Mongrédien Raphaële, Anesio Augusto, Fernandes Gustavo J D, Eagle Andrew L, Maldera Steeve, Pham Cuong, Robert Séverine, Bezerra Fernando, Vilette Adèle, Bianchi Paula C, Franco Clara, Louis Franck, Gruszczynski Carole, Niépon Marie-Laure, Betancur Catalina, Erdozain Amaia M, Robison Alfred J, Boucard Antony A, Cruz Fabio C, Li Dongdong, Heck Nicolas, Gautron Sophie, Vialou Vincent
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Paris, France.
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Paris, France; Department of Pharmacology, Universidade Federal de São Paulo, São Paulo, Brazil.
Biol Psychiatry. 2025 Mar 18. doi: 10.1016/j.biopsych.2025.02.904.
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 signals in vivo and of the astrocyte-secreted protein hevin in the rewarding properties of cocaine.
Ca signals in NAc astrocytes were measured by in vivo fiber photometry during conditioned place preference (CPP) to cocaine. Depletion of Ca and chemogenetic activation were used to evaluate the contribution of astrocyte Ca 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.
Cocaine increased the amplitude of Ca signals in astrocytes during conditioning. Attenuating Ca 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.
These findings reveal a fine-tuning by cocaine of in vivo Ca signals in NAc astrocytes. Astrocyte Ca 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 signals on reward and neuronal plasticity.
伏隔核（NAc）中的星形胶质细胞通过调节谷氨酸能神经传递，在调节由滥用药物诱导的突触可塑性中发挥动态作用。星形胶质细胞分泌的因子也可能有助于导致觅药行为的脑回路重编程。在此，我们研究了星形胶质细胞钙信号在体内的作用以及星形胶质细胞分泌的蛋白hevin在可卡因奖赏特性中的作用。
在对可卡因进行条件性位置偏爱（CPP）实验期间，通过体内光纤光度法测量NAc星形胶质细胞中的钙信号。利用钙耗竭和化学遗传学激活来评估星形胶质细胞钙信号对可卡因CPP的作用。通过对中等棘状神经元棘突成像、电生理学和CPP实验，评估可卡因对hevin基因敲除小鼠以及NAc星形胶质细胞中hevin基因敲低后的影响。通过脑片光片成像监测hevin的分泌。
在条件化过程中，可卡因增加了星形胶质细胞中钙信号的幅度。减弱星形胶质细胞中的钙信号可阻止可卡因诱导的CPP，而增强这些信号则会增强这种条件化作用。星形胶质细胞激活在体外诱导hevin分泌激增。NAc星形胶质细胞中hevin基因敲低导致CPP降低，以及可卡因诱导的中等棘状神经元的结构和突触可塑性降低。
这些发现揭示了可卡因对NAc星形胶质细胞体内钙信号的微调作用。星形胶质细胞钙信号对于获得觅可卡因行为既是充分的也是必要的。Hevin可在星形胶质细胞激活时释放，并且是可卡因和钙信号对奖赏及神经元可塑性作用的主要效应分子。
