我们感谢嫂子安藤在摄影材料方面的帮助。这项研究得到了援助资助的探索性研究 (jsp KAKENHI 赠款号 16K15196)。

<ol>
	<li>Bryan, K. J., Lee, H., Perry, G., Smith, M. A., Casadesus, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Transgenic Mouse Models of Alzheimer's Disease: Behavioral Testing and Considerations. Methods of Behavior Analysis in Neuroscience. , (2009).</li><li>Nestler, E. J., Hyman, S. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Animal+models+of+neuropsychiatric+disorders.">Animal models of neuropsychiatric disorders.</a> Nature Neuroscience. 13 (10), 1161-1169 (2010).</li><li>Crawley, J. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Behavioral+Phenotyping+Strategies+for+Mutant+Mice.">Behavioral Phenotyping Strategies for Mutant Mice.</a> Neuron. 57 (6), 809-818 (2008).</li><li>Zarringhalam, K., Ka, M., 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=An+open+system+for+automatic+home-cage+behavioral+analysis+and+its+application+to+male+and+female+mouse+models+of+Huntington's+disease.">An open system for automatic home-cage behavioral analysis and its application to male and female mouse models of Huntington's disease.</a> Behavioural Brain Research. 229 (1), 216-225 (2012).</li><li>Prusiner, S. B., Jackson, W. S., King, O. D., Lindquist, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+power+of+automated+high-resolution+behavior+analysis+revealed+by+its+application+to+mouse+models+of+Huntington's+and+prion+diseases.">The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington's and prion diseases.</a> Proceedings of the National Academy of Sciences of the United States of America. 95 (23), 13363-13383 (1998).</li><li>Jhuang, H., Garrote, E., 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=Automated+home-cage+behavioural+phenotyping+of+mice.">Automated home-cage behavioural phenotyping of mice.</a> Nature Communications. 1 (6), 1-9 (2010).</li><li>Krackow, S., Vannoni, E., 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=Consistent+behavioral+phenotype+differences+between+inbred+mouse+strains+in+the+IntelliCage.">Consistent behavioral phenotype differences between inbred mouse strains in the IntelliCage.</a> Genes, brain, and behavior. 9 (7), 722-731 (2010).</li><li>Nilsson, P., Saito, T., Saido, T. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=New+mouse+model+of+Alzheimer's.">New mouse model of Alzheimer's.</a> ACS chemical. 5 (7), 499-502 (2014).</li><li>Saito, T., Matsuba, Y., 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=Single+App+knock-in+mouse+models+of+Alzheimer's+disease.">Single App knock-in mouse models of Alzheimer's disease.</a> Nat Neurosci. 17 (5), 661-663 (2014).</li><li>Masuda, A., Kobayashi, Y., Kogo, N., Saito, T., Saido, T. C., Itohara, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cognitive+deficits+in+single+App+knock-in+mouse+models.">Cognitive deficits in single App knock-in mouse models.</a> Neurobiology of Learning and Memory. , (2016).</li><li>Chan, R. C. K., Shum, D., Toulopoulou, T., Chen, E. Y. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+executive+functions:+Review+of+instruments+and+identification+of+critical+issues.">Assessment of executive functions: Review of instruments and identification of critical issues.</a> Archives of Clinical Neuropsychology. 23 (2), 201-216 (2008).</li><li>Jurado, M. B., Rosselli, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Elusive+Nature+of+Executive+Functions:+A+Review+of+our+Current+Understanding.">The Elusive Nature of Executive Functions: A Review of our Current Understanding.</a> Neuropsychology Review. 17 (3), 213-233 (2007).</li><li>Diamond, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Executive+Functions.">Executive Functions.</a> Annual Review of Psychology. 64 (1), 135-168 (2013).</li><li>Kobayashi, Y., Sano, Y., 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=Genetic+dissection+of+medial+habenula-interpeduncular+nucleus+pathway+function+in+mice.">Genetic dissection of medial habenula-interpeduncular nucleus pathway function in mice.</a> Frontiers in behavioral neuroscience. 7, 17 (2013).</li><li>Robinson, O. J., Vytal, K., Cornwell, B. R., Grillon, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+impact+of+anxiety+upon+cognition:+perspectives+from+human+threat+of+shock+studies.">The impact of anxiety upon cognition: perspectives from human threat of shock studies.</a> Frontiers in human neuroscience. 7, 203 (2013).</li><li>Robbins, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+5-choice+serial+reaction+time+task:+behavioural+pharmacology+and+functional+neurochemistry.">The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry.</a> Psychopharmacology. (3-4), 362-380 (2002).</li><li>Asinof, S. K., Paine, T. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+5-Choice+Serial+Reaction+Time+Task:+A+Task+of+Attention+and+Impulse+Control+for+Rodents.">The 5-Choice Serial Reaction Time Task: A Task of Attention and Impulse Control for Rodents.</a> Journal of Visualized Experiments. (90), e51574 (2014).</li><li>Codita, A., Gumucio, A., 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=Impaired+behavior+of+female+tg-ArcSwe+APP+mice+in+the+IntelliCage:+A+longitudinal+study.">Impaired behavior of female tg-ArcSwe APP mice in the IntelliCage: A longitudinal study.</a> Behavioural brain research. 215 (1), 83-94 (2010).</li><li>Blumstein, D. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Habituation+and+sensitization:+new+thoughts+about+old+ideas.">Habituation and sensitization: new thoughts about old ideas.</a> Animal Behaviour. 120, 255-262 (2016).</li><li>Endo, T., Maekawa, F., 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=Automated+test+of+behavioral+flexibility+in+mice+using+a+behavioral+sequencing+task+in+IntelliCage.">Automated test of behavioral flexibility in mice using a behavioral sequencing task in IntelliCage.</a> Behavioural brain research. 221 (1), 172-181 (2011).</li><li>Voikar, V., Colacicco, G., Gruber, O., Vannoni, E., Lipp, H. -. P., Wolfer, D. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Conditioned+response+suppression+in+the+IntelliCage:+assessment+of+mouse+strain+differences+and+effects+of+hippocampal+and+striatal+lesions+on+acquisition+and+retention+of+memory.">Conditioned response suppression in the IntelliCage: assessment of mouse strain differences and effects of hippocampal and striatal lesions on acquisition and retention of memory.</a> Behavioural brain research. 213 (2), 304-312 (2010).</li><li>Pu&#347;cian, A., &#321;&#281;ski, S., G&#243;rkiewicz, T., Meyza, K., Lipp, H. -. P., Knapska, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+novel+automated+behavioral+test+battery+assessing+cognitive+rigidity+in+two+genetic+mouse+models+of+autism.">A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism.</a> Frontiers in Behavioral Neuroscience. 8, 140 (2014).</li><li>Voikar, V., Colacicco, G., Gruber, O., Vannoni, E., Lipp, H. -. P., Wolfer, D. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Conditioned+response+suppression+in+the+IntelliCage:+assessment+of+mouse+strain+differences+and+effects+of+hippocampal+and+striatal+lesions+on+acquisition+and+retention+of+memory.">Conditioned response suppression in the IntelliCage: assessment of mouse strain differences and effects of hippocampal and striatal lesions on acquisition and retention of memory.</a> Behavioural brain research. 213 (2), 304-312 (2010).</li><li>Harda, Z., Dzik, J. M., 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=Autophosphorylation+of+&#945;CaMKII+affects+social+interactions+in+mice.">Autophosphorylation of &#945;CaMKII affects social interactions in mice.</a> Genes, Brain and Behavior. , e12457 (2018).</li><li>Aarts, E., Maroteaux, G., 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+light+spot+test:+Measuring+anxiety+in+mice+in+an+automated+home-cage+environment.">The light spot test: Measuring anxiety in mice in an automated home-cage environment.</a> Behavioural Brain Research. 294, 123-130 (2015).</li><li>Safi, K., Neuh&#228;usser-Wespy, F., 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=Mouse+anxiety+models+and+an+example+of+an+experimental+setup+using+unconditioned+avoidance+in+an+automated+system+-IntelliCage.">Mouse anxiety models and an example of an experimental setup using unconditioned avoidance in an automated system -IntelliCage.</a> Cognition Brain &amp; Behavior. 10 (4), 475-488 (2006).</li><li>Dzik, J. M., Pu&#347;cian, A., Mijakowska, Z., Radwanska, K., &#321;&#281;ski, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=PyMICE:+APython+library+for+analysis+of+IntelliCage+data.">PyMICE: APython library for analysis of IntelliCage data.</a> Behavior Research Methods. 50 (2), 804-815 (2018).</li></ol>

没有宣布利益冲突。

本文介绍了在转基因 AD 模型中, 采用自动家庭笼监控系统进行长期认知行为分析的方法。最关键的一步是在适当位置植入转发器。在执行植入之前, 确保转发器的过期日期没有通过。第二个重要的问题是, 每天检查系统的运行情况, 特别是作为一个小课题, 在研究期间可能会变得更加严重 (i.、堆积门、跌落式转发器、不良电连接等)。.).第三, 必须能够解决问题, 因为在整个实验计划中可能会发生很多事情。
本文介绍了认知评估的基本任务包。这些任务是通过引用常规的行为测试产生的, 但它们不能完全模仿常规测试。例如, 已完成的任务不设置选择模式。五选择序列选择任务 (5CSRTT), 一个工作模式的任务, 通常是在一个房间内进行 9, 5 或3孔, 以测量精度16,17, nosepoke。我们的团队以前试图实施一个选择版本的, 但老鼠没有学习规则在相当长的时间内 (2 周或以上)。该系统的使用者应了解差异, 并仔细讨论数据。
另一个问题是对重复测量的限制。正如前面的研究18所提到的, 第一个是重复实验不能简单地比较年龄的影响。我们观察到, 第二个 PA 测试的数据未能复制 AD 模型10中的内存损伤。所有基因型的表现都比第一次 PA 测试差得多。这种差异可能来自年龄差异或适应厌恶刺激 (以前 PA 任务的经验)。实验者应注意重复效应, 并考虑任务的顺序。为了克服厌恶刺激在第二次 PA 试验中的适应性, 最好使用更强的气吹刺激或添加一些新的环境刺激, 如不同类型的床上用品或声音19。
各研究人员一直在为20、21、22、23、24、25的自动化家庭网箱监测研究开发新的方法和协议, 26、支持软件使用开源库27。因此, 系统的可能性已经扩大。最后, 该系统为长期检测提供了自动化高通量行为筛选, 用于研究广泛的认知功能, 有利于分型和验证疾病模型。

过去十年中, 神经元疾病动物模型的发展提供了对其基础的机械理解, 以促进治疗进展1,2,3。高通量行为测试电池在遗传动物模型中的应用是研究人类疾病的基本机制和药物治疗鉴定的一种启发式的探索工具。用于长期观察衰老和/或痴呆模型的研究测试电池传统上迫使实验室消耗大量的专门人力和时间。家庭网箱监测系统将是一项成本效益高的战略, 因为这将降低人类行为观察的成本。一些研究小组开发了自动化的基于视觉的工具, 帮助单个个体在4、5、6的小型家庭笼子中的行为分型。然而, 这种方法限制了社会互动, 测试环境的大小, 以及包括认知功能在内的各种行为措施。IntelliCage 是第二代家庭网箱监测系统, 旨在在一个社会家庭笼中执行各种认知任务。重要的是, 这种方法可以消除日常处理, 使我们能够进行长期的行为监测和评估的认知功能, 它可以消除对专门的实际处理的要求, 并使高重现性数据采集7。在这里, 我们描述的长期分型和有效性的基因小鼠模型的阿尔茨海默病 (AD) 已产生最近8,9,10使用自动家庭网箱监测系统。一个测试电池, 包括空间学习和执行功能的评估, 反复执行在多个年龄点 (9–12和14–17月老)。这个年龄依赖性的分型使我们能够确定基因在不同认知方面的瞬态和/或永久性影响。我们发现, 一些广告模型显示了一些认知方面的瞬态和永久性表型, 在长期分析中, 使用了自动化的家庭笼监测系统10。因此, 利用家庭网箱监测系统进行的自动化研究对各种认知功能障碍模型的长期行为分型和验证具有很高的效益和成本效益。

<table>
	<tbody>
		<tr>
			<td>IntelliCage</td>
			<td>TSE Systems</td>
			<td>-</td>
			<td>Parchased in 2011 or later</td>
		</tr>
		<tr>
			<td>PC</td>
			<td>Dell</td>
			<td>Inspiron 580s</td>
			<td>-</td>
		</tr>
		<tr>
			<td>Display</td>
			<td>Dell</td>
			<td>SI75T-WL</td>
			<td>-</td>
		</tr>
		<tr>
			<td>ALPHA-dri</td>
			<td>Shepherd Specialty Papers</td>
			<td>-</td>
			<td>Standard bedding</td>
		</tr>
		<tr>
			<td>Aron Alpha (Krasy Glue) 2g</td>
			<td>Toagosei (Krasy Glue)</td>
			<td>#04612</td>
			<td>Cyanoacrylates for gluing magnet and blak arm</td>
		</tr>
		<tr>
			<td>Handheld Transponder Reader</td>
			<td>BTS-ID</td>
			<td>R-560</td>
			<td>Transponder reader, which reads both Trovan and DataMars</td>
		</tr>
		<tr>
			<td>Transponder</td>
			<td>DataMars</td>
			<td>T-VA, T-VAS, or another series</td>
			<td>Basic package of transponders and implanters</td>
		</tr>
		<tr>
			<td>Diamond Grip Plus</td>
			<td>Ansel Microflex</td>
			<td>DGP-INT-M</td>
			<td>Experimental glove</td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>Pfizer</td>
			<td>1119701G1092</td>
			<td>-</td>
		</tr>
		<tr>
			<td>Vaporizer for small animals</td>
			<td>DS Pharma Biomedical</td>
			<td>SF-B01</td>
			<td>Facemask included</td>
		</tr>
		<tr>
			<td>Neo-Medrol</td>
			<td>Pfizer</td>
			<td>006472-001</td>
			<td>Eye ointment</td>
		</tr>
		<tr>
			<td>Ethanol (70%)</td>
			<td>-</td>
			<td>-</td>
			<td>-</td>
		</tr>
		<tr>
			<td>Excel</td>
			<td>Microsoft</td>
			<td>00202-51382-15524-AA928</td>
			<td>For data analysis</td>
		</tr>
	</tbody>
</table>

automated, long-term behavioral assay for cognitive functions in multiple genetic models of alzheimer's disease, using intellicage

多种因素--如衰老和基因--往往与认知下降有关。基因改良的小鼠认知衰退模型, 如阿尔茨海默病 (AD), 已成为一个有希望的工具来阐明的基础机制和促进治疗进展。一个重要的步骤是验证和定性的预期行为异常的模型, 在广告, 认知下降的情况下。对实验动物进行长期行为调查, 研究衰老的影响需要研究人员的大量努力。IntelliCage 系统是一种高吞吐量和经济高效的小鼠测试电池, 它消除了日常人类处理的需要。在这里, 我们描述如何利用该系统的长期分型的基因阿尔茨海默病模型, 特别是关注的认知功能。实验采用重复的测试电池来评估空间学习和执行功能。这种具有成本效益的年龄依赖性分型使我们能够确定基因在各种认知方面的瞬态和/或永久性影响。

在我们以前的研究中, 通过10的自动化家庭网箱监测系统的实验, 检测出 AD 模型中年龄依赖性的认知缺陷。他们的广告模式在 PP 的表现是完整的年轻成人和老科目;然而, PPR 的表现明显和逐渐受损 (图 6)。在适应阶段观察一般行为或焦虑也很重要, 因为这些特质可能影响认知15。广告模型没有显示任何严重异常的访问, nosepoke, 舔数字在法, NP 和 DSA 会议。因此, 广告模型可能具有较低的灵活性。
为了评估执行功能, 记录了在广播和 DD 中的行为表现。旧的广告模型 (NL G F) 在最后阶段缺乏准确性 (测试 2) (图 8)。促进 compulsivity 观察的年轻成人和老对象的 NL-G F 小鼠 (图 9B, 顶部)。有趣的是, 尽管 compulsivity 的小鼠在年老时有了增加, 但它与野生型小鼠 (图 9B, 底部) 相比, 有了很大的提高。这是一个例子的瞬态表型的 NL F 突变。
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/58009/58009fig1.jpg"> 图 1: 自动家庭笼监控系统的组件.(A) 系统概览。(B) 连接器的位置。(C) 带有操作门的转角室。<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/58009/58009fig1large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/58009/58009fig2.jpg"> 图 2: 研究小组住房的例子.通常, 每笼使用12只老鼠。在使用四组 (三种遗传模型和一种野生型) 的情况下, 每 IntelliCage 的三只老鼠被认为是足够的。<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/58009/58009fig2large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/58009/58009fig3.jpg"> 图 3: 系统的软件.(A) "设计师" 是用来制作实验文件的。左边: 动物名单部分包括动物和小组定义的信息。右: 模块空间用于定义实验操作。(B) "控制器" 可用于运行、监测和记录实验。左边: 一个笼子的状态工作与显示动物的参观, nosepoke 和舔在四个角落。右: 如果出现一些问题, 将显示报警窗口。(C) 分析仪可用于处理和输出由控制器获取的数据。左边: 所有数据被标记以动物、环境在笼子之内和时间的信息。筛选将有助于进一步分析 Excel 或其他分析软件。权利: 访问的时间线 (也 nosepoke 或舔) 可以单独地显示。<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/58009/58009fig3large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/58009/58009fig4.jpg"> 图 4: 转发器植入.(A) 转发器 (DataMars) 的微晶片。(B) 转发器植入 (transpondering) 的侧面图。避免导致脊髓损伤。(C) 转发器的最高视图。<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/58009/58009fig4large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/58009/58009fig5.jpg"> 图 5: 实验的时间线为认知评估与自动家庭笼监测系统.对认知评估的测试电池进行了两次 (第一组, 9–12月大; 第二组, 14–17月), 然后进行了评估一般活动的实验 (第三组 [18 月大])。该电池被指定用于评估多个认知领域 (由颜色-红色表示: 一般活动;蓝色: 空间学习和记忆;绿色: 执行功能), 在确认和描述预期的认知缺陷方面具有优势。法: 自由适应;Nosepoke 适应;每日生活津贴: 饮酒会话适应;PP: 地方偏爱;PPR: 地方偏爱逆转;连续反应时间 (冲动和注意);避免; 安置:延迟贴现。<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/58009/58009fig5large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/58009/58009fig6.jpg"> 图 6: PP 和 PPR 任务的实验设计和代表性结果.(A) 顶部, 是 PP 或 PPR 的范例模块设计。底部, 正确的拐角设置被改为在 PPR 的相反一侧。(B) 在年龄较大的情况下, AD 模型中的空间反转学习的赤字 (NL F)。数据被表示为平均标准误差 (SEM)。∗ < 0.05;∗∗ < 0.01。颜色表示比较组: 蓝色: NL vs 重量;红色: F 与重量;绿色: F 与重量。此数字已从参考10修改。<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/58009/58009fig6large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 7" class="xfigimg" src="/files/ftp_upload/58009/58009fig7.jpg"> 图 7: 完成任务的试验流程.左: (imp) 的试验流程。第一个 nosepoke 定义正确的一侧, 并启动一个延迟周期 (0.5–4.0 s), 之后, 黄色指示灯将打开。门然后打开。右: 试验流程。第一个 nosepoke 定义正确的一侧, 并启动延迟周期 (2.0 s), 之后, 黄色指示灯在较短的时间内打开 (0.2–1.0 s)。老鼠被提供一个时间期间在期间 nosepokes 被允许 (有限的举行, 2 s)。门打开 (5 s) 在正确 nosepoke 以后, 是第一个 nosepoke 在有限的举行期间。<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/58009/58009fig7large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 8" class="xfigimg" src="/files/ftp_upload/58009/58009fig8.jpg"> 图 8: 实验设计和工作任务的代表性结果.(A) 用于系统的模块设计实例。(B) 特定于老年的 AD 模型的注意力下降。数据被表示为平均值. ∗p < 0.05;∗∗ < 0.01。颜色表示比较组: 蓝色: NL vs 重量;红色: F 与重量;绿色: F 与重量。此数字已从参考10中修改。<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/58009/58009fig8large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>
<img alt="Figure 9" class="xfigimg" src="/files/ftp_upload/58009/58009fig9.jpg"> 图 9: DD 任务的实验设计和代表性结果.(A) DD 任务的模块示例。(B) 在青年和老年人的广告模式 (compulsivity) 中促进了这方面的宣传。这是表型的一个例子。另一方面, compulsivity 在另一个广告模型中短暂增加 (NL F)。数据被表示为平均值. ∗p < 0.05;∗∗ < 0.01。颜色表示比较组: 蓝色: NL vs 重量;红色: F 与重量;绿色: F 与重量。此数字已从以前的工作10中进行了修改。<a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/58009/58009fig9large.jpg" target="_blank">请单击此处查看此图的较大版本.</a>

Watch this Scientific Journal Video about Automated, Long-term Behavioral Assay for Cognitive Functions in Multiple Genetic Models of Alzheimer's Disease, Using IntelliCage at JoVE.com

Automated, Long-term Behavioral Assay for Cognitive Functions in Multiple Genetic Models of Alzheimer's Disease, Using IntelliCage

本文介绍了一种基于 IntelliCage 系统的阿尔茨海默病遗传模型认知评估的协议, 它是一种具有操作性调节的高通量自动化行为监测系统。

基于 IntelliCage 的阿尔茨海默病多基因模型认知功能的自动、长期行为检测

Multiple factors&#8212;such as aging and genes&#8212;are frequently associated with cognitive decline. Genetically modified mouse models of cognitive ...

automated-long-term-behavioral-assay-for-cognitive-functions-multiple

Nanyang Technological University

Research

JoVE Journal

Behavior

12.0K 次观看.  RIKEN. 本文介绍了一种基于 IntelliCage 系统的阿尔茨海默病遗传模型认知评估的协议, 它是一种具有操作性调节的高通量自动化行为监测系统。

视频: Automated, Long-term Behavioral Assay for Cognitive Functions in Multiple Genetic Models of Alzheimer's Disease, Using IntelliCage

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

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 cognitive functions across the lifespan in a sample of 378 healthy subjects (age range 18-89 years). Consistent with previous findings we found an age-related cognitive decline across a wide range of neuropsychological domains (memory, attention, executive functions), thereby proving the usability of our tablet-based application. Regardless of prior computer experience, subjects of all age groups were able to perform the tasks without instruction or feedback from an experimenter. Increased motivation and compliance proved to be beneficial for task performance, thereby potentially increasing the validity of the results. Our promising findings underline the great clinical and practical potential of a tablet-based application for detection and monitoring of cognitive dysfunction.

We tested the usability of a tablet-computer-based application (EmoCogMeter) in investigating the effects of age on cognition. Results show an age-related cognitive decline, thereby proving the usability of our application. Findings underline the great clinical and practical potential of a tablet-based application for detection and monitoring of cognitive dysfunction.

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 ...

科研

行为学

Nest Building as an Indicator of Health and Welfare in Laboratory Mice

The minimization and alleviation of suffering has moral and scientific implications. In order to mitigate this negative experience one must be able to identify when an animal is actually in distress. Pain, illness, or distress cannot be managed if unrecognized. Evaluation of pain or illness typically involves the measurement of physiologic and behavioral indicators which are either invasive or not suitable for large scale assessment. The observation of nesting behavior shows promise as the basis of a species appropriate cage-side assessment tool for recognizing distress in mice. Here we demonstrate the utility of nest building behavior in laboratory mice as an ethologically relevant indicator of welfare. The methods presented can be successfully used to identify thermal stressors, aggressive cages, sickness, and pain. Observation of nest building behavior in mouse colonies provides a refinement to health and well-being assessment on a day to day basis.

We demonstrate the utility of nest building behavior in laboratory mice as an indicator of welfare. Nest scoring is a sensitive technique that is altered by temperature, illness, and aggression. The time to integrate into nest test (TINT) is a simple cage-side assessment that can detect postoperative pain.

The minimization and alleviation of  suffering has moral and scientific implications. In order to mitigate this  negative experience one must be able to ...

Automated, Quantitative Cognitive/Behavioral Screening of Mice: For Genetics, Pharmacology, Animal Cognition and Undergraduate Instruction

We describe a high-throughput, high-volume, fully automated, live-in 24/7 behavioral testing system for assessing the effects of genetic and pharmacological manipulations on basic mechanisms of cognition and learning in mice. A standard polypropylene mouse housing tub is connected through an acrylic tube to a standard commercial mouse test box. The test box has 3 hoppers, 2 of which are connected to pellet feeders. All are internally illuminable with an LED and monitored for head entries by infrared (IR) beams. Mice live in the environment, which eliminates handling during screening. They obtain their food during two or more daily feeding periods by performing in operant (instrumental) and Pavlovian (classical) protocols, for which we have written protocol-control software and quasi-real-time data analysis and graphing software. The data analysis and graphing routines are written in a MATLAB-based language created to simplify greatly the analysis of large time-stamped behavioral and physiological event records and to preserve a full data trail from raw data through all intermediate analyses to the published graphs and statistics within a single data structure. The data-analysis code harvests the data several times a day and subjects it to statistical and graphical analyses, which are automatically stored in the &#34;cloud&#34; and on in-lab computers. Thus, the progress of individual mice is visualized and quantified daily. The data-analysis code talks to the protocol-control code, permitting the automated advance from protocol to protocol of individual subjects. The behavioral protocols implemented are matching, autoshaping, timed hopper-switching, risk assessment in timed hopper-switching, impulsivity measurement, and the circadian anticipation of food availability. Open-source protocol-control and data-analysis code makes the addition of new protocols simple. Eight test environments fit in a 48 in x 24 in x 78 in&#160;cabinet; two such cabinets (16 environments) may be controlled by one computer.

Fully automated system for measuring physiologically meaningful properties of the mechanisms mediating spatial localization, temporal localization, duration, rate&#160;and probability estimation, risk assessment, impulsivity, and the accuracy and precision of memory, in order to assess the effects of genetic and pharmacological manipulations on foundational mechanisms of cognition in mice.

小鼠自动化，定量认知/行为筛选:对于遗传学，药理学，动物认知与本科教学

We describe a high-throughput, high-volume, fully automated, live-in 24/7 behavioral testing system for assessing the effects of genetic and ...

Automated Visual Cognitive Tasks for Recording Neural Activity Using a Floor Projection Maze

Neuropsychological tasks used in primates to investigate mechanisms of learning and memory are typically visually guided cognitive tasks. We have developed visual cognitive tasks for rats using the Floor Projection Maze1,2&#160;that are optimized for visual abilities of rats permitting stronger comparisons of experimental findings with other species.
In order to investigate neural correlates of learning and memory, we have integrated electrophysiological recordings into fully automated cognitive tasks on the Floor Projection Maze1,2. Behavioral software interfaced with an animal tracking system allows monitoring of the animal's behavior with precise control of image presentation and reward contingencies for better trained animals. Integration with an in vivo electrophysiological recording system enables examination of behavioral correlates of neural activity at selected epochs of a given cognitive task.
We describe protocols for a model system that combines automated visual presentation of information to rodents and intracranial reward with electrophysiological approaches. Our model system offers a sophisticated set of tools as a framework for other cognitive tasks to better isolate and identify specific mechanisms contributing to particular cognitive processes.

We describe protocols for training rats for chronic electrophysiological recordings in fully automated cognitive tasks on a Floor Projection Maze.

使用地面投影迷宫自动化视觉认知任务记录神经活动

Neuropsychological tasks used in primates to investigate mechanisms of learning and memory are typically visually guided cognitive tasks. We have ...

Behavioral Phenotyping of Murine Disease Models with the Integrated Behavioral Station (INBEST)

Due to rapid advances in genetic engineering, small rodents have become the preferred subjects in many disciplines of biomedical research. In studies of chronic CNS disorders, there is an increasing demand for murine models with high validity at the behavioral level. However, multiple pathogenic mechanisms and complex functional deficits often impose challenges to reliably measure and interpret behavior of chronically sick mice. Therefore, the assessment of peripheral pathology and a behavioral profile at several time points using a battery of tests are required. Video-tracking, behavioral spectroscopy, and remote acquisition of physiological measures are emerging technologies that allow for comprehensive, accurate, and unbiased behavioral analysis in a home-base-like setting. This report describes a refined phenotyping protocol, which includes a custom-made monitoring apparatus (Integrated Behavioral Station, INBEST) that focuses on prolonged measurements of basic functional outputs, such as spontaneous activity, food/water intake and motivated behavior in a relatively stress-free environment. Technical and conceptual improvements in INBEST design may further promote reproducibility and standardization of behavioral studies.

Behavioral Phenotyping of Murine Disease Models with the Integrated Behavioral Station INBEST

Prolonged and comprehensive monitoring of mice in a home-cage environment provides a deeper understanding of aberrant behavior in murine models of brain diseases. This paper describes the Integrated Behavioral Station (INBEST) as the key component of contemporary behavioral analysis.

小鼠疾病模型的集成行为车站行为表型（INBEST）

Due to rapid advances in genetic engineering, small rodents have become the preferred subjects in many disciplines of biomedical research. In studies of ...

Behavioral and Locomotor Measurements Using an Open Field Activity Monitoring System for Skeletal Muscle Diseases

The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing locomotive impairment in animal models of neuromuscular disease and efficacy of therapeutic drugs that may improve locomotion and/or muscle function. The open field activity measurement provides a different measure than muscle strength, which is commonly assessed by grip strength measurements. It can also show how drugs may affect other body systems as well when used with additional outcome measures. In addition, measures such as total distance traveled mirror the 6 min walk test, a clinical trial outcome measure. However, open field activity monitoring is also associated with significant challenges: Open field activity measurements vary according to animal strain, age, sex, and circadian rhythm. In addition, room temperature, humidity, lighting, noise, and even odor can affect assessment outcomes. Overall, this manuscript provides a well-tested and standardized open field activity SOP for preclinical trials in animal models of neuromuscular diseases. We provide a discussion of important considerations, typical results, data analysis, and detail the strengths and weaknesses of open field testing. In addition, we provide recommendations for optimal study design when using open field activity in a preclinical trial.

Open field activity levels are used to assess locomotive and behavioral activity levels. This protocol provides a well-designed, standardized protocol to use in preclinical trials for neuromuscular disorders.

行为和运动测量使用一个开放的领域活动监控系统的骨骼肌疾病

The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing ...

Experimental Assessment of Mouse Sociability Using an Automated Image Processing Approach

Mouse is the preferred model organism for testing drugs designed to increase sociability. We present a method to quantify mouse sociability in which the test mouse is placed in a standardized apparatus and relevant behaviors are assessed in three different sessions (called session I, II, and III).
The apparatus has three compartments (see Figure 1), the left and right compartments contain an inverted cup which can house a mouse (called &#34;stimulus mouse&#34;).
In session I, the test mouse is placed in the cage and its mobility is characterized by the number of transitions made between compartments. In session II, a stimulus mouse is placed under one of the inverted cups and the sociability of the test mouse is quantified by the amounts of time it spends near the cup containing the enclosed stimulus mouse vs. the empty inverted cup. In session III, the inverted cups are removed and both mice interact freely. The sociability of the test mouse in session III is quantified by the number of social approaches it makes toward the stimulus mouse and by the number of times it avoids a social approach by the stimulus mouse.
The automated evaluation of the movie detects the nose of the test mouse, which allows the determination of all described sociability measures in session I and II (in session III, approaches are identified automatically but classified manually). To find the nose, the image of an empty cage is digitally subtracted from each frame of the movie and the resulting image is binarized to identify the mouse pixels. The mouse tail is automatically removed and the two most distant points of the remaining mouse are determined; these are close to nose and base of tail. By analyzing the motion of the mouse and using continuity arguments, the nose is identified.
<img alt="Figure 1" src="/files/ftp_upload/52508/52508fig1.jpg" /> 
Figure 1. Assessment of Sociability During 3 sessions. Session I (top): Acclimation of test mouse to the cage. Session II (middle): Test mouse moving freely in the cage while the stimulus mouse is enclosed in an inverted cup. Session III (bottom): Both test mouse and stimulus mouse are allowed to move freely and interact with each other.

This protocol describes a method to quantify mouse sociability. Mice are videotaped as they move and interact in a special cage. Movie processing allows for the automated quantification of sociability with excellent accuracy and reliability.

使用自动图像处理方法鼠标社交性的实验评估

Mouse is the preferred model organism for testing drugs designed to increase sociability. We present a method to quantify mouse sociability in which the ...

Assessment of Social Cognition in Non-human Primates Using a Network of Computerized Automated Learning Device (ALDM) Test Systems

Fagot &#38; Paleressompoulle1 and Fagot &#38; Bonte2 have published an automated learning device (ALDM) for the study of cognitive abilities of monkeys maintained in semi-free ranging conditions. Data accumulated during the last five years have consistently demonstrated the efficiency of this protocol to investigate individual/physical cognition in monkeys, and have further shown that this procedure reduces stress level during animal testing3. This paper demonstrates that networks of ALDM can also be used to investigate different facets of social cognition and in-group expressed behaviors in monkeys, and describes three illustrative protocols developed for that purpose. The first study demonstrates how ethological assessments of social behavior and computerized assessments of cognitive performance could be integrated to investigate the effects of socially exhibited moods on the cognitive performance of individuals. The second study shows that batteries of ALDM running in parallel can provide unique information on the influence of the presence of others on task performance. Finally, the last study shows that networks of ALDM test units can also be used to study issues related to social transmission and cultural evolution. Combined together, these three studies demonstrate clearly that ALDM testing is a highly promising experimental tool for bridging the gap in the animal literature between research on individual cognition and research on social cognition.

Assessment of Social Cognition in Non-human Primates Using a Network of Computerized Automated Learning Device ALDM Test Systems

Fagot &#38; Paleressompoulle1 have published an automated learning device (ALDM) aimed at testing individual cognitive abilities in semi-free ranging monkeys. The main goal of our protocol is to use a network of ALDM test units to study social cognition in non-human primates.

社会认知的非人类灵长类动物评估使用电脑自动学习设备（ALDM）测试系统的网络

Fagot &#38; Paleressompoulle1 and Fagot &#38; Bonte2 have published an automated learning device (ALDM) for the study of cognitive abilities of monkeys ...

The 4 Mountains Test: A Short Test of Spatial Memory with High Sensitivity for the Diagnosis of Pre-dementia Alzheimer's Disease

This protocol describes the administration of the 4 Mountains Test (4MT), a short test of spatial memory, in which memory for the topographical layout of four mountains within a computer-generated landscape is tested using a delayed match-to-sample paradigm. Allocentric spatial memory is assessed by altering the viewpoint, colors and textures between the initially presented and target images.
Allocentric spatial memory is a key function of the hippocampus, one of the earliest brain regions to be affected in Alzheimer&#39;s disease (AD) and impairment of hippocampal function predates the onset of dementia. It was hypothesized that performance on the 4MT would aid the diagnosis of predementia AD, which manifests clinically as Mild Cognitive Impairment (MCI).
The 4MT was applied to patients with MCI, stratified further based on cerebrospinal fluid (CSF) AD biomarker status (10 MCI biomarker positive, 9 MCI biomarker negative), and with mild AD dementia, as well as healthy controls. Comparator tests included tests of episodic memory and attention widely accepted as sensitive measures of early AD. Behavioral data were correlated with quantitative MRI measures of the hippocampus, precuneus and posterior cingulate gyrus.
4MT scores were significantly different between the two MCI groups (p = 0.001), with a test score of &#8804;8/15 associated with 100% sensitivity and 78% specificity for the classification of MCI with positive AD biomarkers, i.e., predementia AD. 4MT test scores correlated with hippocampal volume (r = 0.42) and cortical thickness of the precuneus (r = 0.55).
In conclusion, the 4MT is effective in identifying the early stages of AD. The short duration, easy application and scoring, and favorable psychometric properties of the 4MT fulfil the need for a simple but accurate diagnostic test for predementia AD.

This article describes the 4 Mountains Test (4MT), a hippocampus-dependent test of working allocentric spatial memory. The hippocampus is affected early in Alzheimer's disease (AD) and this article outlines the 4MT methodology and results of patient testing, which demonstrates the value of the 4MT in the diagnosis of pre-dementia AD.

四山测试:空间记忆的一个简短的测试与高灵敏度的预痴呆诊断阿尔茨海默氏病

This protocol describes the administration of the 4 Mountains Test (4MT), a short test of spatial memory, in which memory for the topographical layout of ...

Using the Race Model Inequality to Quantify Behavioral Multisensory Integration Effects

Multisensory integration research investigates how the brain processes simultaneous sensory information. Research on animals (mainly cats and primates) and humans reveal that intact multisensory integration is crucial for functioning in the real world, including both cognitive and physical activities. Much of the research conducted over the past several decades documents multisensory integration effects using diverse psychophysical, electrophysiological, and neuroimaging techniques. While its presence has been reported, the methods used to determine the magnitude of multisensory integration effects varies and typically faces much criticism. In what follows, limitations of previous behavioral studies are outlined and a step-by-step tutorial for calculating the magnitude of multisensory integration effects using robust probability models is provided.

The current study aims to provide a step-by-step tutorial for calculating the magnitude of multisensory integration effects in an effort to facilitate the production of translational research studies across diverse clinical populations.

使用种族模型不平等来量化行为多感官整合效应

Multisensory integration research investigates how the brain processes simultaneous sensory information. Research on animals (mainly cats and primates) ...