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: 10376203
• 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/10376203
• 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/肥胖症有很强的合并症；然而，其因果机制 尚不清楚。我们最近使用星形胶质细胞特异性连接蛋白 43 (Cx43) 基因敲除小鼠 (Cx43 KO）并发现它们同时表现出嗜睡症样表型和代谢失调。这些链接的 由单一基因操作产生的表型提高了我们鉴定细胞和 这种临床联系的分子基础。我们将利用博士们的集体力量。海顿和孔， 他们在研究星形胶质细胞和睡眠/觉醒周期的控制方面拥有丰富的经验（Haydon）和该研究 下丘脑神经回路和代谢控制（Kong）。我们将一起检验以下假设： 星形细胞连接蛋白对于供应乳酸作为食欲素能神经元的能量底物至关重要，并且 在此过程中，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关于代谢耦合的有吸引力的假设 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，然后穿梭这种能量来源 神经元中乳酸转化为丙酮酸，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) 很有吸引力，因为： i) 星形胶质细胞接触脉管系统并表达 GLUT1，一种葡萄糖转运蛋白，它们可以摄取葡萄糖。 ii），星形胶质细胞被认为偏向于 糖酵解，以及 iii) 神经元表达单羧酸转运蛋白 (MCT)，这是摄取 乳酸盐。 我们将扩展我们的初步观察，以检验以下假设：星形胶质细胞衍生的乳酸是 食欲素能神经元促进其电活动以及食欲素能神经元的实验操作 神经元活动对于引起发作性睡病和代谢紊乱是必要且充分的。 目标 I：我们将检验删除 Cx30 和 Cx43 会损害星形胶质细胞-神经元乳酸的假设 Shuttle AND 会促进发作性睡病和全身代谢功能障碍。 目标二：我们将检验星形胶质细胞来源的乳酸调节食欲素能神经元活动的假设。 目标三：我们将检验以下假设：食欲素能神经元的激活足以挽救正常的神经元。 连接蛋白 KO 小鼠的表型。

项目成果

Mechanosensory Signaling in Astrocytes.

• DOI: 10.1523/jneurosci.1249-20.2020
• 发表时间: 2020-12-02
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Turovsky EA;Braga A;Yu Y;Esteras N;Korsak A;Theparambil SM;Hadjihambi A;Hosford PS;Teschemacher AG;Marina N;Lythgoe MF;Haydon PG;Gourine AV
• 通讯作者: Gourine AV