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

作者：Raphaële Mongrédien, Augusto Anésio, Gustavo J. D. Fernandes, Andrew L. Eagle, Steeve Maldera, Cuong Viet Pham, Séverine Robert, F R Bezerra, Adèle Vilette, Paula Bianchi, Clara Franco, Franck Louis, Carole Gruszczynski, Marie-laure Niepon, Catalina Betancur, Amaia M. Erdozain, Alfred J. Robison, Antony A. Boucard, Fábio C. Cruz, Dongdong Li, Nicolas Heck, Sophie Gautron, Vincent Vialou · 发表于：Biological Psychiatry · 年份：2025 · DOI：10.1016/j.biopsych.2025.02.904 · 被引用次数：8 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Neuropeptides and Animal Physiology、Neuroscience and Neuropharmacology Research

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. ...