Mechanisms of GABAergic Signaling in the Suprachiasmatic Nucleus Network

视交叉上核网络中 GABA 信号传导的机制

• 批准号: 10606283
• 负责人: Charles N Allen
• 金额: $ 52.71万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606283
• 关键词: Action Potentials; Animals; Argipressin; Astrocytes; Back; Behavioral; Biological; Brain; Cells; Circadian Rhythms; Communication; Connexin 43; Coupling; Disease; Dorsal; Electrophysiology (science); Feeds; GABA Receptor; GABA transporter; Glutamates; Goals; Health; Human; Hypothalamic structure; Individual; Knowledge; Lead; Location; Maintenance; Mediating; Methods; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuromodulator; Neurons; Neurotransmitters; Output; Pattern; Periodicity; Phase; Phenotype; Physiological; Play; Population Heterogeneity; Property; Regulation; Reporter Genes; Research; Role; Schedule; Schools; Signal Pathway; Signal Transduction; Sleep; Societies; Synapses; Testing; Therapeutic Intervention; Transgenic Mice; Variant; Vasoactive Intestinal Peptide; Work; base; brain cell; circadian; circadian pacemaker; gamma-Aminobutyric Acid; imaging modality; intercellular communication; molecular clock; mouse model; neural network; neuronal patterning; neurotransmission; presynaptic; receptor; sleep onset; small molecule; social; suprachiasmatic nucleus; targeted treatment; transmission process

Project Summary/Abstract Hypothalamic suprachiasmatic nucleus (SCN) neurons express a cell-autonomous molecular clock that generates circadian rhythms and regulates physiological rhythms throughout the body. The molecular clock produces a circadian pattern of neuronal activity that feeds back onto the molecular circadian clock and strengthens its activity. Intercellular communication between SCN neurons and astrocytes further strengthens and synchronizes these neuronal rhythms. This integrated SCN network activity is critical for generating precise circadian timing signals, stabilizing the circadian clock, and determining an animal's behavioral circadian phenotype. Although small in size, the SCN expresses a diverse population of neurons with unique functional properties, spatial locations, and efferent projections that regulate different physiological and behavioral rhythms. SCN neurons expressing vasoactive intestinal peptide (VIP+) or arginine vasopressin (AVP+) are the most extensively studied. These neurons have distinct SCN locations and unique roles in photic entrainment, circadian timing maintenance, and different downstream circadian rhythms. The unique functional properties of the dorsal and ventral SCN regions reflects differences in the number and the coupling mechanisms and strength of oscillating neurons. Most SCN neurons utilize GABA as a neurotransmitter, and GABAergic neurotransmission in the SCN is rhythmic at synaptic and extrasynaptic GABAA receptors and shows significant regional variation. Astrocytes regulate GABA neurotransmission by releasing transmitters that modify GABA release and expressing GABA transporters that control the extrasynaptic GABA concentration. Multiple small-molecule transmitters and neuromodulators regulate GABA neurotransmission, but the cellular mechanisms of this regulation are poorly understood. GABA refines the action potential firing pattern, a critical component in refining the SCN circadian clock output. A complete understanding of how the SCN network generates circadian timing signals requires more detailed knowledge of the signaling pathways that mediate communication between SCN neurons and astrocytes and a deeper understanding of how these signaling pathways differ in different parts of the SCN. Our research's long-term goal is to identify the signaling pathways by which neurons and astrocytes communicate to generate and entrain circadian rhythms. Our short-term goal is to determine the mechanisms mediating GABA neurotransmission and regulating the coupling strength between individual SCN neuronal oscillators and SCN regions. The Specific Aims of the application are: 1) Investigate the different roles of synaptic and tonic GABA receptor-mediated neurotransmission in regulating the activity of SCN. 2) Investigate the mechanisms regulating GABA transporter activity in astrocytes and whether GABA released from astrocytes contributes to the tonic GABA current. 3) Examine the role of glutamate released from astrocytes in regulating GABA synaptic and tonic GABA currents and the activity of AVP+ and VIP+ neurons in the SCN.

项目摘要/摘要 下丘脑上肌核（SCN）神经元表达细胞自主分子时钟 产生昼夜节律并调节整个身体的生理节奏。分子时钟 产生昼夜节律的神经元活动模式，该模式反馈到分子昼夜节律时刻和 增强其活性。 SCN神经元和星形胶质细胞之间的细胞间通信进一步增强 并同步这些神经元节奏。这种集成的SCN网络活动对于生成至关重要 精确的昼夜节律信号，稳定昼夜节律并确定动物的行为 昼夜节律表型。尽管大小很小，但SCN表达了各种各样的神经元，具有独特的神经元 功能特性，空间位置和传出的投影，这些投影调节不同的生理和 行为节奏。表达血管活性肠肽（VIP+）或精氨酸加压素的SCN神经元 （AVP+）是最广泛的研究。这些神经元在 光学夹带，昼夜节律维持和不同的下游昼夜节律。独特 背侧和腹侧SCN区域的功能特性反映了数量和耦合的差异 振荡神经元的机制和强度。 大多数SCN神经元使用GABA作为神经递质，而SCN中的GABA能神经传递为 突触和突触外GABAA受体的节奏，显示出显着的区域变化。星形胶质细胞 通过释放改变GABA释放和表达GABA的发射机来调节GABA神经传递 控制外突触GABA浓度的转运蛋白。多个小分子发射机和 神经调节剂调节GABA神经传递，但该调节的细胞机制很差 理解。 GABA完善了动作潜在的射击模式，这是完善SCN昼夜节律的关键组成部分 时钟输出。完全了解SCN网络如何生成昼夜节律信号需要 对介导SCN神经元之间沟通的信号通路的更详细知识 星形胶质细胞和对这些信号通路在SCN的不同部位如何不同的深入了解。 我们的研究的长期目标是确定神经元和星形胶质细胞的信号传导途径 沟通以产生和夹带昼夜节律。我们的短期目标是确定机制 介导GABA神经传递并调节单个SCN神经元之间的耦合强度 振荡器和SCN区域。应用程序的具体目的是：1）研究 突触和补品GABA受体介导的神经传递在调节SCN活性时。 2）调查 调节星形胶质细胞中GABA转运蛋白活性的机制以及GABA是否从 星形胶质细胞有助于补品GABA电流。 3）检查从星形胶质细胞释放的谷氨酸的作用 调节GABA突触和补品GABA电流以及SCN中AVP+和VIP+神经元的活性。