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基于PFC-NAc-VTA神经环路代谢组学探讨疏肝和胃汤的抗抑郁作用机制
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| 篇名： | 基于PFC-NAc-VTA神经环路代谢组学探讨疏肝和胃汤的抗抑郁作用机制 |
| TITLE： | Exploration of the antidepressant machanism of Shugan hewei tang based on metabolomics of PFC-NAc-VTA neural circuit |
| 摘要： | 目的 基于前额叶皮层（PFC）-伏隔核（NAc）-腹侧被盖区（VTA）神经环路代谢组学探讨疏肝和胃汤（SGHWT）的抗抑郁作用机制。方法将雄性SD大鼠随机分为空白组，模型组，SGHWT低、中、高剂量组[3.67、7.34、14.68g/（kg·d），以生药量计]以及氟西汀组[1.58mg/（kg·d），阳性对照]，每组12只。除空白组外，其余各组大鼠均采用慢性不可预知温和应激结合单笼饲养的方式构建抑郁模型，并于造模同时灌胃相应药液或生理盐水，每天1次，持续6周。末次给药后，检测各组大鼠的体重、糖水偏好率、总移动距离、穿越中心次数和不动时间。收集空白组、模型组、SGHWT中剂量组、氟西汀组大鼠的脑组织PFC、NAc、VTA区样本，观察其组织形态学特征，进行非靶向代谢组学分析（氟西汀组除外）并验证。结果与模型组相比，各药物组大鼠3个脑区细胞溶解、结构受损等病理损伤均明显改善，其体重、糖水偏好率、总移动距离、穿越中心次数均显著升高或延长（P＜0.05），不动时间均显著缩短（P＜0.05）；非靶向代谢组学结果显示，共鉴定出78个内源性差异代谢物，PFC、NAc、VTA区分别有40、35、24个，主要涉及氨基酸、脂质、鞘脂代谢等；代谢通路富集分析结果显示，SGHWT主要通过鞘脂代谢，丙氨酸、天冬氨酸和谷氨酸代谢，不饱和脂肪酸的生物合成3条代谢通路对抑郁大鼠的神经环路产生影响，且以丙氨酸、天冬氨酸和谷氨酸代谢通路为主；验证实验结果显示，SGHWT可显著升高大鼠NAc区蛋白激酶B（Akt）、哺乳动物雷帕霉素靶蛋白（mTOR）的磷酸化水平，显著下调N-甲基-D-天冬氨酸受体1（NMDAR1）蛋白的表达。结论SGHWT可显著改善模型大鼠的抑郁样行为，减轻其PFC-NAc-VTA神经环路组织的病理损伤，上述作用可能与抑制NMDAR1蛋白表达、激活Akt/mTOR信号通路有关。 |
| ABSTRACT： | OBJECTIVE To investigate the antidepressant mechanism of Shugan hewei tang （SGHWT） based on the metabolomics of prefrontal cortex （PFC）-nucleus accumbens （NAc）-ventral tegmental area （VTA） neural circuit. METHODS Male SD rats were randomly divided into blank group， model group， SGHWT low-， medium- and high-dose groups [3.67， 7.34， 14.68 g/（kg·d）， by raw material]， and fluoxetine group [1.58 mg/（kg·d）， positive control]， with 12 rats in each group. Except for the blank group， the depression model was established by chronic unpredictable mild stress combined with individual cage housing in the remaining groups， and the corresponding drug solution or normal saline was administered via gavage during modeling， once a day， for 6 consecutive weeks. After the last administration， the body weight， sucrose preference rate， total moving distance， frequency into the center and immobility time of rats in each group were detected. Samples of PFC， NAc and VTA areas of rats in the blank group， model group， SGHWT medium-dose group and fluoxetine positive control groups were collected，and their histomorphological features were observed， and non-targeted metabolomics analysis （except for fluoxetine group）were performed and validated. RESULTS Compared with model group， the cytolysis， structural damage and other pathological damages in three brain regions of rats were significantly alleviated in each drug group， while their body weight， sucrose preference rate， total moving distance and frequency into the center were all significantly higher or longer （P＜0.05）， and immobility time was significantly shorter （P＜0.05）. The results of non-targeted metabolomics showed that a total of 78 endogenous differential metabolites were identified， with 40， 35 and 24 in the PFC， NAc and VTA regions respectively， mainly involved in amino acid， lipid and sphingolipid metabolism. The results of metabolic pathway enrichment analysis showed that SGHWT affected the neural circuits of depressed rats by regulating sphingolipid metabolism， alanine， aspartic acid and glutamic acid metabolism， saturated fatty acid biosynthesis， among which alanine， aspartic acid and glutamic acid metabolism was predominantly involved. Validation experiments showed that SGHWT significantly increased the phosphorylation levels of protein kinase B （Akt） and mammalian target of rapamycin （mTOR）， and decreased the protein expression of N-methyl-D-aspartic acid receptor 1 （NMDAR1） in the NAc region of rats. CONCLUSIONS SGHWT significantly improves the depression-like behavior and attenuates pathological damage of PFC-NAc-VTA neural circuit of model rats， the mechanism of which is associated with inhibiting NMDAR1 expression and activating the Akt/mTOR signaling pathway. |
| 期刊： | 2025年第36卷第10期 |
| 作者： | 屈鑫月；胡俊杰；李娟；章敏；周贤；刘松林；陈新 |
| AUTHORS： | QU Xinyue，HU Junjie，LI Juan，ZHANG Min，ZHOU Xian，LIU Songlin，CHEN Xin |
| 关键字： | 疏肝和胃汤；抑郁；非靶向代谢组学；PFC-NAc-VTA神经环路；NMDAR1/Akt/mTOR信号通路 |
| KEYWORDS： | Shugan hewei tang； depression； non-targeted metabolomics； PFC-NAc-VTA neural circuit； NMDAR1/Akt/mTOR |
| 阅读数： | 3 次 |
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