2 Summary The menopausal transition is responsible for many of the cognitive impairments reported by women at midlife. In addition to the detrimental effects of the natural loss of endogenous hormones on cognition, and as a probable consequence, the prevalence of Alzheimer’s disease and other related dementias is higher in women than men, with double the lifetime risk of Alzheimer’s disease at age 45. Hormone therapy is the most effective treatment for the vasomotor and sleep disruptions that accompany menopause, but timing of the intervention may have a crucial impact on overall outcome, particularly on the preservation of cognitive capabilities. Whereas late hormone therapy interventions have no benefit, or may even be harmful, early interventions seem to bestow protection against cognitive decline, regardless of the presence of Alzheimer’s disease pathology. In addition, cardiovascular and metabolic complications are directly associated with sharper cognitive decline, which together with the loss of endogenous estrogens, may further increase the risk of developing Alzheimer’s disease and vascular dementia. While it has been described that hypertension and metabolic disease impair neurovascular coupling—the fine-tuned mechanism that matches local blood supply with neuronal activity—it is unknown if disrupted neurovascular coupling is ultimately responsible for the loss of cognitive protection by estrogen. Given that the mechanisms governing neurovascular coupling are tightly regulated by endothelial nitric oxide synthase, we believe that cardiometabolic comorbidities negatively impact the availability of nitric oxide to the extent that it abolishes the estrogen-induced neuroprotection. Therefore, our working hypothesis is that hypertension and metabolic disease prior to menopause impede the beneficial effects of hormone therapy in preventing aging-related cognitive decline by blunting neurovascular coupling. This leads to impaired local network activity, and therefore, to impaired synaptic plasticity required for the formation and stabilization of synapses needed to create functional cortical circuits and therefore for cognition. We will also test the hypothesis that increasing endothelial nitric oxide synthase activity and nitric oxide bioavailability will eliminate the deficits in neurovascular coupling. This study will determine that the preexistence of hypertension and obesity-induced metabolic disease prior to ovariectomy nullifies the positive effects of midlife estradiol treatment on synaptic plasticity and synaptic stabilization, impairing the ability of cortical circuits to store and manage information, and will identify alterations in the cortical microcircuitry responsible for the deficient experience-dependent synaptic plasticity. The study will also examine the role of mitochondria in disrupted neuronal activity and characterize the molecular mechanisms mediating the impaired neurovascular coupling that is associated with t...