Astrocytes Control Cocaine-Induced Synaptic Plasticity and Reward Through the Matricellular Protein Hevin.

BACKGROUND: Astrocytes in the nucleus accumbens (NAc) play a dynamic role in regulating synaptic plasticity induced by drugs of abuse through modulation of glutamatergic neurotransmission. Astrocyte-secreted factors may also contribute to the reprogramming of brain circuitry that leads to drug-seeking behavior. Here, we investigated the role of astrocyte Ca(2+) signals in vivo and of the astrocyte-secreted protein hevin in the rewarding properties of cocaine. METHODS: Ca(2+) signals in NAc astrocytes were measured by in vivo fiber photometry during conditioned place preference (CPP) to cocaine. Depletion of Ca(2+) and chemogenetic activation were used to evaluate the contribution of astrocyte Ca(2+) signals to cocaine CPP. The effects of cocaine in hevin-null mice and after hevin knockdown in NAc astrocytes were evaluated by imaging of medium spiny neuron spines, electrophysiology, and CPP. Hevin secretion was monitored by light-sheet imaging in brain slices. RESULTS: Cocaine increased the amplitude of Ca(2+) signals in astrocytes during conditioning. Attenuating Ca(2+) signals in astrocytes prevented cocaine CPP, whereas augmenting these signals potentiated this conditioning. Astrocyte activation induced a surge in hevin secretion ex vivo. Hevin knockdown in NAc astrocytes led to a decrease in CPP and in structural and synaptic plasticity induced by cocaine in medium spiny neurons. CONCLUSIONS: These findings reveal a fine-tuning by cocaine of in vivo Ca(2+) signals in NAc astrocytes. Astrocyte Ca(2+) signals are sufficient and necessary for the acquisition of cocaine-seeking behavior. Hevin can be released upon astrocyte activation and is a major effector of the action of cocaine and Ca(2+) signals on reward and neuronal plasticity.