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.

睡病和糖尿病/肥胖的合并症很强。但是，因果关系机制 不清楚。我们最近使用星形胶质细胞特异性连接蛋白43（CX43）基因敲除小鼠进行了研究（CX43 ko）发现它们既显示出类似于睡病的表型，又显示了代谢失调。这些链接 由单个遗传操作引起的表型提高了我们已经确定细胞和 该临床连接的分子基础。我们将利用博士的集体优势。海顿和孔， 谁在研究星形胶质细胞和对睡眠/唤醒周期（海顿）和研究的控制方面经验丰富 下丘脑神经回路和代谢控制（Kong）的。一起，我们将检验以下假设 星形胶质细胞连接蛋白对于乳酸作为对甲状腺能神经元的能量底物的供应至关重要 这样一来，调节了对清醒和代谢控制的甲状腺素能控制。 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中星形胶质细胞代谢葡萄糖乳酸，然后穿梭该能源 乳酸转化为丙酮酸的神经元，用于氧化磷酸化。这个星形胶质细胞 - 神经元乳酸班车（ANLS）很有吸引力，因为：i）星形胶质细胞与脉管系统接触并表达 Glut1是一种葡萄糖转运蛋白，它们可以吸收葡萄糖。 ii），星形胶质细胞被认为是偏向于 糖酵解和III）神经元表达单羧酸盐转运蛋白转运蛋白（MCT），这些转运蛋白是摄取所必需的 乳酸。 我们将扩展最初的观察结果，以检验以下假设：星形胶质细胞衍生的乳酸是要求的 促进神经元以促进其电活性并进行实验性操纵ORENCONEGIC 神经元活性既需要引起睡病和代谢性疾病。 目的I：我们将检验以下假设：CX30和CX43的缺失会损害星形胶质细胞 - 乳酸乳酸 班车并促进睡病和全身代谢功能障碍。 AIM II：我们将测试星形胶质细胞衍生的乳酸调节甲状腺能神经元活性的假设。 AIM III：我们将检验以下假设：Orecinagric神经元的激活足以挽救正常 连接蛋白KO小鼠中的表型。

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