UCSF

Astrocytes—the most abundant non-neuronal cell type in the mammalian brain—are integral circuit components that respond to and modulate neuronal activity. While astrocytes are electrically silent, they display highly dynamic intracellular Ca2+ activity. As such, measuring Ca2+ dynamics has become the primary method for studying astrocyte physiology. Astrocyte Ca2+ activity is highly heterogeneous and occurs across multiple spatiotemporal scales: from fast, subcellular activity to slow, synchronized activity that percolates across connected astrocyte networks. Additionally, astrocyte network Ca2+ activity influences a wide range of processes including sleep-wake dynamics, decision making and motor learning. While astrocyte network activity has important implications for neuronal circuit function, it remains unclear if particular neurotransmitter inputs contribute to specific aspects of astrocyte network activity. The primary focus of this dissertation is to investigate input-response dynamics in cortical astrocytes, linking specific neurotransmitter or neuromodulatory inputs to specific astrocyte Ca2+ activity. In Chapter 2, we introduce a new analysis software, AQuA, to accurately quantify heterogenous Ca2+ activity, which is essential for studying the nuances of astrocyte responses to different inputs. In Chapter 3, we use two-photon Ca2+ imaging of astrocytes while mimicking neurotransmitter inputs. We find that brief, subcellular inputs of GABA and glutamate lead to widespread, long-lasting Ca2+ responses within a connected astrocyte network. Further, we find that propagative events differentiate astrocyte network responses to these two major neurotransmitters. In Chapter 4, we expand our toolkit for probing input-response dynamics by introducing a new photoactivatable compound for the release of the neuromodulator norepinephrine. Together, our results demonstrate that local, transient neurotransmitter inputs are encoded by broad cortical astrocyte networks over the course of minutes, contributing to accumulating evidence that significant astrocyte-neuron communication occurs across slow, network-level spatiotemporal scales.