Anti-depression effects of ketogenic diet are mediated via the restoration of microglial activation and neuronal excitability in the lateral habenula
Anti-depression effects of ketogenic diet are mediated via the restoration of microglial activation and neuronal excitability in the lateral habenula
复制标题
生酮饮食的抗抑郁作用是通过恢复外侧缰核的小胶质细胞活化和神经元兴奋性来介导的
DOI：
10.1016/j.bbi.2020.05.032
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发表时间：
2020-08-01
影响因子：
15.1
通讯作者：
Sun, Xiang-Dong
中科院分区：
文献类型：
--
作者：
Guan, Yan-Fei;Huang, Guo-Bin;Sun, Xiang-Dong
抑郁症是一种严重的神经精神疾病，其潜在的病理机制尚不清楚。据报道，生酮饮食（KD）对啮齿动物的抑郁样行为具有预防作用。然而，KD对抑郁样行为的治疗作用迄今尚未得到说明。在这里，我们发现KD治疗显着改善抑郁样行为在重复的社会失败压力（R-SDS）和脂多糖（LPS）模型，表明KD对抑郁症的潜在治疗作用。我们的电生理研究进一步表明，神经元的兴奋性增加，在侧缰（LHb）的小鼠暴露于R-SDS或LPS，这可以逆转在KD治疗的存在。此外，还发现R-SDS和LPS在LHb中诱导强烈的小胶质细胞炎性活化。重要的是，这些表型在饲喂KD的小鼠中得到拯救。此外，我们发现，先天免疫受体Trem 2在LHb的蛋白水平显着降低抑郁症模型。在LHb小胶质细胞中特异性敲低Trem 2诱导抑郁样行为，增加神经元兴奋性以及强烈的小胶质细胞炎症激活。总之，我们证明了KD对抑郁样行为的治疗作用，这可能是通过恢复小胶质细胞炎症激活和神经元兴奋性介导的。此外，我们还提出了一个尚未认识的功能，Trem 2在LHb抑郁症。我们的研究揭示了抑郁症的发病机制，从而提供了一个潜在的治疗干预。
Depression is a severe neuropsychiatric disorder, of which the underlying pathological mechanisms remain unclear. The ketogenic diet (KD) has been reported to exhibit preventative effects on depressive-like behaviors in rodents. However, the therapeutic effects of KD on depressive-like behaviors have not been illustrated thus far. Here, we found that KD treatment dramatically ameliorated depressive-like behaviors in both repeated social defeat stress (R-SDS) and lipopolysaccharide (LPS) models, indicating the potential therapeutic effects of KD on depression. Our electrophysiological studies further showed that neuronal excitability was increased in the lateral habenula (LHb) of mice exposed to R-SDS or LPS, which can be reversed in the presence of KD treatment. Moreover, R-SDS and LPS were also found to induce robust microglial inflammatory activation in the LHb. Importantly, these phenotypes were rescued in mice fed with KD. In addition, we found that the protein level of innate immune receptor Trem2 in the LHb was significantly decreased in depression models. Specific knockdown of Trem2 in LHb microglia induced depressive-like behaviors, increased neuronal excitability as well as robust microglial inflammatory activation. Altogether, we demonstrated the therapeutic effects of KD on depressive-like behaviors, which are probably mediated via the restoration of microglial inflammatory activation and neuronal excitability. Besides, we also proposed an unrecognized function of Trem2 in the LHb for depression. Our study sheds light on the pathogenesis of depression and thereby offers a potential therapeutic intervention.