A Functional Taxonomy of Cortical Astrocytes

项目总结/摘要 最近的工作已经巩固了星形胶质细胞是调节神经元功能的关键电路组件的概念。 神经元活动，特别是同步活动。然而，目前还不清楚星形胶质细胞如何 编码和整合神经元回路信号以介导这种神经元同步。此外， 单个星形胶质细胞作为独立的计算单位或作为合胞体网络运作， 明白在拟议的研究中，我们的目标是通过揭示 神经元信号差异传递到星形胶质细胞网络的机制，以及 星形胶质细胞反馈到神经元网络。我们将集中讨论大脑中的两种主要神经递质 皮质（谷氨酸和GABA）和一种必需的神经调节剂，去甲肾上腺素（NE），因为星形胶质细胞 表达大量的细胞表面G蛋白偶联受体，这些受体被所有这三种神经元激活， 衍生信号。我们将使用离体皮质切片和体内小鼠模型，并应用光学， 电生理学、化学遗传学和遗传学技术来测试星形胶质细胞整合到这些信号传导中， 系统.我们的目标有三个方面：我们将确定1）单个星形胶质细胞响应 谷氨酸、GABA和NE的亚细胞激活，以及这些动力学如何塑造星形胶质细胞的输出，2） 这三种蛋白对局部神经元和星形胶质细胞网络的时空效应 神经递质/神经调质，以及3）星形胶质细胞传递皮质范围信号的机制 到神经元因此，在这三个目标中的每一个目标中，我们将在逐步扩大的范围内探讨类似的机制问题。 神经生物学量表

PROJECT SUMMARY/ABSTRACT Recent work has solidified the concept that astrocytes are critical circuit components that regulate neuronal activity, particularly synchronous types of activity. However, it remains unclear how astrocytes encode and integrate neuronal circuit signals to mediate this neuronal synchronization. Moreover, the extent to which single astrocytes function as individual computational units or operate as a syncytial network is not well understood. In the proposed research, we aim to address these gaps in knowledge by uncovering both the mechanisms by which neuronal signals are differentially transmitted to astrocytic networks, and those by which astrocytes feedback to neuronal networks. We will focus on the two major neurotransmitters in the cerebral cortex (glutamate and GABA) and one essential neuromodulator, norepinephrine (NE), since astrocytes express abundant cell-surface, G-protein coupled receptors that are activated by all three of these neuron- derived signals. We will use both ex vivo cortical slices and in vivo mouse models, and apply optical, electrophysiological, chemogenetic, and genetic techniques to test astrocytic integration into these signaling systems. Our goals are three-fold: We will determine 1) the mechanisms by which single astrocytes respond to subcellular activation of glutamate, GABA, and NE, and how those dynamics shape an astrocytic output, 2) the spatiotemporal effects on local neuronal and astrocytic networks of these three neurotransmitters/neuromodulators, and 3) the mechanisms by which astrocytes transmit cortex-wide signals to neurons. Thus, in each of the three aims, we will probe similar mechanistic questions at progressively wider neurobiological scales.