猪抑郁症模型的构建及评价研究进展

doi:10.12300/j.issn.1674-5817.2025.170

实验动物与比较医学 ›› 2026, Vol. 46 ›› Issue (4): 515-530.DOI: 10.12300/j.issn.1674-5817.2025.170

猪抑郁症模型的构建及评价研究进展

李德生¹^,², 赵彦光¹^,²()

^1.上海实验动物研究中心, 上海 201203
^2.上海无菌(悉生)猪联合研究与转化医学实验室, 上海 201500

收稿日期:2025-10-11 修回日期:2026-02-15 出版日期:2026-08-25 发布日期:2026-08-22
通讯作者: 赵彦光（1973—），男，硕士，研究员，从事小型猪资源评价利用和医学模型创新研究。E-mail： zhaoyanguang@slarc.org.cn。ORCID：0000-0001-7596-0493
作者简介:李德生（1999—），男，硕士，从事实验小型猪资源培育和医学模型构建研究。E-mail： lidesheng@slarc.org.cn
基金资助:
上海实验动物研究中心2024年度“科技创新计划”新星项目“小型猪抑郁模型构建及评价方法研究”(2024NS03)

Research Progress in the Construction and Evaluation of Pig Depression Models

LI Desheng¹^,², ZHAO Yanguang¹^,²()

^1.Shanghai Laboratory Animal Research Center, Shanghai 201203, China
^2.Shanghai Germ-Free (Gnotobiotic) Pig Joint Research and Translational Medicine Laboratory, Shanghai 201500, China

Received:2025-10-11 Revised:2026-02-15 Published:2026-08-25 Online:2026-08-22
Correspondence to: ZHAO Yanguang (ORCID: 0000-0001-7596-0493), E-mail: zhaoyanguang@slarc.org.cn

摘要/Abstract

摘要：

抑郁症是一种复杂、多因素且高度异质性的临床综合征，是常见的精神疾病，严重影响患者的生活质量和社会功能。该病发病机制复杂，涉及遗传、环境、神经生物学与心理社会等多重因素的交互作用，且具有治疗抵抗性和复发性，极大地限制了现有治疗策略的临床效果。目前，主要涉及表观遗传、单胺类神经递质、下丘脑-垂体-肾上腺轴、大脑组织结构和神经可塑性、脑源性神经营养因子、肠道微生物群和炎症等多个角度的假说。因此，需要开发新的治疗策略，而建立能够有效模拟人类抑郁症核心表型与病理机制的动物模型，是推动这一目标实现的关键基础。猪在神经解剖、生理和行为上与人类高度相似，正逐步成为连接基础研究与临床转化的重要桥梁。本文系统阐述了猪抑郁症模型的构建和评价方法，在模型构建方面，重点介绍了急性应激、慢性不可预测温和应激、母子分离、社会挫败等应激造模，以及手术、药物和基因编辑造模的研究进展，并比较了不同方法的优势与局限；在模型评价方面，重点阐述了以摄食行为与蔗糖偏好测试、旷场实验、新物体识别实验、迷宫测试和社交互动测试等为代表的行为学指标，以及单胺类神经递质、下丘脑-垂体-肾上腺轴激素、脑源性神经营养因子和炎症因子等生理生化指标。同时分析了当前猪抑郁症模型在构建和评价体系、成本、设备及伦理等方面面临的挑战。最后，展望了未来猪抑郁症模型研究的发展方向，强调了整合行为学、神经影像、生理生化及分子生物学等多模态评估手段的必要性，以及精准模拟人类抑郁症的迫切需求，以期为相关领域的基础研究与临床转化提供参考与借鉴。

关键词: 抑郁症模型, 发病机制, 行为学指标, 生理生化指标, 猪

Abstract:

Depression is a complex, multifactorial, and highly heterogeneous clinical syndrome. As a common mental disorder, it severely impacts patients' quality of life and social functioning. Its pathogenesis is complex, involving interaction of multiple factors including genetic, environmental, neurobiological, and psychosocial factors. Furthermore, the condition is characterised by treatment resistance and recurrence, which significantly limits the clinical efficacy of existing treatment strategies. At present, hypotheses primarily cover a range of areas, including epigenetic modifications, monoamine neurotransmitter dysfunction, hypothalamic-pituitary-adrenal axis dysregulation, brain structural and neuroplasticity alterations, brain-derived neurotrophic factor abnormalities, the intestinal flora disturbances and inflammation. Therefore, there is a need to develop new treatment strategies, and the construction of animal models that effectively simulate the core phenotypes and pathological mechanisms of human depression is a key foundation for advancing this objective. Pigs exhibit marked similarities to humans in neuroanatomy, physiology, and behaviour, and are increasingly recognized as a valuable translational bridge between basic research and clinical application. This paper provides a systematic review of methods for establishing and evaluating models of depression in pigs. Regarding model development, it focuses on research advances in stress-induced modeling—such as acute stress, chronic unpredictable mild stress, maternal separation, and social defeat—as well as surgical, pharmacological, and gene-editing-based modeling approaches, and compares the advantages and limitations of these different methods. Regarding model evaluation, the paper focuses on behavioral indicators—such as feeding behavior and sucrose preference tests, open-field tests, novel object recognition tests, maze tests, and social interaction tests—as well as physiological and biochemical indicators, including monoamine neurotransmitters, hypothalamic-pituitary-adrenal axis hormones, brain-derived neurotrophic factors, and inflammatory factors. At the same time, the paper analyzes the challenges currently faced in the construction and evaluation of porcine depression models, including those related to model construction and evaluation systems, costs, equipment, and ethical considerations. In conclusion, the paper outlines future directions for research into porcine models of depression, emphasising the need to integrate multimodal assessment methods—including behavioural, neuroimaging, physiological, biochemical and molecular biological approaches—as well as the urgent requirement to accurately simulate human depression, with a view to providing guidance and insights for basic research and clinical translation in this field.

Key words: Depression models, Pathogenesis, Behavioral indicators, Physiological and biochemical indicators, Pigs

中图分类号:

R749.4

李德生,赵彦光. 猪抑郁症模型的构建及评价研究进展[J]. 实验动物与比较医学, 2026, 46(4): 515-530. DOI: 10.12300/j.issn.1674-5817.2025.170.

LI Desheng,ZHAO Yanguang. Research Progress in the Construction and Evaluation of Pig Depression Models[J]. Laboratory Animal and Comparative Medicine, 2026, 46(4): 515-530. DOI: 10.12300/j.issn.1674-5817.2025.170.

图/表 4

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模型 Model	方法 Method	优势 Advantage	局限性 Limitation
急性应激模型 Acute stress model	进行一次或短期的强烈应激刺激	操作简便快捷，适合抗抑郁药物的初步筛选	与人类抑郁症的发病情况吻合度较低，个体差异较大
慢性不可预测温和应激诱导模型 Chronic unpredictable mild stress model	通过长期、低强度、随机的多因素刺激	与人类抑郁症的吻合度高，能较好地模拟长期处于压力状态下所产生的抑郁症症状	造模周期长，工作量大，稳定性和可重复性有待提高
母子分离模型 Maternal separation model	在早期发育阶段分离幼崽与母亲	可模拟早期生活压力导致的抑郁风险因素，诱导其发生长期的神经生物学和行为学的改变	仅适用于新生动物。不同动物种类的研究尚不成熟，难以普遍应用
社会挫败模型 Social defeat stress model	以同物种间的从属关系为基础，使个体反复遭受社会挫败，从而表现出抑郁样行为	从社会层面模拟抑郁症的发病机制，适用于社交压力引发的抑郁样行为	更适用于雄性动物，对雌性动物和青春期动物效果较差，且模型构建难度较大
手术造模 Surgically induced model	通过切除嗅球造成脑区损伤诱导抑郁样行为出现，或通过手术方式联合应激构建卒中后抑郁症模型等	造模成功后效果稳定持久，无药物交互影响，适合抗抑郁药物的筛选及神经生物学机制的研究	技术难度高、动物死亡率高、术后恢复期长，且限制恢复机制及治疗干预的研究
药物造模 Drug-induced model	利用药物诱导单胺类神经递质耗竭，或使下丘脑-垂体-肾上腺轴过度激活等诱发抑郁样行为	模型稳定性较好、操作简便、周期短、可重复性良好	模拟的抑郁症症状较为单一，且在不同物种间药物种类、剂量和生物安全性等方面差异显著
基因编辑模型 Gene editing model	通过基因工程技术对特定基因进行编辑	能特异性研究特定基因的功能，从而阐述抑郁机制	基因修饰特异性强，难以完全模拟抑郁症的复杂多基因与环境交互作用；成本较高，随着研究的深入模型构建可能更困难

模型 Model	方法 Method	优势 Advantage	局限性 Limitation
急性应激模型 Acute stress model	进行一次或短期的强烈应激刺激	操作简便快捷，适合抗抑郁药物的初步筛选	与人类抑郁症的发病情况吻合度较低，个体差异较大
慢性不可预测温和应激诱导模型 Chronic unpredictable mild stress model	通过长期、低强度、随机的多因素刺激	与人类抑郁症的吻合度高，能较好地模拟长期处于压力状态下所产生的抑郁症症状	造模周期长，工作量大，稳定性和可重复性有待提高
母子分离模型 Maternal separation model	在早期发育阶段分离幼崽与母亲	可模拟早期生活压力导致的抑郁风险因素，诱导其发生长期的神经生物学和行为学的改变	仅适用于新生动物。不同动物种类的研究尚不成熟，难以普遍应用
社会挫败模型 Social defeat stress model	以同物种间的从属关系为基础，使个体反复遭受社会挫败，从而表现出抑郁样行为	从社会层面模拟抑郁症的发病机制，适用于社交压力引发的抑郁样行为	更适用于雄性动物，对雌性动物和青春期动物效果较差，且模型构建难度较大
手术造模 Surgically induced model	通过切除嗅球造成脑区损伤诱导抑郁样行为出现，或通过手术方式联合应激构建卒中后抑郁症模型等	造模成功后效果稳定持久，无药物交互影响，适合抗抑郁药物的筛选及神经生物学机制的研究	技术难度高、动物死亡率高、术后恢复期长，且限制恢复机制及治疗干预的研究
药物造模 Drug-induced model	利用药物诱导单胺类神经递质耗竭，或使下丘脑-垂体-肾上腺轴过度激活等诱发抑郁样行为	模型稳定性较好、操作简便、周期短、可重复性良好	模拟的抑郁症症状较为单一，且在不同物种间药物种类、剂量和生物安全性等方面差异显著
基因编辑模型 Gene editing model	通过基因工程技术对特定基因进行编辑	能特异性研究特定基因的功能，从而阐述抑郁机制	基因修饰特异性强，难以完全模拟抑郁症的复杂多基因与环境交互作用；成本较高，随着研究的深入模型构建可能更困难

周期 Period	方式 Method	刺激因素 Stimulus factors	行为学测试 Behavioral test	参数 Parameter	时间 Time	模型效果 Model performance	参考文献 References
24 h	应激（急性）	禁食、禁水、束缚、黑暗	旷场实验	旷场参数3 m×3 m，高1 m	10 min	动物主要表现出典型的抑郁样行为，如快感缺失、坐立不安、焦虑、恐慌和摄食减少，而生理指标的变化较小，如血清皮质醇水平升高，海马中5-羟色胺水平降低等，但该模型存在一定局限性，其可靠性及稳定性需进一步验证	[10]
			新物体识别实验	采用新物体探索[如橙色塑料棒15 cm（长）×6 cm（直径）]	10 min
			蔗糖偏好测试	2%蔗糖溶液和水	24 h
7周 7 weeks	应激（慢性）	单独饲养、声音刺激（警报、金属声、枪声等）、灯光刺激[白天每10 min（误差 ± 30%），夜间每120 min（误差 ± 30%）]、社会隔离	行为观察	姿势（站立、站在料槽上、坐立、跪、卧、靠墙站立）活动（不动、自我清洁、探索、非活动状态、走、观察实验人员、咬、玩耍、排泄、饮食饮水、蹭痒）声音（长声尖叫、咕噜声、吠叫、不发声）	第2、3、5、6周	诱导了与下丘脑-垂体-肾上腺轴、海马及微生物群-肠道-大脑轴显著改变相关的抑郁样行为。唾液中皮质醇显著升高，海马中5-羟色胺受体表达水平显著降低	[26]
			旷场实验	旷场参数3.5 m×3.5 m（高度不详）	10 min
			新奇抑制进食测试	食物+黄色气球	10 min
			约束测试	采用束缚带悬空吊起	5 min
3周 3 weeks	应激（社会挫败）	每周2次，实验猪与优势猪对抗（遭受社会挫败），持续3周（居民-入侵者范式的变体）	行为观察	攻击性行为（定义为实验猪攻击优势对手或进行反击，如推搡、咬击、用头撞击对手）；被动接受攻击（定义为实验猪未进行反击）；主动回避攻击（定义为猪转头避开攻击对象或逃跑）	整个周期	年轻雌性猪在反复社会挫败中会发生行为适应，但不会诱发长期的抑郁样神经内分泌症状	[39]
28 d	应激（慢性）	禁食、禁水、束缚、辛辣刺激、昼夜颠倒、电刺激、笼具倾斜	采食量	造模前期（1～3 d）、中期（13～15 d）和后期（26～28 d）的平均采食量	每个阶段3 d的平均采食量	慢性不可预测温和应激模型表观行为和生理指标变化均与抑郁症相符。行为表现为采食量极显著下降，蔗糖偏好极显著下降甚至拒饮糖水，接触新事物的潜伏期极显著升高，接触次数和时间极显著降低；生理表现为血清皮质醇水平升高，海马中5-羟色胺、去甲肾上腺素和脑源性神经营养因子水平显著下降	[54]
			旷场实验	旷场参数3 m×3 m，高1 m	10 min
			新物体识别实验	复杂花纹的新物体	10 min
			蔗糖偏好测试	2%蔗糖溶液和水	24 h

周期 Period	方式 Method	刺激因素 Stimulus factors	行为学测试 Behavioral test	参数 Parameter	时间 Time	模型效果 Model performance	参考文献 References
24 h	应激（急性）	禁食、禁水、束缚、黑暗	旷场实验	旷场参数3 m×3 m，高1 m	10 min	动物主要表现出典型的抑郁样行为，如快感缺失、坐立不安、焦虑、恐慌和摄食减少，而生理指标的变化较小，如血清皮质醇水平升高，海马中5-羟色胺水平降低等，但该模型存在一定局限性，其可靠性及稳定性需进一步验证	[10]
			新物体识别实验	采用新物体探索[如橙色塑料棒15 cm（长）×6 cm（直径）]	10 min
			蔗糖偏好测试	2%蔗糖溶液和水	24 h
7周 7 weeks	应激（慢性）	单独饲养、声音刺激（警报、金属声、枪声等）、灯光刺激[白天每10 min（误差 ± 30%），夜间每120 min（误差 ± 30%）]、社会隔离	行为观察	姿势（站立、站在料槽上、坐立、跪、卧、靠墙站立）活动（不动、自我清洁、探索、非活动状态、走、观察实验人员、咬、玩耍、排泄、饮食饮水、蹭痒）声音（长声尖叫、咕噜声、吠叫、不发声）	第2、3、5、6周	诱导了与下丘脑-垂体-肾上腺轴、海马及微生物群-肠道-大脑轴显著改变相关的抑郁样行为。唾液中皮质醇显著升高，海马中5-羟色胺受体表达水平显著降低	[26]
			旷场实验	旷场参数3.5 m×3.5 m（高度不详）	10 min
			新奇抑制进食测试	食物+黄色气球	10 min
			约束测试	采用束缚带悬空吊起	5 min
3周 3 weeks	应激（社会挫败）	每周2次，实验猪与优势猪对抗（遭受社会挫败），持续3周（居民-入侵者范式的变体）	行为观察	攻击性行为（定义为实验猪攻击优势对手或进行反击，如推搡、咬击、用头撞击对手）；被动接受攻击（定义为实验猪未进行反击）；主动回避攻击（定义为猪转头避开攻击对象或逃跑）	整个周期	年轻雌性猪在反复社会挫败中会发生行为适应，但不会诱发长期的抑郁样神经内分泌症状	[39]
28 d	应激（慢性）	禁食、禁水、束缚、辛辣刺激、昼夜颠倒、电刺激、笼具倾斜	采食量	造模前期（1～3 d）、中期（13～15 d）和后期（26～28 d）的平均采食量	每个阶段3 d的平均采食量	慢性不可预测温和应激模型表观行为和生理指标变化均与抑郁症相符。行为表现为采食量极显著下降，蔗糖偏好极显著下降甚至拒饮糖水，接触新事物的潜伏期极显著升高，接触次数和时间极显著降低；生理表现为血清皮质醇水平升高，海马中5-羟色胺、去甲肾上腺素和脑源性神经营养因子水平显著下降	[54]
			旷场实验	旷场参数3 m×3 m，高1 m	10 min
			新物体识别实验	复杂花纹的新物体	10 min
			蔗糖偏好测试	2%蔗糖溶液和水	24 h

猪抑郁症模型的构建及评价研究进展

Research Progress in the Construction and Evaluation of Pig Depression Models

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