Every organism inevitably experiences stress. In the face of acute, intense stress, for example, periods of passivity occur when an organism’s actions fail to overcome the challenge. The occurrence of inactive behavior may indicate that struggling would most likely be fruitless. Repeated serious stress has been associated with mood disorders such as depression. The modulation of passive coping response patterns has been explored with a focus on the circuit level. However, the cellular and molecular mechanisms are largely uncharacterized. Here, we report that lactate is a key factor in the astrocytic modulation of the passive coping response to behavioral challenge in adult mice. We found increased extracellular lactate in the medial prefrontal cortex (mPFC) when mice experienced the forced swimming test (FST). Furthermore, we discovered that disturbing astrocytic glycogenolysis, which is a key step for lactate production in the mPFC, decreased the duration of immobility in the FST. Knocking down monocarboxylate transporter 4 (MCT4), which is expressed exclusively in astrocytes and transports lactate from astrocytes to the extracellular space, caused similar results in the FST. The behavioral effect of both the pharmacological disturbance of astrocytic glycogenolysis and viral disruption of MCT4 expression was rescued via the administration of L-lactate. Moreover, we found that both pharmacological and viral modulation of astrocyte-derived lactate in mPFC slices increased the excitability of layer V pyramidal neurons, and this enhancement was reversed by exogenous L-lactate administration. These results highlight astrocyte-derived lactate as a biological mechanism underlying the passive coping response to behavioral challenge and may provide new strategies to prevent mood disorders.

每个有机体都不可避免地经历压力。例如，面对急性、强烈的压力，当有机体的行动未能克服挑战时，就会出现被动时期。不活跃行为的发生可能表明挣扎很可能是徒劳的。反复的严重压力与抑郁症等情绪障碍有关。被动应对响应模式的调制已被探索，重点是电路级别。然而，细胞和分子机制在很大程度上是未知的。在这里，我们报告乳酸是星形胶质细胞调节成年小鼠对行为挑战的被动应对反应的关键因素。当小鼠经历强迫游泳试验 (FST) 时，我们发现内侧前额叶皮层 (mPFC) 中的细胞外乳酸增加。此外，我们发现干扰星形胶质细胞糖原分解，这是 mPFC 中乳酸产生的关键步骤，减少了 FST 中不动的持续时间。敲除单羧酸转运蛋白 4 (MCT4)，它仅在星形胶质细胞中表达并将乳酸从星形胶质细胞转运到细胞外空间，在 FST 中引起了类似的结果。星形胶质细胞糖原分解的药理学干扰和 MCT4 表达的病毒破坏的行为效应都被挽救了通过L-乳酸的给药。此外，我们发现 mPFC 切片中星形胶质细胞衍生的乳酸的药理学和病毒调节都增加了 V 层锥体神经元的兴奋性，并且这种增强被外源性L-乳酸给药逆转。这些结果突出了星形胶质细胞衍生的乳酸作为对行为挑战的被动应对反应的生物学机制，并可能提供预防情绪障碍的新策略。