Methamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation, contributing to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders triggered by neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in individuals who abuse Meth), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a process dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production, or suppressing astrocytic calcium mobilization, prevented Meth-elicited microglia reactivity and re-established risk assessment behavior as tested by elevated plus maze (EPM). Overall, our data indicate that glial crosstalk is critical to relay alterations caused by acute Meth exposure.

甲基苯丙胺 (Meth) 是一种强大的非法精神兴奋剂，广泛用于娱乐目的。除了破坏单胺能系统和促进氧化性脑损伤外，冰毒还会引起神经炎症，导致突触功能障碍和行为缺陷。小胶质细胞是大脑中最大的骨髓细胞群，其异常激活是由神经炎症引发的神经系统疾病的常见特征。在这项研究中，我们研究了冰毒在成年小鼠大脑中引起的小胶质细胞异常激活的潜在机制。我们发现，暴饮暴食冰毒会导致小胶质细胞增生并破坏风险评估行为（这一特征通常发生在滥用冰毒的个体身上），这两者都需要星形胶质细胞与小胶质细胞的串扰。从机械上讲，冰毒引发星形胶质细胞谷氨酸胞吐作用的有害增加（在依赖于 TNF 产生和钙动员的过程中），促进小胶质细胞扩张和反应性。通过高架十字迷宫 (EPM) 测试，消融 TNF 产生或抑制星形胶质细胞钙动员可防止冰毒引发的小胶质细胞反应性并重新建立风险评估行为。总的来说，我们的数据表明神经胶质串扰对于由急性甲基苯丙胺暴露引起的中继改变至关重要。