Melatonin has been well documented for its neuroprotective role through inhibiting oxidative stress against traumatic brain injury (TBI). However, the specific role of melatonin and the exact effects on cell responses (neurons, astrocytes, and microglia) in different brain regions are unclear. Here, we subjected mice to closed head injury, to establish a repeated mild TBI model and detect neuronal activity and glial responses in cognition-related brain regions after melatonin administration. Melatonin only showed cognitive enhancement if administered during early pathological stages, but not in late (chronic) stages. Additionally, we observed a significant increase in neuronal activity and inhibition of astrocyte reactivation in medial prefrontal cortex and hippocampus, but not in other cognitive deficit related brain regions. Furthermore, by activating astrocytes in these brain regions, we found neuronal activity upregulation and cognitive improvement following melatonin treatment. Therefore, we concluded that melatonin administration during the early stages of TBI is necessary to inhibit astrocyte reactivation and to promote cognitive function. Our results provide evidence for use of melatonin for cognitive improvement after TBIs.

褪黑激素通过抑制氧化应激对创伤性脑损伤 (TBI) 的神经保护作用已得到充分证明。然而，褪黑激素的具体作用以及对不同大脑区域细胞反应（神经元、星形胶质细胞和小胶质细胞）的确切影响尚不清楚。在这里，我们对小鼠进行闭合性头部损伤，以建立重复的轻度 TBI 模型并检测褪黑激素给药后认知相关脑区的神经元活动和神经胶质反应。如果在早期病理阶段施用褪黑激素，则仅显示认知增强，而在晚期（慢性）阶段则不会。此外，我们观察到内侧前额叶皮层和海马中神经元活动的显着增加和星形胶质细胞再激活的抑制，但在其他与认知缺陷相关的大脑区域中没有。此外，通过激活这些大脑区域的星形胶质细胞，我们发现褪黑激素治疗后神经元活动上调和认知改善。因此，我们得出结论，在 TBI 的早期阶段服用褪黑激素对于抑制星形胶质细胞的再激活和促进​​认知功能是必要的。我们的结果为使用褪黑激素改善 TBI 后的认知提供了证据。