A Functional Taxonomy of Cortical Astrocytes

项目摘要/摘要 最近的研究巩固了星形胶质细胞是调节 神经元活动，尤指同步类型的活动。然而，目前还不清楚星形胶质细胞如何 对神经元回路信号进行编码和整合，以调节这种神经元同步。而且，到目前为止， 单个星形胶质细胞是作为单独的计算单位发挥作用，还是作为一个合体网络发挥作用，这一点并不好 明白了。在拟议的研究中，我们的目标是通过揭示 神经元信号差异化传递到星形细胞网络的机制，以及通过这些机制 星形胶质细胞反馈给神经元网络。我们将重点关注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 表达丰富的细胞表面G蛋白偶联受体，这些受体由这三个神经元激活- 派生信号。我们将使用体外皮质切片和体内小鼠模型，并应用光学、 用于测试星形胶质细胞整合到这些信号中的电生理学、化学遗传学和遗传学技术 系统。我们的目标有三个：我们将确定1)单个星形胶质细胞对 谷氨酸、GABA和去甲肾上腺素的亚细胞激活，以及这些动力学如何塑造星形细胞的输出，2) 三者对局部神经元和星形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，我们都将在逐步扩大的范围内探讨类似的机械性问题。 神经生物学标尺。

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.