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.

项目总结/摘要 下丘脑视交叉上核（SCN）神经元表达细胞自主分子钟， 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，反馈到分子生物钟上， 加强其活动。SCN神经元和星形胶质细胞之间的细胞间通讯进一步加强 并抑制这些神经元的节律。这种集成的SCN网络活动对于生成 精确的昼夜节律定时信号，稳定生物钟，并确定动物的行为 昼夜节律表型虽然体积小，但SCN表达了具有独特功能的不同神经元群体。 功能特性，空间位置和传出投射，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。这些神经元具有不同的SCN位置和独特的作用， 光夹带、昼夜节律定时维持和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，并且SCN中的GABA能神经传递是 节律性突触和突触外GABAA受体，并显示出显着的区域变化。星形细胞 通过释放调节GABA释放和表达GABA的递质来调节GABA神经传递 控制突触外GABA浓度的转运蛋白。多种小分子递质和 神经调节剂调节GABA神经传递，但这种调节的细胞机制很差 明白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 时钟输出要完全理解SCN网络如何产生昼夜节律定时信号， 更详细地了解介导SCN神经元之间通信的信号通路， 星形胶质细胞和更深入地了解这些信号通路如何在SCN的不同部分不同。 我们研究的长期目标是确定神经元和星形胶质细胞 交流以产生和引导昼夜节律。我们的短期目标是确定 介导GABA神经传递和调节单个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）调查的不同作用， 突触和紧张性GABA受体介导的神经传递调节SCN的活性。2)探讨 星形胶质细胞中GABA转运体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紧张性GABA电流。3)研究星形胶质细胞释放的谷氨酸在 调节GABA突触和紧张性GABA电流以及SCN中AVP+和VIP+神经元的活性。