Astrocyte regulation of cerebral blood flow during hypoglycemia

低血糖期间星形胶质细胞对脑血流的调节

基本信息

批准号：
10518803
负责人：
ERIC A NEWMAN
金额：
$ 38.56万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

项目摘要

Project Summary Hypoglycemia is a serious complication of diabetes resulting from insulin treatment which can lead to cognitive deficits, brain damage, loss of consciousness and death. A primary response to hypoglycemia is an increase in cerebral blood flow (CBF), which augments the supply of glucose to the brain. A hypoglycemia-induced increase in adenosine in the brain is thought to mediate CBF increases. However, astrocytes, which release vasodilating agents and regulate vascular tone, might also contribute to hypoglycemia-induced vessel dilation and CBF increases. This novel hypothesis, that astrocytes contribute to hypoglycemia-induced CBF increases, is supported by our preliminary experiments. We will test this hypothesis by simultaneously monitoring astrocyte Ca2+ signaling and blood vessel diameter in the somatosensory cortex of awake mice with two-photon microscopy as blood glucose is lowered by insulin administration. The hypothesis will be tested in the following aims. Aim 1. Test the hypothesis that astrocytes mediate hypoglycemia-induced vessel dilation. The relation between blood glucose, astrocyte Ca2+ signaling, and vessel diameter will be determined as blood glucose is lowered by insulin administration in control mice and in IP3R2 KO mice, where astrocyte Ca2+ signaling is reduced. As suggested by our preliminary results, we anticipate that vessel dilation will be reduced in IP3R2 KO animals, demonstrating that astrocytes contribute to hypoglycemia-induced vessel dilation. Aim 2. Test the hypothesis that adenosine evokes Ca2+ increases in astrocytes and the release of vasodilating prostaglandins (PGs) and epoxyeicosatrienoic acids (EETs) during hypoglycemia. Adenosine mediates hypoglycemia-induced CBF increases. We will test the hypothesis that adenosine dilation of vessels acts in part by stimulating astrocytes and evoking astrocyte Ca2+ increases. PGs and EETs are released from astrocytes and dilate cerebral vessels. We will test whether one or both of these astrocyte vasodilators contribute to hypoglycemia-induced vessel dilation. Aim 3. Determine whether neurovascular coupling is altered during hypoglycemia. Increases in neuronal activity evoke local increases in CBF. This response, termed functional hyperemia, supplies active neurons with needed glucose and oxygen. We will test whether vessel dilation evoked by whisker stimulation is altered during hypoglycemia.

项目概要低血糖是胰岛素治疗引起的糖尿病严重并发症，导致认知缺陷、脑损伤、意识丧失和死亡。主要回应导致低血糖的原因是脑血流量 (CBF) 增加，从而增加了葡萄糖进入大脑。低血糖引起的大脑腺苷增加被认为介导 CBF 增加。然而，星形胶质细胞释放血管舒张剂并调节血管紧张度，也可能导致低血糖引起的血管扩张和 CBF 增加。这个新的假设是，星形胶质细胞有助于低血糖诱导的 CBF 增加，得到我们初步实验的支持。我们将通过以下方式检验这个假设同时监测星形胶质细胞 Ca2+ 信号传导和血管直径当血糖降低时，用双光子显微镜观察清醒小鼠的体感皮层通过胰岛素给药。该假设将在以下目标中得到检验。目标 1. 检验星形胶质细胞介导低血糖诱导血管的假设扩张。血糖、星形胶质细胞 Ca2+ 信号传导和血管直径之间的关系将由于对照小鼠和 IP3R2 中的胰岛素给药降低了血糖，因此可以确定 KO 小鼠，星形胶质细胞 Ca2+ 信号传导减少。正如我们的初步结果所示，我们预计 IP3R2 KO 动物的血管扩张将会减少，这表明星形胶质细胞有助于低血糖引起的血管扩张。目标 2. 检验腺苷引起星形胶质细胞中 Ca2+ 增加的假设以及释放血管舒张前列腺素 (PG) 和环氧二十碳三烯酸 (EET) 低血糖期间。腺苷介导低血糖引起的 CBF 增加。我们将测试腺苷扩张血管的部分作用是通过刺激星形胶质细胞的假设诱发星形胶质细胞 Ca2+ 增加。星形胶质细胞释放 PG 和 EET 并扩张脑血管。我们将测试这些星形胶质细胞血管舒张剂中的一种或两种是否有助于低血糖引起的血管扩张。目标 3. 确定低血糖期间神经血管耦合是否发生改变。神经元活动的增加引起局部CBF 的增加。这种反应称为功能性反应充血，为活跃的神经元提供所需的葡萄糖和氧气。我们将测试是否胡须刺激引起的血管扩张在低血糖期间会发生改变。