This study was supported by the American Heart Association (IRG 14330015, PRE 16850005, PRE 20380386, EIA 0740129N), and the National Institutes of Health (RR 2865AR; P20 RR 016477).

下面描述的所有程序进行了审查，并在西弗吉尼亚大学健康科学中心批准的机构动物护理和使用委员会。 1.选择动物模型注:在UCMS模型中最常用的品种包括只SD和Wistar大鼠和BALB / CJ鼠标;其他小鼠模型已经显示有限的功效（DBA / 2，C57BL / 6）。然而，仔细考虑应给予的特定鼠标或选择的大鼠品系，由于遗传背景和易感性环境压力变化很大物种之间，并已被证明是影响研究11,14,15的成果的重要因素， 19。 <ol><li>使用适当的年龄的动物（ 例如，如果期 ​​望的终点是在17周大的老鼠进行评估，然 ​​后将老鼠必须启动UCMS议定书〜9周龄）作为本协议需在LEAST 7-9周才能完全诱发抑郁症状。 </li><li>单家动物IACUC批准的笼子和娱乐设施，食品和饲料标准可随意（另有规定的特定协议）进行UCMS。 </li><li>要特别小心，以确保控件安置在一个安静的房间最小的活动，以减少任何可能的未知环境压力的影响。 </li></ol> 2.不可预知的慢性轻度应激协议注:动物接受UCMS每天输送（&gt;每周5天），以清洁室用于UCMS操作。动物暴露于1或2的各天下面列出的压力源。压力都在一个随机计划执行的，并且每个应力给药最少3-4小时的（ 见表 1）。 <ol><li>浇10-20盎司的浸湿被褥。干净的水到每个标准的笼子。调整水的量相应地的大小笼为了充分衰减寝具但不引起的水池。居住在潮湿的笼中的动物为3-4小时。 </li><li>从每个网箱中取出被褥3-4小时，在这之后的动物被转换成另一种应激，需要一个空笼子（浅浴，笼倾斜）或放置到一个干净的笼子里有清新的床上用品。 </li><li>倾斜笼为3-4小时，约45°（无床上用品）。笼可倾斜以将留在原地作为动物走动在笼子一个坚固的对象。 </li><li>改变正常的12小时/ 12小时的光/暗周期为30分钟周期演替持续8小时。后，返回动物的正常循环。 </li><li>从它的笼子转移的每个动物，一个相邻的动物已被删除3小时笼。 </li><li>从每个网箱中取出所有的床上用品和鼠标或加水的深度〜0.25英寸约0.5英寸，只约4小时。使用水，它比室温温暖（〜30℃），以尽量减少hypothermIA潜力。简单干动物用柔软的毛巾在水中暴露之前，放置到干净的笼子里的结论。 </li><li>暴露动物捕食者气味/声音从一个天敌物种添加毛发和尿液（10-20毫升）的随机分布的样品束入笼3-4小时。另外，玩咆哮或从天然食肉动物捕食的噪音在靠近笼子3小时。 </li><li>在每个日常压力期间结束，将所有的动物成清洁笼子里，并将它们返回到壳体设施。 </li></ol> 3.动物监测/美容比分<ol><li>每天检查每个动物的伤口或溃疡，可能需要兽医治疗的发展。动物发展轻度损伤可能会继续在兽医的同意UCMS协议。 <ol><li>两名调查员培训评估大衣疏导检查每个动物和上规模的0-1指定每周大衣得分。这个分数是威慑通过分配个人得分开采（0-干净，1脏），以每8身体regions-头，颈，背大衣，风衣腹，尾，前肢，后肢和生殖器区域。同样的调查人员在整个UCMS协议执行此任务，以保持在分配大衣分数的一致性。 </li><li>那经历了急剧减少体重（ 即 &gt; 15％）任何动物的，应当报的兽医人员，必须从协议中删除。 </li></ol></li></ol> 4。行为测试和测量指标注:评估的几种方法可以用来量化从啮齿动物的UCMS协议行为变化。 <ol><li>累计大衣疏导分数。 <ol><li>如上所述，每周涂层疏导得分被分配给每个动物。 </li></ol></li><li>蔗糖飞溅试验: <ol><li>将动物在干净的笼子内衬的化妆棉或纸巾，以防止床上用品附着在它的皮毛。喷10％的蔗糖溶液到每个动物的头和背涂层和5分钟记录总梳理行为。 </li><li>梳理活性（定义为清洗毛发由舔或刮伤的）由和频率（次数疏导的特定身体部位数）延迟（第一喷射和起始疏导之间的空闲时间）来测定。 </li></ol></li><li>蔗糖偏好测试: <ol><li> ，观察者动物饮用1％的蔗糖溶液（重量/体积）72小时的测试前，然后提供暴露于两瓶（1％蔗糖溶液与自来水中不同瓶）。习惯化后，提供动物随意访问蔗糖溶液和自来水3小时。 3小时后记录的蔗糖溶液的消费量和自来水，计算蔗糖偏好为:[（蔗糖消费量）/（用水量+蔗糖消耗）]×100。 </li></ol></li><li>悬尾实验（仅小鼠）: <ol><li>苏使用胶带（2厘米尾巴尖）稳定杆（20厘米处楼）花鼠的尾巴。记录不动时间超过5分钟。小鼠只有当他们挂被动，完全一动不动被认为是不动的。 </li></ol></li><li>强迫游泳测试: <ol><li>在一个容器的地方动物（〜15-20厘米直径为小鼠;〜55-60厘米直径为只）在26±0.5℃的温度下充满水。记录延迟到第一回合的流动性，并在5分钟测试期间花不动的时间。在试验结束时，将湿动物中在加热垫上（30-35℃）与正常寝具覆盖吸水纸巾直至干燥的保持架。 </li></ol></li><li>高架十字迷宫: <ol><li>允许每只动物自由探索迷宫5分钟。记录总条目到每个臂，和总时间在每个臂中度过，根据推测标准 20。 </li></ol></li><li> Locomo器活动: <ol><li>记录活动量，定义为整体运动，精细动作，饲养的动作，和不活动，对于急性（30分钟）和/或慢性（12小时）的时间段。使用家笼或小说环境为此，取决于个体环境（虽然一致性应维持）实时由观察者或事后通过重放和分析照相机镜头。 </li></ol></li></ol> UCMS议定书5.扩展/变异<ol><li>辖适当的治疗药物或挑战来研究它们要么生硬UCMS致成果的开发（如年初启动），扭转既定UCMS引起的后果严重程度（如果发起晚期）的能力。这是取决于单个实验室或协议11。 </li></ol> 6.最后的结果评估<ol><li>以下的UCMS协议和行为测试结束时，利用动物在后续EXPERiments在解决具体的假设，目的或个人实验室的目标的方式。 注:作为例子，这可以包括心血管疾病，炎症或内分泌反应，慢性应激。备选地，治疗性干预可以在此时被引入以评估它们的有效性和机理基础。 </li></ol>

<ol><li>NIMH Statistical Pages (Depression; Prevalence). , Available from:
 <a target="_blank" href="http://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adults.shtml">http://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adults.shtml</a> (2014).</li>
<li>NIMH Statistical Pages (Depression; Costs). , Available from:
 <a target="_blank" href="http://www.nimh.nih.gov/health/statistics/cost/index.shtml">http://www.nimh.nih.gov/health/statistics/cost/index.shtml</a> (2014).</li>
<li>Lett, H. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Depression+as+a+risk+factor+for+coronary+artery+disease%3A+evidence%2C+mechanisms%2C+and+treatment%5BTitle%5D)+AND+%22Psychosom+Med%22%5BJournal%5D)">Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment.</a> Psychosom Med. 66 (3), 305-315 (2004).</li>
<li>Plante, G. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Depression+and+cardiovascular+disease%3A+a+reciprocal+relationship%5BTitle%5D)+AND+%22Metabolism%22%5BJournal%5D)">Depression and cardiovascular disease: a reciprocal relationship.</a> Metabolism. 54, 45-48 (2005).</li>
<li>Pizzi, C., Manzoli, L., Mancini, S., Bedetti, G., Fontana, F., Costa, G. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Autonomic+nervous+system%2C+inflammation+and+preclinical+carotid+atherosclerosis+in+depressed+subjects+with+coronary+risk+factors%5BTitle%5D)+AND+%22Atherosclerosis%22%5BJournal%5D)">Autonomic nervous system, inflammation and preclinical carotid atherosclerosis in depressed subjects with coronary risk factors.</a> Atherosclerosis. 212 (1), 292-298 (2010).</li>
<li>Barden, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Implication+of+the+hypothalamic-pituitary-adrenal+axis+in+the+physiopathology+of+depression%5BTitle%5D)+AND+%22J+Psychiatry+Neurosci%22%5BJournal%5D)">Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression.</a> J Psychiatry Neurosci. 29 (3), 185-193 (2004).</li>
<li>Bowman, R. E., Beck, K. D., Luine, V. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Chronic+stress+effects+on+memory%3A+sex+differences+in+performance+and+monoaminergic+activity%5BTitle%5D)+AND+%22Horm+Behav%22%5BJournal%5D)">Chronic stress effects on memory: sex differences in performance and monoaminergic activity.</a> Horm Behav. 43, 48-59 (2003).</li>
<li>Baune, B. T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((The+relationship+between+subtypes+of+depression+and+cardiovascular+disease%3A+a+systematic+review+of+biological+models%5BTitle%5D)+AND+%22Transl+Psychiatry%22%5BJournal%5D)">The relationship between subtypes of depression and cardiovascular disease: a systematic review of biological models.</a> Transl Psychiatry. 2, e92(2012).</li>
<li>O'Leary, O. F., Cryan, J. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Towards+translational+rodent+models+of+depression%5BTitle%5D)+AND+%22Cell+Tissue+Res%22%5BJournal%5D)">Towards translational rodent models of depression.</a> Cell Tissue Res. 354 (1), 141-153 (2013).</li>
<li>Mineur, Y. S., Belzung, C., Crusio, W. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Effects+of+unpredictable+chronic+mild+stress+on+anxiety+and+depression-like+behavior+in+mice%5BTitle%5D)+AND+%22Behav+Brain+Res%22%5BJournal%5D)">Effects of unpredictable chronic mild stress on anxiety and depression-like behavior in mice.</a> Behav Brain Res. 175 (1), 43-50 (2006).</li>
<li>Yalcin, I., Belzung, I., Surget, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Mouse+strain+differences+in+the+unpredictable+chronic+mild+stress%3A+a+four-antidepressant+survey%5BTitle%5D)+AND+%22Behav+Brain+Res%22%5BJournal%5D)">Mouse strain differences in the unpredictable chronic mild stress: a four-antidepressant survey.</a> Behav Brain Res. 193 (1), 140-143 (2008).</li>
<li>d'Audiffret, A. C., Frisbee, S. J., Stapleton, P. A., Goodwill, A. G., Isingrini, E., Frisbee, J. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Depressive+behavior+and+vascular+dysfunction%3A+a+link+between+clinical+depression+and+vascular+disease%5BTitle%5D)+AND+%22J+Appl+Physiol%22%5BJournal%5D)">Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease.</a> J Appl Physiol. 108 (5), 1041-1051 (2010).</li>
<li>Stanley, S. C., Brooks, S. D., Butcher, J. T., d'Audiffret, A. C., Frisbee, S. J., Frisbee, J. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Protective+effect+of+sex+on+chronic+stress-+and+depressive+behavior-induced+vascular+dysfunction+in+BALB%2FcJ+mice%5BTitle%5D)+AND+%22J+Appl+Physiol%22%5BJournal%5D)">Protective effect of sex on chronic stress- and depressive behavior-induced vascular dysfunction in BALB/cJ mice.</a> J Appl Physiol. 117 (9), 959-970 (2014).</li>
<li>Ibarguen-Vargas, Y., Surget, A., Touma, C., Palme, R., Belzung, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Multifaceted+strain-specific+effects+in+a+mouse+model+of+depression+and+of+antidepressant+reversal%5BTitle%5D)+AND+%22Psychoneuroendocrinology%22%5BJournal%5D)">Multifaceted strain-specific effects in a mouse model of depression and of antidepressant reversal.</a> Psychoneuroendocrinology. 33 (10), 1357-1368 (2008).</li>
<li>Dalla, C., Pitychoutis, P. M., Kokras, N., Papadopoulou-Daifoti, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Sex+differences+in+animal+models+of+depression+and+antidepressant+response%5BTitle%5D)+AND+%22Basic+Clin+Pharmacol+Toxicol%22%5BJournal%5D)">Sex differences in animal models of depression and antidepressant response.</a> Basic Clin Pharmacol Toxicol. 106 (3), 226-233 (2010).</li>
<li>Mutlu, O., Gumuslu, E., Ulak, G., Celikyurt, I. K., Kokturk, S., Kır, H. M., Akar, F., Erden, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Effects+of+fluoxetine%2C+tianeptine+and+olanzapine+on+unpredictable+chronic+mild+stress-induced+depression-like+behavior+in+mice%5BTitle%5D)+AND+%22Life+Sci%22%5BJournal%5D)">Effects of fluoxetine, tianeptine and olanzapine on unpredictable chronic mild stress-induced depression-like behavior in mice.</a> Life Sci. 91 (25-26), 1252-1262 (2012).</li>
<li>Gumuslu, E., Mutlu, O., Sunnetci, D., Ulak, G., Celikyurt, I. K., Cine, N., Akar, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((The+effects+of+tianeptine%2C+olanzapine+and+fluoxetine+on+the+cognitive+behaviors+of+unpredictable+chronic+mild+stress-exposed+mice%5BTitle%5D)+AND+%22Drug+Res+%28Stuttg%29%22%5BJournal%5D)">The effects of tianeptine, olanzapine and fluoxetine on the cognitive behaviors of unpredictable chronic mild stress-exposed mice.</a> Drug Res (Stuttg). 63 (10), 532-539 (2013).</li>
<li>Isingrini, E., Belzung, C., Freslon, J. L., Machet, M. C., Camus, V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Fluoxetine+effect+on+aortic+nitric+oxide-dependent+vasorelaxation+in+the+unpredictable+chronic+mild+stress+model+of+depression+in+mice%5BTitle%5D)+AND+%22Psychosom+Med%22%5BJournal%5D)">Fluoxetine effect on aortic nitric oxide-dependent vasorelaxation in the unpredictable chronic mild stress model of depression in mice.</a> Psychosom Med. 74 (1), 63-72 (2012).</li>
<li>Ripoll, N., David, D. J., Dailly, E., Hascoët, M., Bourin, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Antidepressant-like+effects+in+various+mice+strains+in+the+tail+suspension+test%5BTitle%5D)+AND+%22Behav+Brain+Res%22%5BJournal%5D)">Antidepressant-like effects in various mice strains in the tail suspension test.</a> Behav Brain Res. 143, 193-200 (2003).</li>
<li>Komada, M., Takao, K., Miyakawa, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Elevated+plus+maze+for+mice%5BTitle%5D)+AND+%22J+Vis+Exp%22%5BJournal%5D)">Elevated plus maze for mice.</a> J Vis Exp. (22), 1088(2008).</li>
<li>Golbidi, S., Frisbee, J. C., Laher, I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Chronic+stress+impacts+the+cardiovascular+system%3A+animal+models+and+clinical+outcomes%5BTitle%5D)+AND+%22Am.+J.+Physiol.+Heart+Circ.+Physiol%22%5BJournal%5D)">Chronic stress impacts the cardiovascular system: animal models and clinical outcomes.</a> Am. J. Physiol. Heart Circ. Physiol. , (2015).</li>
</ol>

The authors have nothing to disclose.

Extensive clinical and epidemiological evidence has indicated that chronic stress is one of the most potent precipitating factors for depression. Repeated exposure to stressors may potentiate individual vulnerability to depression and other neuropsychiatric disorders as a consequence of the psychological and physical demands within the body that accumulate over time. The use of validated preclinical animal models offers a valuable translational tool for studying depression and comorbid diseases. Firstly, an ideal animal ...

抑郁症精神疾病是目前世界公认的残疾和疾病负担的一个主要原因一种复杂的神经系统疾病。镍氢报告说，美国约12％的临床抑郁症，有两倍多的影响相对于男性1女。仅在美国，抑郁症占了数十亿美元的直接医疗费用估计有$ 193个十亿以上的间接成本（降低收入和生产力损失）2。抑郁症的症状包括快感缺乏，体重变化和睡眠周期，体力活动减少和个人卫生，绝望或内疚，和/或死亡或自杀的想法再次发生感情。在过去十年中，流行病学和临床研究已经表明，抑郁症是心血管疾病（CVD）的发病率和死亡率3的独立危险因素，并且是预测更严重的预后的心血管病症，包括的therosclerosis，高血压，心肌梗塞，冠状动脉疾病，不管明显的CVD 4之前的历史。尽管日益流行和抑郁症的不利公众健康的影响，这种疾病的病因学和相关的病理生理学是知之甚少和病症由于各种因素（例如，遗传，生物和环境组分）的异质性使得临床诊断难以定义。 有证据表明，无法解决的心理压力为显影抑郁疾病的一个主要因素，也可以是一种有效的致病因子联抑郁症和心血管疾病，部分是由于破坏和下丘脑-垂体-肾上腺轴（HPA）5,6-失调。 HPA轴的功能障碍是，已被链接到在抑郁症中观察到的行为和生理变化和几个CVD危险因素的发展的一个主要机制，包括血脂异常，肥胖症，糖尿病和7。抑郁症的多种临床前模型，已经开发了试图复制临床抑郁症的改变的HPA轴的活性特性的机制;这种模型提供了有效的手段进行调查慢性和急性应激动物相关的行为，神经系统和生理变化。的疾病的动物模型的有效性是基于模型的设计和其复述解剖学，神经生理学能力，和在人类疾病观察行为特征的病因和进展的相关性。此外，临床前对治疗的反应（如SSRIs的）应产生相似的结果的那些在临床环境观察。 应激抑郁的几种动物模型的研究，目前利用，如习得性无助，早期的生活压力，社会溃败的压力。然而，这些模型都有固有的缺点这减轻他们的翻译疗效8。在过去的几十年中，不可预知的慢性轻度应激（UCMS）协议已成为最翻译相关的车型之一是研究抑郁症的病理生理啮齿类动物9。该模型是基于长期暴露于压力破坏应激反应系统，并最终导致抑郁症的发展的基本概念。在UCMS协议，动物暴露于每天随机一系列温和的环境和社会压力的。它增强了该模型对人类的情况下的相关性的一个关键因素在于高度不可预测性和压力的不可控的，以及在其被引入的时间。此外，UCMS协议使用，而不是依赖于生命早期或积极的物理刺激只有轻微的压力。经过一段UCMS曝光，抑郁行为发展和媲美临床iCal的症状，包括反应减少到奖励（快感缺乏），改变身体活动和调查行为（无助和绝望），大衣状态恶化和改变性活动10。几乎所有的抑郁症症状可证实已经报道使用这种模型，并且研究已经证明，这些行为持续数周后应力的停止。此外，这些UCMS诱发抑郁行为可以逐渐被慢性尊敬，但不是急性的，治疗特别抗抑郁药，提示治疗改善了密切反映在人类中这些药物的临床操作和可变功效类似的神经效应11,14- 18。这里，我们报告了UCMS协议的详细描述，并描述典型行为和血管的结果在小鼠中。

<table><tbody><tr><td>Temporary animal cages with lids</td><td></td><td></td><td>Provided by your animal care facility</td></tr><tr><td>Rodent bedding</td><td></td><td></td><td>Provided by your animal care facility</td></tr><tr><td>Predator fur or urine</td><td></td><td></td><td>Provided by your animal care facility</td></tr><tr><td>Rodent cage drinking bottles</td><td></td><td></td><td>Provided by your animal care facility</td></tr><tr><td>1,000 ml graduated cylinder</td><td>variable</td><td>variable</td><td>This is optional.&amp;nbsp; Any container from which a known quantiity of water can be poured will be appropriate</td></tr><tr><td>Wooden blocks cut from 2x4</td><td>variable</td><td>variable</td><td>8 inch sections are cut to facilitate cage tilt procedures</td></tr><tr><td>Soft paper towels</td><td></td><td></td><td>Provided by your institution</td></tr><tr><td>Small spray bottle&amp;nbsp;</td><td>Walmart</td><td></td><td>100-200 ml volume is sufficient, used for sucrose splash test</td></tr><tr><td>Medium (mice) or large (rats) plastic tubs for swim testing</td><td>Walmart</td><td>variable</td><td>Should be of sufficient depth that the animals cannot touch bottom (&lt;I&gt;e.g.&lt;/I&gt;, 2 feet)</td></tr></tbody></table>

an unpredictable chronic mild stress protocol for instigating depressive symptoms, behavioral changes and negative health outcomes in rodents

慢性，未解决的压力是临床抑郁症的发展的一个主要危险因素。而应激抑郁的许多临床前模型已报道，在不可预测的慢性应激（UCMS）协议是用于诱导行为症状通常与临床抑郁症有关，如快感缺乏，改变的梳理行为建立翻译相关的模型，和习得性无助在啮齿类动物。该UCMS协议也引起生理（E·G。，hypercortisolemia，高血压）和神经系统（ 例如 ，快感缺乏，习得性无助感），其在临床上与抑郁症相关的变化。重要的是，UCMS引起的抑郁症状可以通过长期得到改善，但不严重，治疗常见的SSRIs类药物。这样，UCMS协议提供了许多优点急性应激协议或，利用更极端的压力源协议。我们的协议包括随机，每天暴露于7不同的STREssors:潮湿的床上用品，拆除床上用品，笼倾斜，改变光/暗周期，社会压力，浅水洗澡，捕食者的声音/气味。 3-4小时，每天给这些轻度压力使鼠类为8周后，我们证明这两种显著的行为改变和不良的健康后果心血管系统。这种方法允许进行深入询问慢性应激抑郁相关联，以及用于新的潜在的治疗剂或干预策略测试神经，行为和生理改变的。

一周之后UCMS过程的时间表的一个例子示于表1中。每个星期，压力被随机防止鼓掌，并确保挑战应力的不可预测的每一天。 抑郁像行为措施继8周UCMS，有显著改变双方的行为和生理的结果相对于其非强调控制株慢性应激啮齿动物。抑郁像下面UCMS症状的发展是通过外套得分，蔗糖飞溅测试和尾吊评估（只老鼠，引用12,13）。在大衣疏导?...

Watch this Scientific Journal Video about An Unpredictable Chronic Mild Stress Protocol for Instigating Depressive Symptoms, Behavioral Changes and Negative Health Outcomes in Rodents at JoVE.com

An Unpredictable Chronic Mild Stress Protocol for Instigating Depressive Symptoms, Behavioral Changes and Negative Health Outcomes in Rodents

The unpredictable chronic mild stress (UCMS) protocol is a validated method for studying behavioral and physiological changes associated with chronic stress and depressive symptoms. Eight weeks of imposition of the UCMS protocol induces behavioral changes and poor health outcomes in rodents of either gender.

煽动抑郁症状，行为变化和不利健康结果鼠害一个不可预知的慢性轻度应激协议

Chronic, unresolved stress is a major risk factor for the development of clinical depression. While many preclinical models of stress-induced depression ...

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Research

JoVE Journal

Behavior

22.4K 次观看.  West Virginia University Health Sciences Center. The unpredictable chronic mild stress (UCMS) protocol is a validated method for studying behavioral and physiological changes associated with chronic stress and depressive symptoms. Eight weeks of imposition of the UCMS protocol induces behavioral changes and poor health outcomes in rodents of either gender.

视频: An Unpredictable Chronic Mild Stress Protocol for Instigating Depressive Symptoms, Behavioral Changes and Negative Health Outcomes in Rodents

Using Chronic Social Stress to Model Postpartum Depression in Lactating Rodents

Exposure to chronic stress is a reliable predictor of depressive disorders, and social stress is a common ethologically relevant stressor in both animals and humans. However, many animal models of depression were developed in males and are not applicable or effective in studies of postpartum females. Recent studies have reported significant effects of chronic social stress during lactation, an ethologically relevant and effective stressor, on maternal behavior, growth, and behavioral neuroendocrinology. This manuscript will describe this chronic social stress paradigm using repeated exposure of a lactating dam to a novel male intruder, and the assessment of the behavioral, physiological, and neuroendocrine effects of this model. Chronic social stress (CSS) is a valuable model for studying the effects of stress on the behavior and physiology of the dam as well as her offspring and future generations. The exposure of pups to CSS can also be used as an early life stress that has long term effects on behavior, physiology, and neuroendocrinology.

This article describes the use of chronic resident intruder social stress as an ethologically relevant paradigm to model postpartum depression and anxiety in lactating rodents.

哺乳期鼠害使用慢性社会压力型号产后抑郁症

Exposure to chronic stress is a reliable predictor of depressive disorders, and social stress is a common ethologically relevant stressor in both animals ...

科研

行为学

A Mouse Model of Subchronic and Mild Social Defeat Stress for Understanding Stress-induced Behavioral and Physiological Deficits

Stressful life events often increase the incidence of depression in humans. To study the mechanisms of depression, the development of animal models of depression is essential. Because there are several types of depression, various animal models are needed for a deeper understanding of the disorder. Previously, a mouse model of subchronic and mild social defeat stress (sCSDS) using a modified chronic social defeat stress (CSDS) paradigm was established. In the paradigm, to reduce physical injuries from aggressors, the duration of physical contact between the aggressor and a subordinate was reduced compared to in the original CSDS paradigm. sCSDS mice showed increased body weight gain, food intake, and water intake during the stress period, and their social behaviors were suppressed after the stress period. In terms of the face validity of the stress-induced overeating and overdrinking following the increased body weight gain, the sCSDS mice may show some features related to atypical depression in humans. Thus, a mouse model of sCSDS may be useful for studying the pathogenic mechanisms underlying depression. This protocol will help establish the sCSDS mouse model, especially for studying the mechanisms underlying stress-induced weight gain and polydipsia- and hyperphagia-like symptoms.

Here, methods for developing a mouse model of subchronic and mild social defeat stress are described and used to investigate the pathogenic features of depression including hyperphagia- and polydipsia-like symptoms following increased body weight.

亚慢性和温和的社会失败应激的小鼠模型理解应激诱导行为和生理赤字

Stressful life events often increase the incidence of depression in humans. To study the mechanisms of depression, the development of animal models of ...

A Rat Methyl-Seq Platform to Identify Epigenetic Changes Associated with Stress Exposure

As genomes of a wider variety of animals become available, there is an increasing need for tools that can capture dynamic epigenetic changes in these animal models. The rat is one particular model animal where an epigenetic tool can complement many pharmacological and behavioral studies to provide insightful mechanistic information. To this end, we adapted the SureSelect Target Capture System (referred to as Methyl-Seq) for the rat, which can assess DNA methylation levels across the rat genome. The rat design targeted promoters, CpG islands, island shores, and GC-rich regions from all RefSeq genes. 
To implement the platform on a rat experiment, male Sprague Dawley rats were exposed to chronic variable stress for 3 weeks, after which blood samples were collected for genomic DNA extraction. Methyl-Seq libraries were constructed from the rat DNA samples by shearing, adapter ligation, target enrichment, bisulfite conversion, and multiplexing. Libraries were sequenced on a next-generation sequencing platform and the sequenced reads were analyzed to identify DMRs between DNA of stressed and unstressed rats. Top candidate DMRs were independently validated by bisulfite pyrosequencing to confirm the robustness of the platform.
Results demonstrate that the rat Methyl-Seq platform is a useful epigenetic tool that can capture methylation changes induced by exposure to stress.

Here, we describe the protocol and implementation of Methyl-Seq, an epigenomic platform, using a rat model to identify epigenetic changes associated with chronic stress exposure. Results demonstrate that the rat Methyl-Seq platform is capable of detecting methylation differences that arise from stress exposure in rats.

大鼠甲基 Seq 平台识别与应力接触相关的表观变化

As genomes of a wider variety of animals become available, there is an increasing need for tools that can capture dynamic epigenetic changes in these ...

生物化学

The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice

Depression is a highly prevalent and debilitating condition, only partially addressed by current pharmacotherapies. The lack of response to treatment by many patients prompts the need to develop new therapeutic alternatives and to better understand the etiology of the disorder. Pre-clinical models with translational merits are rudimentary for this task. Here we present a protocol for the unpredictable chronic mild stress (UCMS) method in mice. In this protocol, adolescent mice are chronically exposed to interchanging unpredictable mild stressors. Resembling the pathogenesis of depression in humans, stress exposure during the sensitive period of mice adolescence instigates a depressive-like phenotype evident in adulthood. UCMS can be used for screenings of antidepressants on the variety of depressive-like behaviors and neuromolecular indices. Among the more prominent tests to assess depressive-like behavior in rodents is the sucrose preference test (SPT), which reflects anhedonia (core symptom of depression). The SPT will also be presented in this protocol. The ability of UCMS to induce anhedonia, instigate long-term behavioral deficits and enable reversal of these deficits via chronic (but not acute) treatment with antidepressants strengthens the protocol&#39;s validity compared to other animal protocols for inducing depressive-like behaviors.

Here we present the unpredictable chronic mild stress protocol in mice. This protocol induces a long-term depressive-like phenotype and enables to assess the efficacy of putative antidepressants in reversing the behavioral and neuromolecular depressive-like deficits.

诱导小鼠快感缺失的不可预测慢性轻度应力协议

Depression is a highly prevalent and debilitating condition, only partially addressed by current pharmacotherapies. The lack of response to treatment by ...

A Chronic Immobilization Stress Protocol for Inducing Depression-Like Behavior in Mice

Depression is not yet fully understood, but various causative factors have been reported. Recently, the prevalence of depression has increased. However, therapeutic treatments for depression or research on depression is scarce. Thus, in the present paper, we propose a mouse model of depression induced by movement restriction. Chronic mild stress (CMS) is a well-known technique to induce depressive-like behavior. However, it necessitates a complex procedure consisting of a combination of various mild stresses. In contrast, chronic immobilization stress (CIS) is a readily accessible chronic stress model, modified from a restraint model that induces depressive behavior by restricting movement using a restrainer for a certain period. To evaluate the depressive-like behaviors, the sucrose preference test (SPT), the tail suspension test (TST), and the ELISA assay to measure stress marker corticosterone levels are combined in the present experiment. The described protocols illustrate the induction of CIS and evaluation of the changes in behavior and physiological factors for the validation of depression.

This article provides a simplified and standardized protocol for induction of depressive-like behavior in chronically immobilized mice by using a restrainer. In addition, behavior and physiological techniques to verify induction of depression are explained.

诱导小鼠抑郁行为的慢性固定性压力协议

Depression is not yet fully understood, but various causative factors have been reported. Recently, the prevalence of depression has increased. However, ...

Chronic Stress Shifts Effort-Related Choice Behavior in a Y-Maze Barrier Task in Mice

Mood disorders, including major depressive disorder, can be precipitated by chronic stress. The Y-maze barrier task is an effort-related choice test that measures motivation to expend effort and obtain reward. In mice, chronic stress exposure significantly impacts motivation to work for a higher value reward when a lesser value reward is freely available compared to unstressed mice. Here we describe the chronic corticosterone administration paradigm, which produces a shift in effortful responding in the Y-maze barrier task. In the Y-maze task, one arm contains 4 food pellets, while the other arm contains only 2 pellets. After mice learn to select the high reward arm, barriers with progressively increasing height are then introduced into the high reward arm over multiple test sessions. Unfortunately, most chronic stress paradigms (including corticosterone and social defeat) were developed in male mice and are less effective in female mice. Therefore, we also discuss chronic non-discriminatory social defeat stress (CNSDS), a stress paradigm we developed that is effective in both male and female mice. Repeating results with multiple distinct chronic stressors in male and female mice combined with increased usage of translationally relevant behavior tasks will help to advance the understanding of how chronic stress can precipitate mood disorders.

The Y-maze barrier task is a behavior test that examines motivation to expend effort for reward. Here, we discuss testing multiple well-validated chronic stressors including chronic corticosterone and social defeat stress with this behavior, as well as the novel chronic non-discriminatory social defeat stress (CNSDS), which is effective in females.

在小鼠的 Y-Maze 障碍任务中，慢性应力转移与工作量相关的选择行为

Mood disorders, including major depressive disorder, can be precipitated by chronic stress. The Y-maze barrier task is an effort-related choice test that ...

<meta charset="utf8"></head><body>对小鼠的早期生活创伤进行建模以研究 PTSD 和社交回避行为

Chronic Social Defeat Stress in Early Adolescent Male Mice

Physical abuse and trauma in childhood is reported in as many as 1 in 7 children and is a major risk factor for the development of psychiatric diseases, such as Post-Traumatic Stress Disorder (PTSD), in adolescence and adulthood. Hallmark behavioral symptoms of PTSD include avoidance of cues and contexts associated with trauma. The ability to model long-lasting changes in the brain due to early life trauma is critical to determine potential circuit and molecular targets for the modulation of resultant symptoms. This manuscript describes a protocol for modeling early life physical and psychological trauma in early adolescent male mice that produces socially avoidant behavior. Adolescent male mice are exposed to repeated aggressive encounters followed by overnight housing, which provides an added dimension of psychological stress, with an adult male aggressor every day for 10 days. Repeated social defeat paired with overnight housing by the aggressor in early adolescence produces robust social avoidance behavior that lasts throughout adulthood. Social avoidance can be readily quantified in early adolescents, adolescents, and adults using open field social interaction testing. Early adolescent social defeat robustly produces more than 60% susceptible animals in adulthood.

<meta charset="utf8"></head><body>青春期早期雄性小鼠的慢性社交挫败应激

This protocol details how to perform 10 day chronic social defeat stress in early adolescent male mice to produce long-lasting social avoidance in adulthood in more than 60% of mice.

青春期早期雄性小鼠的慢性社交挫败应激

Physical abuse and trauma in childhood is reported in as many as 1 in 7 children and is a major risk factor for the development of psychiatric diseases, ...

建立和验证慢性不可预测的轻度应激大鼠模型

Chronic Unpredictable Mild Stress in Rats based on the Mongolian medicine

Depression is a prevalent affective disorder and constitutes a leading cause of global disability. The limitations of current pharmacological interventions contribute to the substantial health burden attributed to this condition. There is a pressing need for a deeper understanding of the underlying mechanisms of depression, making pre-clinical models with translational potential highly valuable. Mongolian medicine, a subset of traditional medicine, posits that disease occurrence is closely tied to the equilibrium of wind, bile, and Phlegm. In this study, we introduce a protocol for the chronic unpredictable mild stress (CUMS) method in rats. Within this framework, rats are subjected to a series of fluctuating, mild stressors to induce a depression-like phenotype, mimicking the pathogenesis of human depression. Behavioral assays employed in this protocol include the sucrose preference test (SPT), indicative of anhedonia-a core symptom of depression; the open field test (OFT), which measures anxiety levels; and the Morris water maze test (MWM), which evaluates spatial memory and learning abilities. The CUMS method demonstrates the capability to induce anhedonia and to cause long-term behavioral deficits. Furthermore, this protocol is more aligned with Mongolian medical theory than other animal models designed to elicit depression-like behavior. The development of this animal model and subsequent research provide a robust foundation for future innovative studies in the realm of Mongolian medicine.

作者聚焦:建立啮齿动物模型以研究传统蒙古医学中的抑郁因素

This protocol outlines a chronic unpredictable mild stress (CUMS) model for depression based on Mongolian medical theory, along with methods for validating behavioral tests.

煽动抑郁症状，行为变化和不利健康结果鼠害一个不可预知的慢性轻度应激协议

摘要

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哺乳期鼠害使用慢性社会压力型号产后抑郁症

亚慢性和温和的社会失败应激的小鼠模型理解应激诱导行为和生理赤字

大鼠甲基 Seq 平台识别与应力接触相关的表观变化

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