Experimental Neurovascular Uncoupling Promotes Cognitive Impairment in Mice: Implications for Brain and Cerebromicrovascular Aging

There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus and obesity, promote cognitive impairment, however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiological conditions. To establish a direct, causal relation between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MS‐PPOH, the NOS inhibitor L‐NAME and the COX inhibitor indomethacin decreased NVC by 75% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y‐maze), recognition memory (Novel object recognition) and impairment in motor coordination (Rotarod). Blood pressure (tail cuff), basal cerebral perfusion (arterial spin labeling perfusion MRI) and synaptic activity (evoked field potential) were unaffected. Thus, targeted experimental disruption of NVC per se leads to significant impairment of cortical function, including cognitive decline, recapitulating neurological symptoms and signs observed in brain aging and pathophysiological conditions associated with accelerated cerebromicrovascular aging.