Mechanisms of GABAergic Signaling in the Suprachiasmatic Nucleus Network

项目摘要/摘要 下丘脑视交叉上核(SCN)神经元表达一种细胞自主的分子时钟， 产生昼夜节律，并调节全身的生理节律。分子钟 产生神经元活动的昼夜节律模式，反馈到分子昼夜节律时钟和 加强了它的活动。SCN神经元和星形胶质细胞之间的细胞间通讯进一步加强 并使这些神经元的节律同步。这种集成的SCN网络活动对于 精确的昼夜节律信号，稳定生物钟，并确定动物的行为 昼夜节律表型。虽然SCN的体积很小，但它表达了不同的神经元群体，具有独特的 功能属性、空间位置和传出投射，调节不同的生理和 行为节律。表达血管活性肠肽(VIP+)或精氨酸加压素的SCN神经元 (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。独一无二的 背侧和腹侧SCN区域的功能特性反映了数量和耦合的不同 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，SCN中的GABA能神经传递是 突触和突触外GABAA受体有节律性，并显示出显著的区域差异。星形胶质细胞 通过释放调节GABA释放和表达GABA的递质来调节GABA的神经传递 控制突触外GABA浓度的转运体。多个小分子发射器和 神经调节剂调节GABA的神经传递，但这种调节的细胞机制很差。 明白了。GABA改善了动作电位的激发模式，这是改善SCN昼夜节律的关键组成部分 时钟输出。完全理解SCN网络如何产生昼夜节律定时信号需要 更详细地了解SCN神经元和SCN之间的信号通路 并更深入地了解这些信号通路在SCN不同部分的不同。 我们研究的长期目标是确定神经元和星形胶质细胞 交流以产生和携带昼夜节律。我们的短期目标是确定这些机制 介导GABA神经传递和调节单个SCN神经元间的偶联强度 振荡器和SCN区域。申请的具体目的是：1)调查不同的角色 突触和紧张性GABA受体介导的神经传递对SCN活性的调节。2)调查 星形胶质细胞GABA转运体活性的调节机制及GABA是否从星形胶质细胞释放 星形胶质细胞参与强直的GABA电流。3)检测星形胶质细胞释放的谷氨酸在 调节脊髓核内GABA突触和紧张性GABA电流以及AVP+和VIP+神经元的活动。

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.