Control of brain blood flow by astrocytes

大脑能量需求与血液供应的耦合称为充血，是正常大脑功能的关键标志。充血可能涉及多种机制，包括来自称为星形胶质细胞的脑细胞的贡献，星形胶质细胞可以通过分别对应于减少或增加的血流量产生减少或扩大的血管直径来响应神经元活动。最近的研究表明，组织氧水平决定了星形胶质细胞反应的方向性，在氧气充足的时候收缩是首选，而在氧气较低的时候扩张则占主导地位。我们将描述组织氧合如何通过影响代谢产物乳酸和腺苷的产生来影响星形胶质细胞诱导的脑血管直径变化的极性。目的1是确定星形胶质细胞神经递质诱导的血管舒张和血管收缩所需的氧范围。我们将使用创新的脑切片双光子成像来研究乳酸的产生和星形胶质细胞介导的血管在改变氧浓度时的反应。这将允许定义从收缩到扩张的极性转换所需的临界氧水平。目的2是确定星形胶质细胞介导的血管直径增加的关键乳酸产生途径。将使用双光子成像和血管直径的同步成像，在脑切片和体内充血模型中测试乳酸盐产生的三种不同途径对血管直径和血流变化的相对贡献。这些研究有望首次将神经递质（谷氨酸）转运确定为血流的关键决定因素。目的3：阐明内源性腺苷在星形胶质细胞调控血管直径和血流量中的作用。最近的证据表明，腺苷可以促进星形胶质细胞介导的血管扩张。我们将首次研究腺苷是否是星形胶质细胞极性从血管收缩到扩张的转换所必需的。这一建议将提供有关星形胶质细胞控制脑血流的方向是如何确定的有价值的信息，从而将揭示充血时脑血流反应的高度组织性。

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.