Pericyte function in anesthetic-induced vasodilation and developmental neurotoxicity

Project Summary Mounting evidence suggests that repeated exposure to anesthetic drugs at a very young age causes widespread brain cell apoptosis and long-lasting behavioral and cognitive impairments. The mechanisms underlying this anesthesia-induced developmental neurotoxicity remain unclear. It is well known that the brain has an exceptionally high energy demand, and its function is rapidly disrupted in the absence of blood flow. The adult brain can maintain adequate perfusion during general anesthesia by altering vessel diameter through vascular mural cells, such as pericytes. However, this mechanism may not be fully developed in the immature brain. In support, our preliminary data suggest that cerebral arterioles dilate in response to inhaled anesthetics, with the magnitude of dilation pronounced in adult brains but insignificant in the brains of infant mice, using in vivo imaging of cerebral vasculature through a cranial window. Moreover, we have found that vascular pericytes are two-fold less abundant in infant than adult brains. Based on these findings, we hypothesize that the lack of contractile pericytes and vasodilatory responses to anesthesia in the infant brain causes a deficiency in cerebral blood flow, which may lead to a critical metabolic shortage of oxygen and nutrient supply that ultimately causes brain cell death when lasting for a prolonged duration. In this application, we will test this hypothesis by combining in vivo two-photon imaging of cerebral vessel diameter, flow velocity, and pericyte activity, region/cell-type-specific optogenetic modulation, and immunohistochemical analysis of cell apoptosis. Specifically, in Aim 1, we will characterize volatile anesthetic-evoked vasodilation in the cerebral cortex of infant, juvenile, and young adult mice. We will test the hypothesis that the vasodilatory response to inhaled anesthetics is age-dependent and inadequate vasodilation in the developing brain contributes to anesthesia-induced extensive cell apoptosis. In Aim 2, we will investigate the roles of neocortical pericytes in age-related vasodilatory responses to volatile anesthetics by combining in vivo calcium imaging with optogenetic modulation. Together, our proposed research will identify the deficiency of pericyte-mediated vasodilation as a novel mechanism of anesthesia-induced developmental neurotoxicity and suggest that targeting pericyte function to preserve cerebral blood flow may confer neuroprotection in infants undergoing general anesthesia.