Control of brain blood flow by astrocytes

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Coupling of brain energy demand with blood supply is called hyperemia and is a critical hallmark of normal brain function. Multiple mechanisms are likely involved in hyperemia, including contributions from brain cells known as astrocytes, which can respond to neuronal activity by producing either reduced or expanded blood vessel diameters, corresponding to decreased or increased blood flow, respectively. Tissue oxygen levels have recently been shown to dictate the directionality of astrocyte responses, with constriction preferred in times when oxygen is plentiful and dilation prevailing in lower oxygen. We will characterize how tissue oxygenation affects the polarity of astrocyte-induced changes in brain vessel diameter by influencing production of the metabolites, lactate and adenosine. Aim 1 is to identify oxygen ranges required for neurotransmitter-induced vasodilation and vasoconstriction by astrocytes. We will use innovative 2-photon imaging of brain slices to study lactate production and astrocyte-mediated vessel responses in changing oxygen concentrations. This will allow definition of critical oxygen levels required for polarity conversion from constriction to dilation. Aim 2 is to define the pathways of lactate generation critical for astrocyte-mediated increases in vessel diameter. Three distinct routes of lactate production will be tested for relative contributions to vessel diameter and blood flow changes in brain slices and in vivo hyperemia models using 2-photon imaging and simultaneous imaging of vascular diameter. These studies area expected to identify neurotransmitter (glutamate) transport as a critical determinant of blood flow for the first time. Aim 3 is to elucidate the roles of endogenous adenosine on astrocyte control of vessel diameter and blood flow. Recent evidence suggests that adenosine may facilitate astrocyte-mediated vessel dilation. We will investigate for the first time whether adenosine is required for switching of astrocyte polarity from vessel constriction to dilation. This proposal will provide valuable information about how the direction of astrocyte control of brain blood flow is determined and thus will shed new light on the highly organized nature of brain blood flow responses in hyperemia.