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.

Grant Number: 1R21HD111955-01A1
NIH Institute/Center: NIH
Principal Investigator: Ansgar Brambrink