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: 10709658
• 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/10709658
• 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; 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; Synaptic Receptors; Testing; Therapeutic Intervention; Transgenic Mice; Variant; Vasoactive Intestinal Peptide; Work; 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.

项目概要/摘要 下丘脑视交叉上核（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律。分子钟 产生神经元活动的昼夜节律模式，反馈到分子生物钟 加强其活性。 SCN神经元和星形胶质细胞之间的细胞间通讯进一步加强 并同步这些神经元节律。这种集成的 SCN 网络活动对于生成 精确的昼夜节律计时信号，稳定昼夜节律时钟，并确定动物的行为 昼夜节律表型。尽管尺寸很小，但 SCN 表达了具有独特功能的多样化神经元群。 调节不同生理和心理的功能特性、空间位置和传出投射 行为节奏。 SCN 神经元表达血管活性肠肽 (VIP+) 或精氨酸加压素 (AVP+) 是研究最广泛的。这些神经元具有不同的 SCN 位置和独特的作用 光夹带、昼夜节律维持以及不同的下游昼夜节律。独特的 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 神经元利用 GABA 作为神经递质，而 SCN 中的 GABA 能神经传递是 突触和突触外 GABAA 受体有节奏，并显示出显着的区域差异。星形胶质细胞 通过释放改变 GABA 释放的递质并表达 GABA 来调节 GABA 神经传递 控制突触外 GABA 浓度的转运蛋白。多个小分子发射器和 神经调节剂调节 GABA 神经传递，但这种调节的细胞机制尚不清楚 明白了。 GABA 改善动作电位放电模式，这是改善 SCN 昼夜节律的关键组成部分 时钟输出。完整了解 SCN 网络如何生成昼夜节律信号需要 更详细地了解介导 SCN 神经元之间通信的信号通路 星形胶质细胞，并更深入地了解这些信号传导途径在 SCN 不同部分的差异。 我们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 沟通以产生和控制昼夜节律。我们的短期目标是确定机制 介导 GABA 神经传递并调节个体 SCN 神经元之间的耦合强度 振荡器和 SCN 区域。该应用程序的具体目标是： 1) 调查不同角色 突触和强直 GABA 受体介导的神经传递调节 SCN 的活性。 2）调查 星形胶质细胞中 GABA 转运蛋白活性的调节机制以及 GABA 是否从星形胶质细胞中释放 星形胶质细胞有助于补强 GABA 电流。 3) 检查星形胶质细胞释放的谷氨酸在 调节 GABA 突触和强直 GABA 电流以及 SCN 中 AVP+ 和 VIP+ 神经元的活动。