Summary The prefrontal cortex (PFC) is a hub for cognitive control, and dopamine profoundly influences its functions. In other brain regions, astrocytes sense diverse neurotransmitters and neuromodulators and, in turn, orchestrate regulation of neuroactive substances. However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to and how they contribute to PFC function, is lacking. Here, we characterize divergent signaling signatures in astrocytes of PFC and primary sensory cortex in mice, which are linked to differential responsivity to locomotion. We find that PFC astrocytes express receptors for dopamine, but are unresponsive through the G s /G i -cAMP pathway. Instead, fast calcium signals in PFC astrocytes are time-locked to dopamine release, and are mediated by α1-adrenergic receptors both ex vivo and in vivo . Further, we describe dopamine-triggered regulation of extracellular ATP at PFC astrocyte territories. Thus, we identify astrocytes as active players in dopaminergic signaling in PFC, contributing to PFC function though neuromodulator receptor crosstalk. Graphical Abstract

Dopamine Activates Astrocytes in Prefrontal Cortex via α1-Adrenergic Receptors