A Functional Taxonomy of Cortical Astrocytes

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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.