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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10518803
• 关键词: Acids; Adenosine; Animals; Astrocytes; Blood Glucose; Blood Vessels; Blood capillaries; Brain; Brain Injuries; Calcium Signaling; Caliber; Cells; Cerebrovascular Circulation; Cerebrum; Cessation of life; Cognitive deficits; Coma; Complications of Diabetes Mellitus; Deoxyglucose; Fluorescent Dyes; Glucose; Health; Human; Hyperemia; Hypoglycemia; Impaired cognition; Injections; Inositol; Insulin; Knockout Mice; Lead; Measures; Mediating; Mediator of activation protein; Membrane; Modeling; Monitor; Mus; Neurons; Oxygen; Process; Prostaglandins; Purinergic P1 Receptors; Regulation; Research; Risk; Signal Transduction; Somatosensory Cortex; Testing; Unconscious State; Vasodilator Agents; Vibrissae; Work; antagonist; arteriole; awake; deprivation; diabetic patient; experimental study; inhibitor; neuronal cell body; neurovascular coupling; novel; receptor; response; two photon microscopy

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.

项目摘要 低血糖是胰岛素治疗引起的糖尿病的严重并发症，可以 导致认知缺陷，脑损伤，意识丧失和死亡。主要响应 低血糖是脑血流（CBF）的增加，它增加了供应 葡萄糖向大脑。降糖引起的大脑腺苷的增加被认为是 介导CBF增加。但是，星形胶质细胞释放血管散发剂并调节 血管张力，也可能导致低血糖诱导的血管扩张和CBF 增加。这个新的假设是星形胶质细胞有助于低血糖引起的CBF 我们的初步实验支持增加。我们将通过 同时监测星形胶质细胞CA2+信号传导和血管直径 随着血糖的降低，带有两光子显微镜的清醒小鼠的体感皮质 通过胰岛素给药。该假设将在以下目的中进行检验。 AIM 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 在对照小鼠和IP3R2中通过胰岛素给药降低血糖的确定是确定的 KO小鼠，其中星形胶质细胞CA2+信号传导减少。正如我们的初步结果所建议的那样 我们预计IP3R2 KO动物的血管扩张将减少，表明 星形胶质细胞有助于低血糖诱导的血管扩张。 AIM 2。检验以下假设：腺苷会引起星形胶质细胞和 释放血管散发前列腺素（PGS）和环氧树钠酸（EET） 在低血糖期间。腺苷介导降糖诱导的CBF增加。我们将测试 假设血管的腺苷扩张部分通过刺激星形胶质细胞和 唤起星形胶质细胞CA2+增加。 PG和EET从星形胶质细胞释放并扩张 大脑容器。我们将测试这两个星形胶质细胞血管扩张剂中的一个或两个 低血糖引起的血管扩张。 目标3。确定在低血糖期间神经血管耦合是否改变。 神经元活性的增加引起了CBF的局部增加。这种响应称为功能 充血，为活性神经元提供所需的葡萄糖和氧气。我们将测试是否 低血糖期间，晶须刺激引起的血管扩张会改变。