Jarvis Rachel, Tamashiro-Orrego Alessandra, Promes Vanessa, Tu Leona, Shi Jinyuan, Yang Yongjie
Department of Neuroscience, Tufts University School of Medicine, Boston, MA, United States.
Graduate School of Biomedical Sciences, Tufts University, Boston, MA, United States.
Front Cell Neurosci. 2020 Jan 10;13:581. doi: 10.3389/fncel.2019.00581. eCollection 2019.
Alteration of glutamatergic synaptic plasticity in the Nucleus Accumbens (NAc) has been implicated in cocaine-seeking behaviors. Astroglial mechanisms for maintaining extracellular glutamate homeostasis through cysteine/glutamate exchanger (xCT) and glutamate transporter GLT1 are dysregulated following cocaine exposure and contribute to altered glutamatergic synaptic plasticity. However, how these astroglial proteins become dysregulated in cocaine addiction remains unknown. We recently showed that neuron to astroglial exosome signaling is essential to maintain GLT1 protein expression by transferring neuronal miR-124-3p into astrocytes to suppress GLT1-inhibiting microRNAs (miRs) in astrocytes. In the current study, by selectively labeling neuronal exosomes using CD63-GFP exosome reporter mice, we examined how the self-administration and extinction stages of the mouse cocaine self-administration model alter neuronal exosome signaling to astrocytes and microglia in the NAc. We found that cocaine (but not food) self-administration strongly reduces the internalization of neuronal exosomes, particularly in astrocytes in the NAc (but not in motor cortex), which can be effectively reversed by extinction training. In parallel, cocaine self-administration alone specifically and differentially affects activation of glial cells by decreasing GFAP expression in astrocytes but increasing Iba1 expression in microglia. However, extinction training fully reverses the increased Iba1 expression in microglia but only partially reverses the reduction of GFAP in astrocytes. Taken together, our study reveals altered dynamics of NAc neuronal exosomes in the cocaine addiction model, providing new insights about how altered neuron to glial exosome signaling may contribute to astroglial dysfunction in cocaine addiction.
伏隔核（NAc）中谷氨酸能突触可塑性的改变与觅可卡因行为有关。可卡因暴露后，通过半胱氨酸/谷氨酸交换体（xCT）和谷氨酸转运体GLT1维持细胞外谷氨酸稳态的星形胶质细胞机制失调，并导致谷氨酸能突触可塑性改变。然而，这些星形胶质细胞蛋白在可卡因成瘾中如何失调仍不清楚。我们最近发现，神经元到星形胶质细胞的外泌体信号传导对于通过将神经元miR-124-3p转移到星形胶质细胞中以抑制星形胶质细胞中GLT1抑制性微小RNA（miRs）来维持GLT1蛋白表达至关重要。在本研究中，通过使用CD63-GFP外泌体报告小鼠选择性标记神经元外泌体，我们研究了小鼠可卡因自我给药模型的自我给药和消退阶段如何改变NAc中神经元外泌体向星形胶质细胞和小胶质细胞的信号传导。我们发现，可卡因（而非食物）自我给药强烈降低神经元外泌体的内化，特别是在NAc的星形胶质细胞中（而非运动皮层中），消退训练可有效逆转这种情况。同时，单独的可卡因自我给药通过降低星形胶质细胞中的GFAP表达但增加小胶质细胞中的Iba1表达，特异性且差异性地影响胶质细胞的激活。然而，消退训练完全逆转了小胶质细胞中Iba1表达的增加，但仅部分逆转了星形胶质细胞中GFAP的减少。综上所述，我们的研究揭示了可卡因成瘾模型中NAc神经元外泌体动力学的改变，为神经元到胶质细胞外泌体信号传导改变如何导致可卡因成瘾中的星形胶质细胞功能障碍提供了新见解。
