Astrocytes control cocaine-induced synaptic plasticity and reward through the matricellular protein hevin.

Abstract

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 leading to drug-seeking behavior. Here we investigated the role of astrocyte Ca²⁺ signals in vivo and of the astrocyte-secreted protein hevin in the rewarding properties of cocaine.

Methods: Ca²⁺ signals in NAc astrocytes were measured by in vivo fiber photometry during conditioned place preference (CPP) to cocaine. Depletion of Ca²⁺ and chemogenetic activation were employed to evaluate the contribution of astrocyte Ca²⁺ 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 Ca²⁺ signals in astrocytes during conditioning. Attenuating Ca²⁺ 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 in medium spiny neurons induced by cocaine.

Conclusions: These findings reveal a fine-tuning by cocaine of in vivo Ca²⁺ signals in NAc astrocytes. Astrocyte Ca²⁺ 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 Ca²⁺ signals on reward and neuronal plasticity.