小鼠快感缺失诱导的不可预测性慢性轻度应激方案

Or Burstein; Ravid Doron

doi:10.3791/58184

方法文章

小鼠快感缺失诱导的不可预测性慢性轻度应激方案

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DOI：

10.3791/58184

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2018年10月24日

Or Burstein¹ , Ravid Doron¹^,²

¹School of Behavioral Science, The Academic College Tel-Aviv-Yaffo, ²Department of Education and Psychology, Open University

本文内容

摘要

本文介绍了小鼠中不可预测的慢性温和应激方案。该方案可诱导长期的类抑郁表型，并可用于评估潜在抗抑郁药物在逆转行为学及神经分子水平类抑郁缺陷方面的有效性。

摘要

抑郁症是一种高度普遍且致残的疾病，目前的药物治疗仅能部分缓解症状。许多患者对治疗无反应，这促使人们需要开发新的治疗替代方案，并更深入地理解该疾病的病因。具有转化价值的临床前模型是完成这一任务的基础。本文介绍了一种在小鼠中建立不可预测性慢性轻度应激（UCMS）模型的实验方案。在此方案中，青春期小鼠长期暴露于交替出现的不可预测的轻度应激刺激。类似于人类抑郁症的发病过程，在小鼠青春期这一敏感时期施加应激，可导致成年后出现明显的抑郁样表型。UCMS可用于在多种抑郁样行为及神经分子指标上筛选抗抑郁药物。在评估啮齿类动物抑郁样行为的诸多实验中，蔗糖偏好实验（SPT）尤为突出，该实验可反映快感缺失（抑郁症的核心症状）。本方案也将详细介绍SPT的实施方法。UCMS能够诱导快感缺失、引发长期的行为缺陷，并且可通过慢性（而非急性）抗抑郁药物治疗逆转这些缺陷，这些特点使其相较于其他诱导抑郁样行为的动物模型具有更高的有效性。

引言

重度抑郁症（MDD）是一种致残性疾病，已被列为全球疾病负担的第11位主要原因。^th 全球疾病负担的原因¹，终生患病率为11%–16%²^,³重度抑郁症（MDD）与患者社会功能和职业功能的严重损害、生活质量下降、多种精神和躯体疾病以及死亡风险升高相关。⁴^,⁵^,⁶^,⁷目前有多种治疗重度抑郁症（MDD）的有效药物疗法和心理干预手段；然而，超过三分之一的患者无法通过现有的治疗方案达到症状缓解。⁸^,⁹^,¹⁰^,¹¹因此，进一步阐明重度抑郁症的病理生理机制并研发新型药物仍然至关重要。为完成这些任务，需要采用经过科学验证的动物模型。

不可预测的慢性轻度应激（UCMS）是一种著名的大鼠和小鼠实验范式，用于诱导类似抑郁和焦虑的行为¹²^,¹³^,¹⁴^,¹⁵。UCMS 的主要目的是在小鼠和大鼠中引发行为缺陷（例如快感缺失和行为绝望¹²^,¹⁵），并促进潜在治疗性药物的筛选。该方法最初由 Katz 提出¹⁶，随后由 Willner 进一步发展¹⁷^,¹⁸，产生了大量与抑郁症状相似的行为学和神经生物学结果¹²。该模型最初为大鼠设计，之后被调整适用于小鼠¹³^,¹⁹。在该实验过程中，青春期动物会长期暴露于多种不可预测的轻度应激刺激中，随后给予药理学干预。在治疗结束后获取行为学和生物学指标。UCMS 后常进行的重要测试之一是蔗糖偏好实验（SPT）。SPT 基于啮齿类动物天生更偏好甜味溶液而非水的特性，被广泛认为是评估快感缺失的关键转化模型¹²^,¹⁸^,²⁰^,²¹（快感缺失是人类抑郁症的核心症状之一²²^,²³）。

自首次引入以来，不可预测的慢性轻度应激（UCMS）模型已进入其应用的第四十个年头，被广泛用于小鼠和大鼠的大量研究中。其中大多数研究采用UCMS作为诱导抑郁样行为的方法¹²^,¹³^,²¹^,²⁴。也有研究利用该模型产生促焦虑效应²⁵^,²⁶^,²⁷^,²⁸^,²⁹。蔗糖和糖精偏好测试是评估UCMS后快感缺失的主要方法¹²^,¹⁸^,³⁰^,³¹^,³²^,³³。在UCMS相关文献中广泛采用的其他重要结局指标包括：悬尾实验（TST）²⁸^,³⁴^,³⁵、强迫游泳实验（FST）²⁸^,³⁴^,³⁶^,³⁷（两者均用于测量应激应对能力/行为绝望）、开放旷场实验（OFT；用于测量探索行为、类焦虑行为及运动活动能力）²⁵^,²⁸^,³⁸、高架十字迷宫（EPM；用于测量类焦虑行为）²⁵^,³⁹^,⁴⁰，以及其他用于测量抑郁样行为、焦虑样行为、认知功能和社会行为的测试¹²。已有研究表明，长期给予三环类抗抑郁药（TCAs；如丙米嗪³⁵^,⁴¹^,⁴²^,⁴³、去甲替林¹⁸^,⁴⁴^,⁴⁵）、四环类抗抑郁药（TeCAs；如马普替林⁴⁶^,⁴⁷、米安色林⁴⁸）、选择性5-羟色胺再摄取抑制剂（SSRIs；如氟西汀⁴⁶^,⁴⁷^,⁴⁹、艾司西酞普兰³⁰^,⁵⁰、帕罗西汀⁵¹^,⁵²）、褪黑素⁴³^,⁴⁹、阿戈美拉汀⁵³、脂肪酸酰胺水解酶（FAAH）抑制剂URB597⁵⁴以及多种天然化合物³⁰^,³⁷^,⁵⁰^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸，均可逆转UCMS诱导的抑郁样和焦虑样症状。总体而言，这些治疗效果无法通过急性给药实现¹²（例如，帕罗西汀⁵¹^,⁵²、丙米嗪⁵³^,⁵⁴^,⁵⁹^,⁶⁰、氟西汀⁵³、阿戈美拉汀⁵³、URB597⁵⁴、溴法罗明⁶⁰）。

童年和青少年时期的压力暴露是成年后发生重度抑郁症（MDD）（以及其他多种精神障碍）的主要危险因素⁶¹^,⁶²^,⁶³下丘脑-垂体-肾上腺（HPA）轴是调节应激生物行为反应的主要神经内分泌系统⁶⁴儿童和青少年时期是神经发育的敏感阶段，此期间的长期压力会破坏下丘脑-垂体-肾上腺轴（HPA轴）的平衡。这种压力可能引发交感神经持续过度激活、反应失衡以及静息状态下仍存在的高皮质醇血症；从而增加个体罹患抑郁或焦虑相关精神疾病的风险。⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸UCMS 能够充分模拟这种发病机制：在小鼠青春期施加应激可诱导出长期的抑郁样易感性。此外，UCMS 所引发的行为缺陷与下丘脑-垂体-肾上腺（HPA）轴功能的显著改变密切相关。例如，通过降低海马体脑源性神经营养因子 [BDNF；一种高度参与 HPA 轴平衡的蛋白质] 水平⁶⁹^,⁷⁰]³⁰，或通过干扰皮质酮分泌到血液中的调节过程⁷¹^,⁷²），与人类的病理生理学相似¹²^,⁵⁰^,⁷³.

UCMS 作为抑郁症模型具有多项支持性特征：例如（i）可诱导快感缺失（这被认为是重度抑郁症的内表型²³^,⁷⁴）；（ii）UCMS 能够评估多种类抑郁行为，如行为绝望、社交行为减少、毛发状态恶化等³⁴；以及（iii）在应激暴露后，抗抑郁药的慢性（2–4 周）给药而非急性给药，可产生持久的治疗效应，这与相同药物在人类患者中产生的效应相似³⁰^,⁷⁵^,⁷⁶^,⁷⁷。

与其它抑郁症动物模型相比，这些特征增强了UCMS模型的有效性。强迫游泳实验（FST⁷⁸）和悬尾实验（TST⁷⁹）是两种常用于诱导或评估类抑郁行为的模型。作为诱导类抑郁行为的模型，它们与UCMS相比存在明显不足：无法引发长期的行为改变，可能仅反映对急性应激的适应性反应，而非产生持久的类抑郁表现⁷⁶。

另一种抑郁症动物模型是社会挫败模型。与强迫游泳实验（FST）和悬尾实验（TST）不同，该模型（与不可预测的慢性轻度应激模型UCMS类似）需要施加慢性应激即 [即], 动物反复遭受与优势个体的厌恶性社交互动）⁷⁶^,⁷⁷^,⁸⁰^,⁸¹^,⁸²社会挫败模型的主要优势在于采用社会性刺激作为应激源，从而反映了心理社会应激在人类抑郁症发病机制中的作用。与不可预测的慢性轻度应激（UCMS）类似，社会挫败模型可引发长期的抑郁样行为及神经内分泌改变。与UCMS相同的是，社会挫败所导致的行为缺陷可通过长期而非急性给予抗抑郁药物得以逆转。总体而言，大量证据支持将UCMS和社会挫败模型作为研究抑郁症病理生理机制的临床前研究工具。⁷⁶^,⁷⁷^,⁸¹^,⁸²然而，社交挫败模型的一个主要缺陷是，该模型仅能应用于雄性啮齿类动物，因为雌性个体彼此之间不会表现出足够的攻击性行为⁸³相比之下，UCMS被证明可在雄性和雌性小鼠中均产生多种类似抑郁的效果³⁴.

可预测的慢性轻度应激（PCMS）是另一种啮齿类动物模型，其特点是每天重复施加束缚应激²⁸^,⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷。多项研究表明，PCMS会增加类似焦虑的行为²⁸^,⁸⁷；然而，关于PCMS是否能够诱导长期类似抑郁行为的能力，目前仍存在相互矛盾的报道。与不可预测的慢性轻度应激（UCMS）不同，PCMS在诱导类似快感缺失状态方面效果较差²⁸^,⁸⁴^,⁸⁶。这一结果与人类现象学一致，即不可预测的应激源比可预测的应激源更具危害性⁸⁸。

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方案

本文所述所有方法均已获得特拉维夫-雅法学术学院机构动物护理与使用委员会的批准。

1. 动物

使用青春期前（即，3周龄雄性ICR远交系小鼠。
将小鼠随机分为两个大小相等的应激组（UCMS组与未处理组），每组使用15只小鼠（例如：如果有3个药理学治疗组，则总共使用90只小鼠；2 [UCMS vs. naïve] × 3 [处理方式] × 15 [小鼠] = 90
根据应激分组的家鼠；即，仅包含未受应激家鼠的家鼠对照组，以及仅包含来自UCMS组家鼠的家鼠UCMS组。
标准家庭笼具中的实验动物（30 × 15 × 14 cm；每笼5只小鼠；每笼包含所有处理组的小鼠）即，药物处理组]；除特别说明外，实验期间将小鼠保持在相同的笼具中。
在饲养笼中装入新鲜木屑（每周更换两次），并添加一块棉絮以增加环境丰富度。
在标准饲养笼中对动物进行为期一周的适应性饲养。允许 随意摄取 可自由获取啮齿类动物饲料和水（在施加UCMS应激源期间除外）。
保持12小时光照/12小时黑暗的恒定循环（除非另有说明）。在UCMS实验过程中，将未处理小鼠保留在其原代饲养笼中。

2. UCMS

在实验室中指定一个独立的房间，专门用于UCMS方案。
设计一个为期4周的应激源方案，其中包含七种不同的应激源（即，湿笼、湿润锯末、倾斜笼具、空笼、社会应激、小鼠束缚以及明暗周期干扰）每周使用一次，每次在不同日期进行（有关可能的设计方案参见 补充的 表1).
在适应环境1周后（见1.6），开始施加应激源（确保小鼠年龄约为4周）。
每天在施加应激源之前，将UCMS组的笼子从饲养室转移到UCMS室。
在施加应激源期间，除光照/黑暗周期颠倒期间外，对UCMS组大鼠禁食和禁水。
注意：可通过将含有食物和水的原始笼盖替换为无物的笼盖来实现此步骤。
根据先前设计的方案（参见2.2）施加以下应激因素：
1. 湿垫料笼具
  1. 将小鼠与其同笼饲养的同伴一起放入一个空笼中（即，无锯末垫料的笼具）
  2. 将空笼子注入温度为24 ± 1 °C的水，水深1 cm（注水时需小心，避免水直接溅到小鼠身上）。将小鼠置于潮湿笼子中4小时。
  3. 将每只小鼠分别转移至独立的临时干燥笼中，笼子上方放置加热灯，下方放置加热垫，并铺有纸巾垫料。在临时笼内放置温度计，以确认温度不超过37 °C。
  4. 将每只小鼠保留在临时笼中，直至其毛发干燥且状态活跃（约10–15分钟）。随后将小鼠放回原笼，与同组小鼠一同饲养。
2. 潮湿的锯末
  1. 将温度保持在24 ± 1 °C的水倒入饲养笼中，直至木屑适度湿润（倾倒时需小心，避免水直接溅到小鼠身上）。
    注意：倾倒水之前无需使用新鲜锯末。
  2. 4小时后，按照2.6.1.3节所述，将小鼠置于临时笼具中干燥。将小鼠与其原饲养笼中的同伴一起放入含新鲜木屑的无菌笼具中。
3. 倾斜笼具
  1. 将笼子以45°角倾斜靠墙放置4小时。
    注意：在此期间，施加应激刺激的小鼠与其对照组小鼠一同保留在各自的饲养笼中。
4. 空笼
  1. 将小鼠与其对应的特定原饲养笼一起从原饲养笼转移至一个空笼中，持续4小时。
5. 社会压力
  1. 将小鼠及其对应的特定原饲养笼一起，从原饲养笼转移至另一群小鼠至少提前3天居住过的笼子中，在施加应激原前使小鼠在陌生笼子中停留4小时。
    注意：为避免混淆，应在每个笼子上贴上标签，注明小鼠的来源笼。
6. 小鼠固定
  1. 将每只小鼠分别放入清洁的小鼠固定器中固定4小时。之后将小鼠放回原笼，与相同同伴共同饲养。
7. 光/暗周期紊乱
  1. 将小鼠与其特定的同伴一同放入原饲养笼中，转移至UCMS实验房间。保持灯光持续开启24小时。
    注意：仅在此应激期间允许小鼠进行 随意摄取 可自由获取啮齿类动物饲料和水。
施加应激源后，将UCMS组的笼子从UCMS室移回饲养室。
在为期4周的应激暴露期间，将未处理组小鼠保留在饲养室内的原饲养笼中。
注意：不将未受处理的小鼠转移至UCMS实验房间，因为即使未直接接触应激源，暴露于正在接受应激处理的其他小鼠也可能诱发应激效应。⁸⁹^,⁹⁰.
监测动物在不可预测的慢性轻度应激（UCMS）过程中的状态
1. 在施加应激源期间（光/暗循环干扰除外），应由有经验的实验人员每30分钟监测一次小鼠。若出现非典型的痛苦表现（例如，颤抖、嗜睡、活动减少）时，应立即停止应激刺激（在“湿笼”和“湿润木屑”操作中需特别注意小鼠可能出现低体温）。
2. 每天检查每只小鼠是否有伤口或其他身体或行为异常。若发现上述情况，应咨询实验室兽医，以确定该小鼠是否应被排除在实验之外。
3. 每3天称量一次小鼠体重。显著的体重下降（即, >较基线体重减轻10%或 >体重较上次测量减少15%时，必须向实验室兽医报告，并将该小鼠排除出实验。

3. 抗抑郁药物筛选

在停止UCMS方案的次日，开始给予假定具有治疗作用的药理学药物（即，艾司西酞普兰 [15 mg/kg；腹腔注射；每日给药，持续3周]³⁰^,⁵⁰，或新型草药治疗 [NHT；30 mg/kg；腹腔注射；3周；每日给药一次]³⁰^,⁵⁰).
注意：有关本方案未包含的其他药物剂量，请参见：flouxetine^{46, 47, 49, 89, 90}帕罗西汀⁵¹，丙米嗪^35,41,42,43, 地昔帕明^18,44,45，马普替林^46,47，米安色林⁴⁸，褪黑素^43,49，URB59754 及其他天然化合物^{37,55,56,57,58}.
注意：NHT 是一种由本实验室研发的中药复方，由以下4种成分组成：
山楂，小麦，布朗百合 和 酸枣仁将各组分（以冻干颗粒形式获得）共同溶解于含有1% DMSO的生理盐水中，配制该配方，使每种成分的终浓度为0.47 mg/ml^27,50.
设置对照处理组，向该组给予生理盐水（腹腔注射；3周；每日一次）。
根据此前称重所得的小鼠体重计算药物剂量。
长期给药（通常通过腹腔注射（i.p.）每日给药一次，持续3周）。
注意：腹腔注射前无需对小鼠进行麻醉。
继续每3天称重小鼠一次；最后一次称重应在末次给药前3天进行。

4. SPT 中享乐水平的评估

处理阶段结束后，将每只小鼠从原笼中取出，单独放入装有新鲜木屑和一块脱脂棉作为环境丰富物的笼子中。
准备两个瓶子，一个装蒸馏水，另一个装2%蔗糖溶液（也可使用其他物质：例如，糖精⁹¹乙醇³⁰).
注意：每个瓶子应装有相同体积的液体。在引入液体前，无需进行预先适应或习惯化阶段。
称量两个瓶子，并将其放置在笼盖上，以便小鼠使用 随意摄取 24/48/72/144 小时内同时接触两种溶液。
将两个瓶子分别放置在笼盖的两端，在两个瓶子之间放置啮齿类动物饲料，以允许 随意摄取 食物获取
每24小时更换一次瓶子，使用含新鲜液体的无菌瓶子。
注意：由于小鼠为单只饲养，即使经过144小时也无需更换木屑⁹².
每12小时（当测试持续时间为24小时时）或每天一次（当测试持续时间超过24小时时）交换喷嘴的位置，以消除因位置偏好导致结果偏差的可能性。
每天称量瓶子以估算每瓶的消耗量。
将蔗糖摄入量除以总液体摄入量，计算蔗糖偏好率（即，蔗糖/蔗糖+水）

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结果

为了验证不可预测的慢性轻度应激（UCMS）造模方法在诱导类似抑郁缺陷方面的有效性，进行了操作验证。将雄性ICR远交系小鼠随机分配至UCMS组或正常对照组（持续4周，见方案2.2）。随后，进行糖水偏好实验（SPT，持续6天，见方案4），以评估经历UCMS处理的小鼠是否出现快感缺失。紧接着，处死小鼠并完整分离海马组织，采用酶联免疫吸附测定法（ELISA）检测脑源性神经营养因子（BDNF）水平（BDNF是一种与抑郁症病理生理机制密切相关的蛋白⁷⁰^,⁹³）。研究设计详见图1。

独立样本t检验显示，两组在蔗糖偏好性方面存在显著差异（t₍₂₃₎ = 2.32，p < 0.05）。UCMS组的蔗糖偏好性低于正常...

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讨论

鉴于重度抑郁症（MDD）是一种普遍且致残性极高的疾病，而现有治疗手段仅能部分缓解症状，因此寻找更有效疗法的科学探索仍是一项紧迫任务。除心理治疗技术的创新外，对于大量对现有药物无反应的患者，还需开发新的药物治疗方案。严谨的动物抑郁模型是实现这一目标的关键。此类模型有助于筛选新型抗抑郁药物，并加深对疾病病因的理解。UCMS 是目前较为突出的啮齿类动物抑郁模型之一，其重要地位体现在大量已发表的研究成果以及重要的科学发现¹²^,¹⁸^,⁸²^,⁹⁵^,⁹⁶^,⁹⁷中。

快感缺失是重度抑郁障碍（MDD）的核心症状之一²²^,

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披露

作者无任何利益冲突需要披露。

致谢

作者感谢Gali Breuer在视频制作过程中提供的帮助。本研究由以色列科学与技术部资助 & 空间（资助号 313552）、以色列国家心理生物学研究所（NIPI-208-16-17b）以及开放大学基金会

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材料

本文使用的材料清单
姓名	公司	目录编号	评论
加热灯	Ikea	AA-19025-3
加热垫	Sachs	EF-188B
小鼠固定器
便携式电子天平（.* g）
标准橡胶塞，5号规格	Ancare	#5.5R	用于避免SPT过程中液体溢出
直口开放式饮水管（2.5"）	Ancare	OT-100	用于避免SPT过程中液体溢出（将饮水管插入橡胶塞中）
2%蔗糖溶液
50 mL 圆锥形离心管			用于SPT实验
青春期前（约20日龄）ICR远交系小鼠	Envigo	Hsd:ICR (CD-1)

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