Astrocyte-derived lactate modulates orexinergic neuron activity and behavior

星形胶质细胞衍生的乳酸调节食欲素能神经元的活动和行为

• 批准号: 9904787
• 负责人: PHILIP G HAYDON
• 金额: $ 40.46万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904787
• 关键词: Apoptosis; Astrocytes; Behavior; Brain region; CRISPR/Cas technology; Cells; Clinical; Connexin 43; Connexins; Coupling; Diabetes Mellitus; Dialysis procedure; Electroencephalography; Energy Metabolism; Energy-Generating Resources; Fluorescence Resonance Energy Transfer; GJB6 gene; Genes; Glucose; Glucose Transporter; Glycolysis; Hippocampus (Brain); Hypothalamic structure; Image; Impairment; Knockout Mice; Lactate Dehydrogenase; Lateral; Lead; Link; Measurement; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic dysfunction; Molecular; Mus; Narcolepsy; Neurons; Obesity; Oxidative Phosphorylation; Pathway interactions; Pharmacology; Phenocopy; Phenotype; Property; Publishing; Pyruvate; Regulation; Role; SLC2A1 gene; Signal Transduction; Sleep Wake Cycle; Testing; Wakefulness; base; comorbidity; experience; feeding; genetic manipulation; hypocretin; in vivo; locus ceruleus structure; neural circuit; prevent; restoration; sleep pattern; sleep regulation; uptake

There is a strong comorbidity of narcolepsy and diabetes/obesity; however, the causal underlying mechanism is unclear. We recently performed studies using astrocyte-specific connexin 43 (Cx43) knockout mice (Cx43 KO) and found that they display both a narcolepsy-like phenotype and metabolic dysregulation. These linked phenotypes, arising from a single genetic manipulation, raise the potential that we have identified a cellular and molecular underpinning of this clinical linkage. We will use the collective strengths of Drs. Haydon and Kong, who are highly experienced in studying astrocytes and the control of sleep/wake cycles (Haydon) and the study of the hypothalamic neural circuits and metabolic control (Kong). Together, we will test the hypothesis that astrocytic connexins are essential for the supply of lactate as an energy substrate to orexinergic neurons, and in doing so, modulate orexinergic control of wakefulness and metabolic control. Pierre Magistretti and colleagues proposed an attractive hypothesis concerning metabolic coupling between astrocytes and neurons in which the astrocyte metabolizes glucose to lactate, then shuttle this energy source to neurons where lactate is converted to pyruvate, which is used in oxidative phosphorylation. This Astrocyte- Neuron Lactate Shuttle (ANLS) is attractive because: i) astrocytes contact the vasculature and express GLUT1, a glucose transporter, they can take up glucose. ii), astrocytes are considered to be biased towards glycolysis, and iii) neurons express monocarboxylate transporters (MCT) that are required for the uptake of lactate. We will extend our initial observations to test the hypothesis that astrocyte-derived lactate is required by orexinergic neurons to promote their electrical activity and that experimental manipulation of orexinergic neuronal activity is both necessary and sufficient to cause narcolepsy and metabolic disorders. Aim I: We will test the hypothesis that the deletion of Cx30 and Cx43 impairs the Astrocyte-Neuron Lactate Shuttle AND promotes narcolepsy and systemic metabolic dysfunction. Aim II: We will test the hypothesis that astrocyte-derived lactate modulates orexinergic neuron activity. Aim III: We will test the hypothesis that the activation of orexinergic neurons is sufficient to rescue normal phenotypes in connexin KO mice.

发作性睡病和糖尿病/肥胖症有很强的共病性;然而， 还不清楚我们最近使用星形胶质细胞特异性连接蛋白43（Cx43）敲除小鼠（Cx43）进行了研究。 KO），发现它们显示出发作性睡病样表型和代谢失调。这些链接 表型，从一个单一的遗传操作，提高了潜力，我们已经确定了一个细胞， 这种临床联系的分子基础。我们将利用海顿博士和孔博士的集体力量， 他在研究星形胶质细胞和控制睡眠/觉醒周期方面经验丰富（Haydon）， 下丘脑神经回路和代谢控制（Kong）。我们将一起测试这个假设， 星形胶质细胞连接蛋白对于作为能量底物向食欲素能神经元供应乳酸是必需的，并且 在这样做时，调节食欲素对觉醒和代谢控制的控制。 Pierre Magistretti及其同事提出了一个有吸引力的假设， 星形胶质细胞和神经元，其中星形胶质细胞将葡萄糖代谢为乳酸，然后穿梭于这种能量来源 到神经元，在那里乳酸转化为丙酮酸，丙酮酸用于氧化磷酸化。这个星形胶质细胞 神经元乳酸穿梭（ANLS）是有吸引力的，因为：i）星形胶质细胞接触血管系统并表达 GLUT 1，一种葡萄糖转运蛋白，它们可以摄取葡萄糖。ii），星形胶质细胞被认为偏向于 iii）神经元表达摄取糖酵解所需的单羧酸转运蛋白（MCT）， 乳酸盐 我们将扩展我们最初的观察，以检验星形胶质细胞来源的乳酸是必需的假设， 食欲素能神经元促进其电活动和食欲素能神经元的实验操作 神经元活动是引起发作性睡病和代谢紊乱的必要和充分条件。 目的一：我们将检验Cx 30和Cx43的缺失损害星形胶质细胞-神经元乳酸的假说。 Shuttle AND促进发作性睡病和全身代谢功能障碍。 目的二：我们将测试的假设，星形胶质细胞衍生的乳酸调节食欲素能神经元的活动。 目的III：我们将检验食欲素能神经元的激活足以拯救正常的 连接蛋白KO小鼠的表型。