经皮耳迷走神经刺激通过下丘脑 α7nAchR/JAK2/STAT3/NF-κB 通路对慢性不可预测轻度应激大鼠抑郁样行为的抗神经炎症作用。

Anti-neuroinflammation effects of transcutaneous auricular vagus nerve stimulation against depression-like behaviors via hypothalamic α7nAchR/JAK2/STAT3/NF-κB pathway in rats exposed to chronic unpredictable mild stress.

机构信息

Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

出版信息

CNS Neurosci Ther. 2023 Sep;29(9):2634-2644. doi: 10.1111/cns.14207. Epub 2023 Apr 10.

BACKGROUND

Transcutaneous auricular vagus nerve stimulation (taVNS) is a vital neuromodulation for the treatment of depression, but its antidepressant molecular mechanism is unclear. The α7 nicotinic acetylcholine receptor (α7nAchR) is a key mediator of the vagus nerve that mediates its anti-inflammatory efficacy. Here, we investigated whether the antidepressant effect of taVNS in chronic unpredicted mild stress (CUMS)-exposed rats works through the α7nAchR/JAK2/STAT3/NF-κB pathway.

METHODS

The depression model was established by CUMS for continuous 6 weeks in rats. From the 4th week of the experiment, CUMS-exposed rats were subjected to taVNS for 3 weeks. To clarify the role of α7nAchR in the antidepressant effect of taVNS, we used α7nAchR gene knockout rats. The sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST) were used to evaluate depression-like behaviors of rats. Immunofluorescent staining was used to observe the morphology of microglia in the hypothalamus. Western blot was used to examine the protein expression of α7nAchR, p-JAK2, p-STAT3, IL-1β, NF-κB p65, and p-NF-κB p65 in the hypothalamus.

RESULTS

Depression-like behaviors in CUMS-exposed rats were manifested by decreased SPT ratio, increased FST immobility time, decreased total distance, vertical movement score, and activity time of OFT. Hypothalamic neuroinflammation in CUMS-exposed rats was manifested by an amoebic-like activated state of microglia, downregulated expression of α7nAchR, p-JAK2, p-STAT3, and upregulated expression of NF-κB p65, p-NF-κB p65, and IL-1β. TaVNS could significantly reverse the above-mentioned phenomena, but had a poor improvement effect for CUMS-exposed α7nAchR rats.

CONCLUSION

The hypothalamic α7nAchR/JAK2/STAT3/NF-κB signaling pathway may play an important role in the antidepressant-like behavior of taVNS.

背景

经皮耳迷走神经刺激（taVNS）是治疗抑郁症的重要神经调节方法，但它的抗抑郁分子机制尚不清楚。α7 烟碱型乙酰胆碱受体（α7nAchR）是迷走神经的关键介质，介导其抗炎功效。在这里，我们研究了 taVNS 对慢性不可预测轻度应激（CUMS）暴露大鼠的抗抑郁作用是否通过 α7nAchR/JAK2/STAT3/NF-κB 通路发挥作用。

方法

通过 CUMS 连续 6 周对大鼠建立抑郁模型。实验第 4 周开始，CUMS 暴露的大鼠接受 taVNS 治疗 3 周。为了阐明 α7nAchR 在 taVNS 抗抑郁作用中的作用，我们使用了 α7nAchR 基因敲除大鼠。蔗糖偏好测试（SPT）、旷场测试（OFT）和强迫游泳测试（FST）用于评估大鼠的抑郁样行为。免疫荧光染色用于观察下丘脑小胶质细胞的形态。Western blot 用于检测下丘脑 α7nAchR、p-JAK2、p-STAT3、IL-1β、NF-κB p65 和 p-NF-κB p65 的蛋白表达。

结果

CUMS 暴露大鼠表现出抑郁样行为，表现为 SPT 比值降低、FST 不动时间增加、总距离、垂直运动评分和 OFT 活动时间减少。CUMS 暴露大鼠下丘脑神经炎症表现为小胶质细胞阿米巴样激活状态，α7nAchR、p-JAK2、p-STAT3 表达下调，NF-κB p65、p-NF-κB p65 和 IL-1β 表达上调。TaVNS 可显著逆转上述现象，但对 CUMS 暴露的 α7nAchR 大鼠的改善效果较差。