Name: using a murine model of psychosocial stress in pregnancy as a translationally relevant paradigm for psychiatric disorders in mothers and infants
Uploaded: 2021-06-13T13:00:00
Description: Watch this Scientific Journal Video about Using a Murine Model of Psychosocial Stress in Pregnancy as a Translationally Relevant Paradigm for Psychiatric Disorders in Mothers and Infants at JoVE.com

作者希望感谢国家普通医学研究所T32 GM063483-14赠款和辛辛那提儿童研究基金会的支持。对于改编自 Zoubovsky 等人的数据，2019 年，创意通用许可证可在以下位置找到：http://creativecommons.org/licenses/by/4.0/。

描述的所有动物实验都得到了辛辛那提儿童医疗中心动物护理和使用委员会的批准，并且符合国家卫生研究院的指导方针。在CGS范式期间，随时向小鼠提供标准啮齿动物和水的 广告利比图姆 。小鼠被安置在14小时/10小时的光暗循环（灯在06：00h），除非另有规定（即，暴露在灯光过夜）。
1. 准备分时交配
<ol><li>在建立定时交配前至少2周，将成年雌性小鼠安置在标准?...

<ol>
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L., Pedersen, C. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Brief+vs.+long+maternal+separations+in+infancy:+Contrasting+relationships+with+adult+maternal+behavior+and+lactation+levels+of+aggression+and+anxiety.">Brief vs. long maternal separations in infancy: Contrasting relationships with adult maternal behavior and lactation levels of aggression and anxiety.</a> Psychoneuroendocrinology. 26 (7), 657-672 (2001).</li><li>Boccia, M. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Repeated+long+separations+from+pups+produce+depression-like+behavior+in+rat+mothers.">Repeated long separations from pups produce depression-like behavior in rat mothers.</a> Psychoneuroendocrinology. 32 (1), 65-71 (2007).</li><li>Nephew, B. C., Bridges, R. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+chronic+social+stress+during+lactation+on+maternal+behavior+and+growth+in+rats.">Effects of chronic social stress during lactation on maternal behavior and growth in rats.</a> Stress. 14 (6), 677-684 (2011).</li><li>Carini, L. M., Murgatroyd, C. A., Nephew, B. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Using+chronic+social+stress+to+model+postpartum+depression+in+lactating+rodents.">Using chronic social stress to model postpartum depression in lactating rodents.</a> Journal of Visualized Experiments: JoVE. (76), e50324 (2013).</li><li>Pardon, M., G&#233;rardin, P., Joubert, C., P&#233;rez-Diaz, F., Cohen-Salmon, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Influence+of+prepartum+chronic+ultramild+stress+on+maternal+pup+care+behavior+in+mice.">Influence of prepartum chronic ultramild stress on maternal pup care behavior in mice.</a> Biological Psychiatry. 47 (10), 858-863 (2000).</li><li>Misdrahi, D., Pardon, M. C., P&#233;rez-Diaz, F., Hanoun, N., Cohen-Salmon, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prepartum+chronic+ultramild+stress+increases+corticosterone+and+estradiol+levels+in+gestating+mice:+Implications+for+postpartum+depressive+disorders.">Prepartum chronic ultramild stress increases corticosterone and estradiol levels in gestating mice: Implications for postpartum depressive disorders.</a> Psychiatry Research. 137 (12), 123-130 (2005).</li><li>Zoubovsky, S. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chronic+psychosocial+stress+during+pregnancy+affects+maternal+behavior+and+neuroendocrine+function+and+modulates+hypothalamic+CRH+and+nuclear+steroid+receptor+expression.">Chronic psychosocial stress during pregnancy affects maternal behavior and neuroendocrine function and modulates hypothalamic CRH and nuclear steroid receptor expression.</a> Translational Psychiatry. 10 (6), 1-13 (2020).</li><li>Yim, I. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Biological+and+psychosocial+predictors+of+postpartum+depression:+systematic+review+and+call+for+integration.">Biological and psychosocial predictors of postpartum depression: systematic review and call for integration.</a> Annual Review of Clinical Psychology. 11, 99-137 (2015).</li><li>Slomian, J., Honvo, G., Emonts, P., Reginster, J. Y., Bruyere, O. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Consequences+of+maternal+postpartum+depression:+a+systematic+review+of+maternal+and+infant+outcomes.">Consequences of maternal postpartum depression: a systematic review of maternal and infant outcomes.</a> Women's Health. 15, 1-55 (2019).</li><li>Chow, K. H., Yan, Z., Wu, W. 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(109), e53643 (2016).</li><li>Zalaquett, C., Thiessen, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+effects+of+odors+from+stressed+mice+on+conspecific+behavior.">The effects of odors from stressed mice on conspecific behavior.</a> Physiology and Behavior. 50 (1), 221-227 (1991).</li><li>Burstein, O., Doron, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+unpredictable+chronic+mild+stress+protocol+for+inducing+anhedonia+in+mice.">The unpredictable chronic mild stress protocol for inducing anhedonia in mice.</a> Journal of Visualized Experiments: JoVE. (140), e58184 (2018).</li><li>Zheng, H. T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+detrimental+effects+of+stress-induced+glucocorticoid+exposure+on+mouse+uterine+receptivity+and+decidualization.">The detrimental effects of stress-induced glucocorticoid exposure on mouse uterine receptivity and decidualization.</a> FASEB Journal: Official publication of the Federation of American Societies for Experimental Biology. 34 (11), 14200-14216 (2020).</li><li>Mueller, B. R., Bale, T. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sex-specific+programming+of+offspring+emotionality+after+stress+early+in+pregnancy.">Sex-specific programming of offspring emotionality after stress early in pregnancy.</a> Journal of Neuroscience. 28 (36), 9055-9065 (2008).</li><li>Bale, T. 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将怀孕小鼠暴露在CGS干扰产后产妇神经内分泌功能，包括HPA轴对新压力源的反应，并与与围产期情绪和焦虑障碍相关的各种行为异常有关。鉴于该模型采用了环境危险因素的利用，预计表型变异性会高于遗传模型22中观察到的。然而，如果注意尽量减少可能混淆结果的变量，则从应用 CGS 范式中获得的结果可以在各研究实验室中保持一致。
协议中的关键步骤?...

在产妇在产妇期出现不良接触后，母亲和婴儿患神经精神病的易感性增加的机制在很大程度上仍不得而知。在怀孕期间和向产后期过渡期间，会发生重大的产妇生理变化，包括一些神经内分泌适应，这些适应被认为是不仅对健康的后代神经发育，而且对保护产妇心理健康至关重要。在母体下丘脑垂体肾上腺（HPA）轴的水平，观察到昼夜和压力诱发的糖皮质激素释放水平的适应，包括更扁平的昼夜HPA轴活动节奏和抑制HPA轴对急性应激器的反应3，4，5。鉴于在产后情感调节障碍的一部分妇女中报告了增强的HPA轴活动，包括循环糖皮质激素水平增加和抑制的阴性反馈6、7、8，接触压力源导致产后压力反应增加，并防止产妇HPA轴适应被认为会增加对神经精神病的易感性。
为了阐明压力对母亲和婴儿情感调节不良的影响，在产中产生了几个啮齿动物压力模型。这些模型的特点是物理压力剂的应用，导致家庭静止的挑战和改变大坝生理状态9，如慢性约束应激10和游泳压力在妊娠期11，或产后休克暴露12。虽然这些范式已被证明导致产后抑郁症状行为的出现和产妇护理10，11，12的改变，他们一直受到限制，因为他们无法准确地捕捉人类母亲通常经历的压力源的心理社会性质。这变得特别重要时，试图揭示神经内分泌后果的慢性压力在产期，因为处理不同类型的压力源被认为是由不同的神经网络协调HPA轴激活9。
为了克服这一限制，一些团体设计了压力范式，采用社会心理侮辱或身体和社会心理压力因素的组合。产妇分离模型，在产后13、14期间，水坝每天与幼崽分离数小时，而长期社会压力模型，即水坝在15、16号垃圾面前暴露在男性入侵者面前，能够再现产妇护理异常和与身体压力范式相关的抑郁症状表型的出现。慢性超牛奶应激范式，其中怀孕的雌性小鼠暴露在各种社会心理侮辱，包括笼子倾斜和隔夜照明，以及大量的生理侮辱，如约束压力和食物限制，进一步揭示了暴露在混合性质的压力因素导致母亲行为异常，包括母体攻击性损伤， 以及HPA轴17，18的昼夜活动失调。与这些结果一致，妊娠期间交替的约束压力和过度拥挤模型导致产后母体昼夜皮质激素水平升高以及产妇护理的改变，尽管产后暴露于新的急性侮辱1后HPA轴的再活动没有观察到任何差异。
这项工作的扩展，产生一个妊娠压力范式，采用多种社会心理侮辱呈现在不可预知的方式，并尽量减少使用生理压力源。此前的研究表明，这种慢性社会心理应激范式（CGS）导致母体HPA轴功能障碍的发展，包括19日产后早期压力反应能力增强。这些变化与产妇行为的异常有关，包括幼崽接受的产妇护理质量的改变，以及出现无兴和焦虑样行为19，特征与围产期情绪和焦虑障碍20，21一一致。此外，在子宫内接触CGS19后产后，后代体重增加减少，这表明CGS可能对后代产生持续的负面编程影响。
开发 CGS 范式的目标是主要利用临床相关的压力源，准确捕获通常与神经内分泌调控和围产期情绪和焦虑障碍发展相关的侮辱类型、强度和频率。在这里，该研究提供了如何让怀孕的雌性小鼠接受CGS的详细协议，以及可用于测试模型有效性的下游评估。

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Animal lancet</td>
			<td>Braintree Scientific Inc.</td>
			<td>GR4MM</td>
			<td></td>
		</tr>
		<tr>
			<td>Blunt end probe</td>
			<td>Fine Science Tools</td>
			<td>10088-15</td>
			<td>Used to check for copulatory plugs</td>
		</tr>
		<tr>
			<td>Bottles for SPT</td>
			<td>Braintree Scientific Inc.</td>
			<td>WTRBTL S-BL</td>
			<td>100 mL glass water bottle with stopper and sipper ball point tube, graduted by 1 mL.</td>
		</tr>
		<tr>
			<td>Conical tubes (50 mL)</td>
			<td>Corning Inc.</td>
			<td>352098</td>
			<td>Used for restraining mice to measure HPA axis response to acute stress. Make sure conical tube has small opening at the end for ventilation.</td>
		</tr>
		<tr>
			<td>Legos</td>
			<td>Amazon</td>
			<td>-</td>
			<td></td>
		</tr>
		<tr>
			<td>Marbles</td>
			<td>Amazon</td>
			<td>-</td>
			<td></td>
		</tr>
		<tr>
			<td>Mouse Corticosterone ELISA kit</td>
			<td>Biovendor</td>
			<td>RTC002R</td>
			<td></td>
		</tr>
		<tr>
			<td>Mouse EZM</td>
			<td>TSE Systems</td>
			<td>-</td>
			<td></td>
		</tr>
		<tr>
			<td>Reciprocal laboratory shaker</td>
			<td>Labnet international</td>
			<td>S2030-RC-B</td>
			<td></td>
		</tr>
		<tr>
			<td>Serum separator tubes</td>
			<td>Becton Dickinson</td>
			<td>365967</td>
			<td></td>
		</tr>
		<tr>
			<td>Static cage- bottom</td>
			<td>Alternative Design Manufacturing and Supply Inc.</td>
			<td>RC71D-PC</td>
			<td></td>
		</tr>
		<tr>
			<td>Static cage - filtered ventilated tops</td>
			<td>Alternative Design Manufacturing and Supply Inc.</td>
			<td>FT71H-PC</td>
			<td></td>
		</tr>
	</tbody>
</table>

using a murine model of psychosocial stress in pregnancy as a translationally relevant paradigm for psychiatric disorders in mothers and infants

产前期被认为是一个敏感期，母亲不良暴露可对母亲和后代造成长期的负面后果，包括神经精神病的发展。与母婴染料中出现情感调节不良有关的危险因素已得到广泛研究。怀孕期间暴露在社会心理压力中一直是最有力的预测因素之一。已创建若干啮齿动物模型来探索这种关联：然而，这些模型依赖于使用物理压力源或以重复方式呈现的有限数量的社会心理压力源，这些压力源无法准确捕捉女性经历的压力源的类型、强度和频率。为了克服这些限制，产生了一种慢性社会心理压力（CGS）范式，它采用了各种不同强度的社会心理侮辱，以不可预知的方式表现出来。手稿描述了这一新颖的CGS范式，怀孕的雌性小鼠，从妊娠期的6.5天到17.5日，在白天和夜间暴露在各种压力源中。日间压力源，每天两次，间隔2小时，范围从接触异物或捕食者气味到床上用品的频繁变化、床上用品的拆卸和笼子倾斜。隔夜压力因素包括连续光照射、更换笼子伴侣或湿床上用品。我们以前已经表明，接触CGS会导致孕产妇神经内分泌和行为异常的发展，包括压力反应性增加，产妇护理模式支离破碎的出现，厌食症和焦虑相关行为，患有围产期情绪和焦虑症的妇女的核心特征。因此，这个CGS模型成为一个独特的工具，可用于阐明孕产妇情感调节不良背后的分子缺陷，以及影响胎儿神经发育并导致后代长期行为不良后果的跨胎盘机制。

将怀孕的雌性小鼠暴露在CGS中会导致慢性应激相关参数的变化，包括怀孕期间体重增加（图2A）减少，产后早期肾上腺重量增加（图2B）19。重要的是，接触CGS会导致产妇神经内分泌功能的产后异常。CGS大坝表现出一个过度活跃的HPA轴，这表现为血清皮质激素水平增加后，应用一种新的急性侮辱（图3）19。<sup class...

Watch this Scientific Journal Video about Using a Murine Model of Psychosocial Stress in Pregnancy as a Translationally Relevant Paradigm for Psychiatric Disorders in Mothers and Infants at JoVE.com

Using a Murine Model of Psychosocial Stress in Pregnancy as a Translationally Relevant Paradigm for Psychiatric Disorders in Mothers and Infants

慢性社会心理压力（CGS）范式利用小鼠怀孕期间的临床相关压力源来模拟母亲和婴儿的精神疾病。在此，我们提供了一个逐步应用 CGS 范式和下游评估来验证此模型的程序。

使用妊娠期心理社会压力的Murine模型作为母亲和婴儿精神障碍的翻译相关范式

The peripartum period is considered a sensitive period where adverse maternal exposures can result in long-term negative consequences for both mother and ...

我们的协议意义重大，因为它代表了评估慢性压力，特别是社会心理压力对怀孕结果的影响的新范式。在这个协议中，我们以不可预知的方式让怀孕的老鼠受到各种不同强度的社会心理侮辱。以前的动物模型模式采用物理压力源或重复施用的有限数量的压力源，这不能反映妇女怀孕期间的经历。我们的慢性社会心理压力模型克服了这些限制。这种方法对各种研究领域具有广泛的影响，包括产妇心理健康和与婴儿发育不良有关的研究，更广泛地说，通过宫内不良事件来了解成人疾病的发展起源。在启动 CGS 范式中的每个压力源之前，将 CGS 组鼠标从住房室带入 CGS 指定的房间。在妊娠期6.5至17.5日11天的压力源方案后，将小鼠暴露在不同的压力源中。为了让老鼠接触异物，随机将六个形状不同的弹珠或六个Legos放入一个干净的静态笼子里，用老鼠床上用品，没有老鼠窝。将所有小鼠从一个家庭笼子放入静态笼中，用异物放置两个小时，然后将小鼠送回其家中笼子。要让老鼠暴露在捕食者的气味中，将雌性大鼠一厘米厚的脏床上用品放入一个干净的静态笼子中，没有老鼠的床上用品或巢穴。将所有老鼠从一个家庭笼子放入静态笼子里，用脏老鼠床上用品放置两个小时，然后把老鼠送回家里的笼子里。要使老鼠暴露在笼子倾斜处，将所有来自一个家庭笼子的老鼠放入一个干净的静态笼子，没有老鼠窝。将笼子以30度角靠墙倾斜两小时，然后将老鼠送回家中的笼子。为了使老鼠经常更换床上用品，将所有来自一个家庭笼子的老鼠放入一个干净的静态笼子里，没有老鼠窝。每10分钟，轻轻地将老鼠移到另一个干净的笼子里，更换老鼠床上用品。两小时后，把老鼠送回家里的笼子里。要让老鼠被拆掉床上用品，将一个家庭笼子里的所有老鼠放入一个空的、干净的静态笼子里，两个小时没有老鼠被窝或窝窝，然后把老鼠送回家里的笼子里。要使老鼠在摇床上移动，将所有来自一个家庭笼子的老鼠放入一个干净的静态笼子，没有老鼠窝。将静态笼子放在互惠实验室摇床上，每分钟140次，每次两小时，然后将老鼠送回家中的笼子。为了让老鼠在一夜之间暴露在灯光下，将所有老鼠从一个家庭笼子放入一个干净的静态笼子里，没有老鼠窝。保持灯亮过夜，以干扰黑暗循环。第二天，把老鼠送回家里的笼子里。要将鼠标暴露在新的笼子伴侣中，将鼠标转移到一个干净的静态笼子中，并配有包含两只不熟悉的雌性小鼠的鼠标床上用品。将鼠标与不熟悉的笼子伙伴一起关在静态笼子里过夜。第二天，老鼠和熟悉的笼友们一起回到了笼子里。要让老鼠暴露在潮湿的床上，在静态笼子里用24摄氏度的清洁水使老鼠床上用品饱和。将所有老鼠从一个家庭笼子放入静态笼子与湿床上过夜。第二天，把老鼠送回家里的笼子里。压力源方案在妊娠期17.5日完成后，单屋所有实验鼠准备进行分泌和下游功能评估。将怀孕雌性小鼠暴露在CGS中会导致慢性压力相关参数的变化，例如怀孕期间体重增加和产后早期肾上腺重量增加。重要的是，CGS大坝表现出产后异常和母体神经内分泌功能，这从新锐侮辱后血清皮质酮水平增加就证明了这一点。此外，CGS大坝显示，幼崽收到的母体信号碎片化程度增加，反映了产妇护理的改变。舔/梳妆回合的平均持续时间减少，而平均回合数增加，表明许多短集的培养行为。与控制水坝相比，CGS 大坝中的蔗糖偏好也很低，这表明存在安希多尼亚。最后，CGS 大坝还显示与焦虑相关的行为增加，与控制大坝相比，EZM 开放象限所花费的时间减少。在后代中，在子宫中接触CGS会导致产后第7天至21日期间体重增加减少，尽管出生时没有差异。体重增加的这种减少存在于两性后代身上。在尝试此程序时，确定获得定时怀孕的时间表并持续实施整个系列时，可变不可预知的心理社会压力源至关重要。这种技术可以帮助回答有趣的问题，如母亲社会心理压力是否会对胎盘功能或后代大脑发育和行为产生特定的性别影响？这些影响可以通过药理干预或产后产妇护理来逆转或改变吗？

Research

JoVE Journal

Behavior

The Resident-intruder Paradigm: A Standardized Test for Aggression, Violence and Social Stress

驻地入侵者范式：一种标准化考试的侵略，暴力和社会压力

This video publication explains in detail the experimental protocol of the resident-intruder paradigm in rats. This test is a standardized method to ...

科研

行为学

P50 Sensory Gating in Infants

P50感觉门控的婴幼儿

Attentional deficits are common in a variety of neuropsychiatric disorders including attention deficit-hyperactivity disorder, autism, bipolar mood ...

Using Chronic Social Stress to Model Postpartum Depression 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 ...

The Crossmodal Congruency Task as a Means to Obtain an Objective Behavioral Measure in the Rubber Hand Illusion Paradigm

一致性的任务作为一种手段来获取目标行为的措施中的橡胶手错觉范式Crossmodal

The rubber hand illusion (RHI) is a popular experimental paradigm. Participants view touch on an artificial rubber hand while the participants' own hidden ...

Assessment of Age-related Changes in Cognitive Functions Using EmoCogMeter, a Novel Tablet-computer Based Approach

与年龄相关的变化认知功能使用EmoCogMeter，新型平板计算机基础法评估

The main goal of this study was to assess the usability of a tablet-computer-based application (EmoCogMeter) in investigating the effects of age on ...

A Cognitive Paradigm to Investigate Interference in Working Memory by Distractions and Interruptions

认知范式调查干扰工作记忆的干扰和中断

Goal-directed behavior is often impaired by interference from the external environment, either in the form of distraction by irrelevant information that ...

Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning

迷走神经刺激作为一种工具来诱导可塑性相关途径灭绝学习

Extinction describes the process of attenuating behavioral responses to neutral stimuli when they no longer provide the reinforcement that has been ...

The Social Dimension of Stress: Experimental Manipulations of Social Support and Social Identity in the Trier Social Stress Test

应力的社会问题：社会支持和社会认同的特里尔社会的实验操作压力测试

In many situations humans are influenced by the behavior of other people and their relationships with them. For example, in stressful situations ...

Ultrasound Images of the Tongue: A Tutorial for Assessment and Remediation of Speech Sound Errors

舌的超声图像：一个教程评估和修复声音讲话的错误

Diagnostic ultrasound imaging has been a common tool in medical practice for several decades. It provides a safe and effective method for imaging ...

Reinstatement of Drug-seeking in Mice Using the Conditioned Place Preference Paradigm

用条件位置偏好范式恢复小鼠药物寻毒作用

The present protocol describes the Conditioned Place Preference (CPP) as a model of relapse in drug addiction. In this model, animals are first trained to ...