Brain energetics disturbance is a hypothesized cause of depression. Glucose is the predominant fuel of brain energy metabolism; however, the cell-specific change of glucose metabolism and underlying molecular mechanism in depression remains unclear. In this study, we firstly applied ¹⁸F-FDG PET and observed brain glucose hypometabolism in the prefrontal cortex (PFC) of corticosterone-induced depression of rats. Next, astrocytic glucose hypometabolism was identified in PFC slices in both corticosterone-induced depression of rats and cultured primary astrocytes from newborn rat PFC after stress-level corticosterone (100 nM) stimulation. Furthermore, we found the blockage of glucose uptake and the decrease of plasma membrane (PM) translocation of glucose transporter 1 (GLUT1) in astrocytic glucose hypometabolism under depressive condition. Interestingly, thioredoxin interacting protein (TXNIP), a glucose metabolism sensor and controller, was found to be over-expressed in corticosterone-stimulated astrocytes in vivo and in vitro. High TXNIP level could restrict GLUT1-mediated glucose uptake in primary astrocytes in vitro. Adeno-associated virus vector-mediated astrocytic TXNIP over-expression in rat medial PFC suppressed GLUT1 PM translocation, consequently developed depressive-like behavior. Conversely, TXNIP siRNA facilitated GLUT1 PM translocation to recover glucose hypometabolism in corticosterone-exposed cultured astrocytes. Notably, astrocyte-specific knockdown of TXNIP in medial PFC of rats facilitated astrocytic GLUT1 PM translocation, showing obvious antidepressant activity. These findings provide a new astrocytic energetic perspective in the pathogenesis of depression and, more importantly, provide TXNIP as a promising molecular target for novel depression therapy.

中文翻译：

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硫氧还蛋白相互作用蛋白在皮质酮诱导的抑郁状态下驱动星形胶质细胞葡萄糖低代谢

脑能量紊乱是抑郁症的一个假设原因。葡萄糖是脑能量代谢的主要燃料；然而，抑郁症中葡萄糖代谢的细胞特异性变化和潜在的分子机制仍不清楚。在这项研究中，我们首先应用了¹⁸F-FDG PET 和观察到皮质酮诱导的大鼠抑郁的前额叶皮层 (PFC) 中的脑葡萄糖代谢减退。接下来，在应激水平皮质酮 (100 nM) 刺激后，在皮质酮诱导的大鼠抑郁和新生大鼠 PFC 培养的原代星形胶质细胞的 PFC 切片中发现星形胶质细胞葡萄糖低代谢。此外，我们发现在抑郁条件下星形胶质细胞葡萄糖低代谢中葡萄糖摄取受阻和葡萄糖转运蛋白 1 (GLUT1) 的质膜 (PM) 易位减少。有趣的是，硫氧还蛋白相互作用蛋白 (TXNIP)，一种葡萄糖代谢传感器和控制器，被发现在体内和体外皮质酮刺激的星形胶质细胞中过度表达。高 TXNIP 水平可以限制体外初级星形胶质细胞中 GLUT1 介导的葡萄糖摄取。大鼠内侧 PFC 中腺相关病毒载体介导的星形胶质细胞 TXNIP 过表达抑制了 GLUT1 PM 易位，因此发展为抑郁样行为。反过来，TXNIP siRNA 促进 GLUT1 PM 易位以恢复暴露于皮质酮的培养星形胶质细胞中的葡萄糖低代谢。值得注意的是，大鼠内侧 PFC 中TXNIP的星形胶质细胞特异性敲低促进了星形胶质细胞 GLUT1 PM 易位，显示出明显的抗抑郁活性。这些发现为抑郁症的发病机制提供了一个新的星形细胞能量视角，更重要的是，提供了 TXNIP 作为新型抑郁症治疗的有希望的分子靶点。