舒郁胶囊通过激活dPAG脑区γ-氨基丁酸能神经元和下调GABA<sub>A</sub>受体δ亚基的表达改善经前烦躁症小鼠动情周期依赖性抑郁样行为

许佳玲; 刘坤; 崔雅茹; 张浩; 王新宇; 胡明会; 李自发; 高鹏; 刘伟; 乔明琦; 崔文强; 耿希文; 魏盛

doi:10.1631/jzus.B2400410

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舒郁胶囊通过激活dPAG脑区γ-氨基丁酸能神经元和下调GABA_A受体δ亚基的表达改善经前烦躁症小鼠动情周期依赖性抑郁样行为

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Research Article | Updated：2026-01-27

舒郁胶囊通过激活dPAG脑区γ-氨基丁酸能神经元和下调GABA_A受体δ亚基的表达改善经前烦躁症小鼠动情周期依赖性抑郁样行为
Shuyu capsule improves estrous cycle-dependent depression-like behavior in premenstrual dysphoric disorder (PMDD) mice by increasing GABAergic neuronal activation and downregulating GABA_AR δ subunit expression in the dorsal periaqueductal gray (dPAG) region
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2026年27卷第1期页码：73-88
Affiliations：

1.Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education / Shandong Key Laboratory of Innovation and Application Research in Basic Theory of Traditional Chinese Medicine / Shandong Provincial Engineering Research Center for the Prevention and Treatment of Major Brain Diseases with Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
2.Institute for Chinese Medicine and Brain Science, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
3.Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
4.Department of Encephalopathy, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250001, China
5.College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
6.Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, China
Funds：

the National Natural Science Foundation of China(81974553);the High Level Key Disciplines of Traditional Chinese Medicine: Basic Theory of Traditional Chinese Medicine, National Administration of Traditional Chinese Medicine(zyyzdxk-2023118);the Special Funding for the Taishan Scholars Project(tsqn202211137;tsqn201909186;tsqn202211355);the Natural Science Foundation of Shandong Province(ZR2020ZD17;ZR2021LZY018);the City-School Integration Development Strategy Project of Jinan City(JNSX2023056);the Chinese Medicine and Brain Science Youth Scientific Research Innovation Team, Shandong University of Traditional Chinese Medicine(22202101)
DOI：10.1631/jzus.B2400410
中图分类号：
CSTR：
收稿：2024-08-08，

修回：2024-11-17，

网络出版：2025-12-17，

纸质出版：2026-01-27
Accepted：

许佳玲,刘坤,崔雅茹等.舒郁胶囊通过激活dPAG脑区γ-氨基丁酸能神经元和下调GABA_A受体δ亚基的表达改善经前烦躁症小鼠动情周期依赖性抑郁样行为[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2026,27(01):73-88.

Jialing XU, Kun LIU, Yaru CUI, et al. Shuyu capsule improves estrous cycle-dependent depression-like behavior in premenstrual dysphoric disorder (PMDD) mice by increasing GABAergic neuronal activation and downregulating GABA_AR δ subunit expression in the dorsal periaqueductal gray (dPAG) region[J]. Journal of Zhejiang University-SCIENCE B, 2026, 27(1): 73-88.
许佳玲,刘坤,崔雅茹等.舒郁胶囊通过激活dPAG脑区γ-氨基丁酸能神经元和下调GABA_A受体δ亚基的表达改善经前烦躁症小鼠动情周期依赖性抑郁样行为[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2026,27(01):73-88. DOI： 10.1631/jzus.B2400410.

Jialing XU, Kun LIU, Yaru CUI, et al. Shuyu capsule improves estrous cycle-dependent depression-like behavior in premenstrual dysphoric disorder (PMDD) mice by increasing GABAergic neuronal activation and downregulating GABA_AR δ subunit expression in the dorsal periaqueductal gray (dPAG) region[J]. Journal of Zhejiang University-SCIENCE B, 2026, 27(1): 73-88. DOI： 10.1631/jzus.B2400410.

摘要

经前烦躁症（PMDD）是经前综合征（PMS）的一种亚型，该病的身体和情绪症状会影响患者日常生活和工作，亟需可靠且无副作用的临床干预。舒郁胶囊在临床上是一种可有效治疗PMDD的中药制剂，但其治疗机制尚不清楚。既往研究表明，中脑导水管周围灰质（PAG）中的γ-氨基丁酸能（GABAergic）系统可能在中药治疗PMDD中发挥作用，但缺乏功能验证。本研究旨在揭示舒郁胶囊治疗PMDD的潜在机制。通过聚焦雌性C57BL/6J和Vgat-Cre小鼠背侧中脑导水管周围灰质（dPAG）中的GABAergic系统，以评估舒郁胶囊对PMDD的影响。经强迫游泳测试检测小鼠抑郁样行为，并使用蛋白质印迹法和免疫荧光法检测激活的GABAergic神经元数量和γ-氨基丁酸A型受体δ亚基（GABRD）的表达量；分别使用化学遗传学技术和腺相关病毒载体，特异性地激活GABAergic神经元和敲低GABRD的表达，为舒郁胶囊具备治疗PMDD的神经生物学机制研究提供参考。结果显示，受到强迫游泳应激后，舒郁胶囊干预的PMDD小鼠在动情间期后期（LD）的不动时间缩短，表明舒郁胶囊可以改善PMDD小鼠动情周期依赖性抑郁样行为。此外，应用舒郁胶囊可下调PMDD模型小鼠dPAG脑区中GABRD的表达量，并逆转GABAergic神经元激活下降的趋势。研究还发现，操控二者中的单个靶点足以改善PMDD模型小鼠的抑郁样行为。本研究还建立了GABRD敲除的转基因小鼠，并通过行为学检测揭示其探索行为的变化，表明GABRD可能与焦虑症相关疾病密切相关。综上所述，舒郁胶囊可通过激活dPAG脑区GABAergic神经元以及下调GABRD的表达水平，发挥对PMDD的抗抑郁样作用，这不仅为中医治疗PMDD的临床应用提供了理论依据，也为PMDD新型治疗药物的研发奠定了科学基础。

Abstract

Premenstrual dysphoric disorder (PMDD)

a subtype of premenstrual syndrome (PMS)

involves physical and emotional symptoms that impact patients’ daily lives and productivity. A reliable

side-effect-free clinical intervention is needed. Shuyu capsule is an effective traditional Chinese medicine preparation for PMDD used in the clinics

but its therapeutic mechanism remains unclear. Previous research has suggested that the γ-aminobutyric acidergic (GABAergic) system in the periaqueductal gray (PAG) may play a role in treating PMDD with traditional Chinese medicine

but there is a lack of functional verification. This study aims to reveal the potential mechanism of the Shuyu capsule in treating PMDD. The study employed an experimental design using female C57BL/6J and Vgat-Cre mice to assess the effects of Shuyu capsules on PMDD

with a focus on the GABAergic system in the dorsal PAG (dPAG). Assessments were conducted using the forced swimming test (FST) to gauge depression-like behaviors and western blot (WB) and immunofluorescence (IF) to measure the numbers of active GABAergic neurons and the γ-aminobutyric acid type A receptor

(GABA

R) δ subunit (GABRD) expression. Chemogenetic techniques and adeno-associated virus were specifically used to activate GABAergic neurons and knock down the expression of subunits

respectively

providing insights into the neurobiological mechanisms underpinning the therapeutic effects of Shuyu capsules in treating PMDD. After being stressed by FST

the immobility duration of PMDD mice in the late dioestrus (LD) phase decreased after the Shuyu capsule intervention

implying that it can improve the estrous cycle-dependent depression-like phenotype in PMDD mice. Additionally

the application of Shuyu capsule can downregulate the expression of GABRD and reverse the downtrend of activated GABAergic neurons in the dPAG of PMDD model mice. We also found that single-target manipulation was enough to improve the depression-like behavior of PMDD model mice. Transgenic mice with

GABRD

knockout were established

and their behaviors were tested

revealing changes in their exploratory behaviors

indicating that the GABRD may be closely related to anxiety disorders. Shuyu capsule plays an anti-PMDD role by activating GABAergic neurons and downregulating the expression of GABRD in the dPAG. This provides a theoretical basis for the clinical treatment of PMDD with traditional Chinese medicine and promotes the development of drugs for treating PMDD.

关键词

Keywords

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舒郁胶囊通过激活dPAG脑区γ-氨基丁酸能神经元和下调GABAA受体δ亚基的表达改善经前烦躁症小鼠动情周期依赖性抑郁样行为

Shuyu capsule improves estrous cycle-dependent depression-like behavior in premenstrual dysphoric disorder (PMDD) mice by increasing GABAergic neuronal activation and downregulating GABAAR δ subunit expression in the dorsal periaqueductal gray (dPAG) region

DOI：10.1631/jzus.B2400410

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舒郁胶囊通过激活dPAG脑区γ-氨基丁酸能神经元和下调GABA_A受体δ亚基的表达改善经前烦躁症小鼠动情周期依赖性抑郁样行为

Shuyu capsule improves estrous cycle-dependent depression-like behavior in premenstrual dysphoric disorder (PMDD) mice by increasing GABAergic neuronal activation and downregulating GABA_AR δ subunit expression in the dorsal periaqueductal gray (dPAG) region