This work was supported by the Translational Animal Research Center of the University Medical Center of the Johannes Gutenberg-University Mainz. The authors are most grateful to Thomas Wacker for his technical support.

伦理声明:老鼠和实验程序的处理是按照欧洲，国家和动物保健机构的指导方针进行。 注:该协议包括干预五天（周一至周五），上周末（周六，周日）休息。该协议可以很容易地适应，以满足特定需要。 1.确定适合作为第二增强剂悬赏注:使用食物奖励，如真空包装的食品或符合食品安全标准的饲料。例如，不同种类的坚果，巧克力，软糖，或干果都适合。 <ol><li>插入的小培养皿不同食物奖励进入家庭笼（ 图1）（在0.5厘米3个）。 </li><li> 10分钟后，检查是否有剩菜。 </li><li>如果所有的奖励是在10分钟后食用，缩短时间跨度之前的偏好可被估计。 </li><li>天4和5（ 例如，Thursday和星期五），加少量首选（"赢家"）的奖励到户笼，以建立所有小鼠的做作在笼子里的奖励。 </li><li>如果老鼠不习惯于鼠标隧道，（开始训练， 例如，在上周末前至少2天）增加隧道笼子。 </li><li>重复步骤1.2 - 1.4连续3天（ 例如，周一至周三）。 </li></ol> 2.响片训练<ol><li>筹备每次训练 注意:每次需要鼠标在这个协议被解除后，将其在一个平静和温和的态度。把鼠标下用手去抬不起来。在最初的几次，老鼠可能会烦躁，但是习惯的过程将在几天后完成。如果此步骤产生的困难，它是非常有用的参考协议28"上的开放的手拔罐"。 <ol><li>准备用床上用品材料的笼子。 </li><li>茶nsfer鼠标的笼子里被训练到一个安静的地方。 </li><li>准备奖励，有一个定时器和唱首歌/目标棒组合准备就绪。 注意:如果将小鼠习惯于操作和已经信任的用实验者的关系，小鼠可以用手送入。否则，附加的奖励到棒或镊子以这样的方式，该小鼠可以保持从实验者的距离。 </li><li>取下家笼，现在作为训练区域中的所有对象（ 例如，鼠标的房子，筑巢材料等 ）。 </li><li>转笼同伴准备好的笼子里。 </li></ol></li><li>这适用于所有的培训课程一般规则 注:以下一般规则适用于所有的会话，并不会在整个协议再次提及。 <ol><li>培养各小鼠5分钟。之间30秒的培训和15秒的休息时间替代。 </li><li>让在奖励鼠标啃不超过第二。然后，花棒（含奖励）出笼子。 </li><li>执行奖励的方式如下: 1 - 行为的10场演出:奖励每一次。 11 - 行为表现21:奖励每第二次。 从行为表现22:奖励每3次。 </li><li>的训练4分钟后，所期望的行为的下一次执行是由一个累积奖池奖励加强。让鼠标在食物奖励比以前长三倍啃。 </li></ol></li><li>训练结束第1天:"用食物奖励链接二级强化物" <ol><li>定时器设置为5分钟，按开始，将鼠标隧道添加到主笼。 注:取小鼠的先天thigmotaxis的优点和隧道放置旁边的壁（ 图2）。在最初的几个会话，这将提高进入隧道鼠标的概率。 </li><li>等到鼠标检查隧道。只要备忘录Ë进入隧道，单击并在隧道的尽头呈现奖励。 </li><li>让在奖励鼠标饲料而坐在隧道。 </li><li>而鼠标是坐在隧道按连续15秒。 </li><li>当鼠标离开隧道，回到步骤3.2。 </li></ol></li><li>培训课程天2 - 5:"通过隧道暗战" <ol><li>定时器设置为5分钟，按开始，将鼠标隧道添加到主笼。 </li><li>当鼠标进入隧道后，单击并在隧道的尽头呈现奖励。 </li><li>只要鼠标在隧道中，单击并立即呈现奖励以同样的方式。 </li><li>重复此为下一个30秒，再暂停15秒采取隧道出笼子。 </li><li>再次添加隧道，当鼠标再次进入隧道立即点击。 </li><li>目前该奖励在隧道的尽头。 </li><li>让鼠标咋长达1秒。 </li&gt; <li>拿走奖励。 </li><li>只要鼠标开始重新进入由本身的隧道，呈现奖励在隧道（ 图3）的端部的前方。 </li></ol></li><li>训练结束第2周:"经过一个目标棒" <ol><li>定时器设置为5分钟，按下启动，并把地球在笼子目标棒的末端。 </li><li>只要鼠标示出了在全球的兴趣，点击并呈现旁边的地球的奖励（ 图4和5）。 </li><li>奖励倒是用它的鼻子地球后才鼠标。 </li><li>当鼠标已链接的执行行动，奖励，培训会（ 图6）时改变地球的位置。 </li><li>等待鼠标满足这一最后的挑战。 </li><li>将全球在笼子里。 </li><li>鼠标触及全球前不久，缓慢而仔细地1厘米改变地球的位置。 </l我&gt; <li>点击和奖励如果鼠标已经越过的距离，触动全球。 </li><li>直到鼠标遵循可靠地重复此过程。 </li><li>慢慢地延长鼠标有跨越的距离。 </li></ol></li><li>培训课程每周3:"继目标粘在实验者的手" <ol><li>将一只手在训练笼按住唱首歌/目标棒组合，并用另一只手的奖励。 </li><li>定时器设置为5分钟，按启动，并放置在全球在旁边的手的目标棒的端头。 </li><li>当鼠标显示在全球的利益，请点击并提出旁边的全球奖励。 </li><li>只要鼠标已满足这种挑战，移动地球几个步骤靠近手。 </li><li>将地球上的手掌。单击并同时鼠标坐在手掌（ 图7）奖励。 </li></ol></li></ol>

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The authors have nothing to disclose.

有效实施与男女各12只BALB / c近交系小鼠的队列唱首歌培训协议被证明是简单的。以前的研究已经证实唱首歌培训的效果与几个品种，我们扩展了这个小鼠。由于老鼠是实验动物中最低的开发哺乳动物，他们的能力常常被低估。因此，数据的最令人吃惊的一方面是，训练成功可以与几乎所有小鼠来实现。 此协议中的一个关键步骤是第二加强件，这是为了建立显示行为和加强之间的连接很重要的定时。由于老鼠都非常激动，这是稍显吃力，而他们身边蹦蹦跳跳庆祝一个确切的性能。更有经验的教练，则越快培训成就才能实现。我们观察到，老鼠很快了解到，即使没有经验的火车ERS。即使是小错误可能会在响片训练协议的过程中得到补偿。错误的常见来源包括强化一个错误的行为和缺乏在点击后的食物奖励的兴趣。 一个无法控制的因素是各小鼠的个性。虽然这项研究与近交系小鼠，在同等条件下出生和长大的执行，他们开发了各种不同的人物。由于以前的研究和我们自己的经验数据，我们知道，这包括不同口味，食欲不同的表情，不同的探索行为，29日 ，30。第一个关键步骤是要找到一个合适的食物奖励。小鼠被提供了不同种类的螺母，糖溶液，果酱，和不同类型的巧克力。用于本研究中的小鼠，白巧克力被证明是最合适的奖励。此协议的成功取决于间在训练的老鼠EST。如果什么都引起他们的兴趣越多，培训达到了极限。即加入到笼子履行训练会话的更多的设备，该少的小鼠参加了培训。在周围所有引人注目的项目的淘汰是必要的（ 例如，在笼子里留下的床上用品材料即使是少量，以防止打洞的老鼠）。有时小鼠habituating新环境几分钟后，才能在训练中更多的利益。 柔和处理方案已确定受益小鼠的福祉友善9，10，11时处理。本研究的结果表明，仔细一人与动物的关系，有助于鼠标耐受治疗。在操控，驯兽显示更少的焦虑相关行为（ 我.E，排尿，排便，和发声）31。在莫里斯水迷宫实验，未受过训练的，但轻拿轻放小鼠表达浮动行为的显著发病率较高。训练小鼠显示较少的这抑郁症相关的行为32。可以这样认为，积极的结果是由于在训练小鼠增加的幸福感。 该研究的限制是只有一个近交小鼠品系进行了研究。由于小鼠的不同菌株，附加近交系，以及远交品系之间的高的行为差异，应进行调查29。在进一步的研究中，有关鼠标健康补充信息，例如作为一个整体的行为电池，生理数据（ 例如，皮质酮水平），或对脑发育训练的影响，应该收集。 唱首歌培训的进一步应用可以帮助我ñ改善动物卫生设施和卫生条件。通过施加答题训练协议，我们成功地教学小鼠遵循目标棒和从一个笼过桥到另一个（ 图13）。如果这种技术完善，它使手动笼变化不必要的。此外，老鼠也可能会被训练有素的自愿走路到测量设备（如规模或行为区）。这可以提供对抗anthropozoonotic疾病传播可靠的保护，与动物的直接接触将不再是必需的。 积极强化训练强烈推荐圈养的动物，因为它有利于他们的心理健康33。如果小鼠体验健康水平高，他们几个显示各自不同的应对策略。答题训练，因此，使向3R的一个值得注意的贡献，因为以前的工作表明，在杂物减少小鼠的相容性表型导致必须满足统计要求27的动物的数量减少。这项研究表明，在小鼠中答题训练强烈在早期研究中观察到的具有不同物种34人类小鼠相互作用和比赛结果的降低的恐惧相关。响片训练有更多的潜力，因为它可以被视为认知富集。的广泛实施的实验动物设施的积极强化训练可以对3R原则的宝贵贡献，因为它提炼出保持和小鼠的生物医学研究。

新的细化策略实验室老鼠的发展是一个具有挑战性的任务，有助于3R原则的实验动物科学1的履行（替代，减少和细化）。在细化方面的改进可以进一步促进数以百万计的动物被用于实验目的福祉。因此，需要在该领域的深入研究。这也是一个定义的欧盟指令六十三分之二千零十的目的。指令63分之2010/ EU指出，实验动物的生存经验已得到加强，而且"机构应当建立适合于动物的习惯和培训计划，程序和项目的长度"（第3.7条）2。 而他们被关押和饲养实验，实验动物可以经历许多紧张的情况下。一般，劳动力之间的相互作用atory小鼠和负责人是相当有限的。因此，互相信任的关系就不能发展。这可引起在反应处理增加的焦虑和压力，这是不利的动物3，4，5，6的行为和生理的，因此，福祉。此外，常规进行的实验室程序像一般处理，克制，血液或组织取样可引起应激反应，这可以通过测量不同的参数，如压力荷尔蒙或行为7,8进行检查。它已经显示，处理的程序可以有效地降低朝向研究者焦虑在实验室啮齿动物9，10，11。处理程序，因此可以提高动物条件和可能大大有助于动物福利5。 这项研究的目的是引入小鼠作为特定处理程序积极强化训练。正强化训练是操作性条件反射的一种形式，让研究者塑造动物行为的一种手段。当动物执行所期望的行为，它后面是一个正刺激（这里，食物奖励）。我们的目的是，动物链接奖励到相应的行为。响片训练是使用空调的二级强化物正强化培训的形式，"咔嚓"一唱首歌声音，并已被证明为加强特定的行为12。 更具体而言，点击声用作行为和即将到来的奖励13之间的"时间桥"。培训师点击正是当动物执行所需的行为，没有任何时间延迟14，然后介绍了食物奖励。这增强了奖励行为，这将具有更高的频率来执行。响片训练是广泛与伴侣动物使用，并作出了自己的方式进入实验动物科学，它已与非人灵长类动物13，15，16已成功实施。由于老鼠当操作性条件反射范式的挑战很快就学会相反，引入第二增强剂不应过度紧张他们的认知能力5，17，18，19。 通过引入响片训练小鼠的饲养，我们只能够体验到认知富集。认知富集的设计必须使老鼠用他们的认知技能SOLVE麻烦并得到控制他们的环境20,21。不同种类的几项研究证明认知富集对圈养动物22，23，24福利的积极影响。加强动物与环境挑战成功应对的能力，有助于他们的福利25,26。 此外，如果动物在其一生中会遇到的应力水平较低，它们不易于开发当与发生在生物医学研究中的压力源面临不利的应对策略。因此，始终如一地贯彻认知富集可以向受试者的表型的同质化。这将有助于减少的3R原则，因为它可以减少所需的对象的数目以满足统计要求27。 通过开发可靠的协议，可以轻松集成到饲养实验室老鼠的作息，我们可以显着提高福利的一生经历。

<table><tbody><tr><td>Lid for open housing</td><td>Tecniplast</td><td>GM500LID117</td><td></td></tr><tr><td>SealSAfe Plus top for open housing</td><td>Tecniplast</td><td>GM500400SU</td><td></td></tr><tr><td>Type II long, filter top cages</td><td>Tecniplast</td><td>GM500PFSPC</td><td></td></tr><tr><td>Aspen bedding material&amp;nbsp;</td><td>Lab &amp;amp; Vet Service GmbH</td><td>H0234-300</td><td>Environmental enrichment</td></tr><tr><td>Red polycarbonate Mouse House</td><td>Tecniplast</td><td>ACRE011</td><td>Environmental enrichment</td></tr><tr><td>Tissue papers</td><td>Tork, SCA Hygiene Products GmbH</td><td>290179</td><td>Environmental enrichment</td></tr><tr><td>Food - ssniff M-H Extrudat</td><td>ssniff</td><td>V1126-000</td><td>ad libitum</td></tr><tr><td>Target Stick with Clicker</td><td>Trixie</td><td>2282</td><td></td></tr><tr><td>PVC Tube (Tunnels)&amp;nbsp;</td><td>Thyssen Krupp</td><td>RTPVCU04003005</td><td></td></tr><tr><td>White Chocolate/ white chocolate cream</td><td></td><td></td><td>Company doesn&#039;t matter, preferable organic quality</td></tr><tr><td>Forceps</td><td>FineScienceTools</td><td>&lt;em&gt;e.g.&lt;/em&gt; 11150-10</td><td>Or any other tool to fixate chocolate</td></tr><tr><td>Prism Version 6.0 for Windows&amp;nbsp;</td><td>GraphPad Software</td><td></td><td></td></tr></tbody></table>

introducing clicker training as a cognitive enrichment for laboratory mice

Establishing new refinement strategies in laboratory animal science is a central goal in fulfilling the requirements of Directive 2010/63/EU. Previous research determined a profound impact of gentle handling protocols on the well-being of laboratory mice. By introducing clicker training to the keeping of mice, not only do we promote the amicable treatment of mice, but we also enable them to experience cognitive enrichment. Clicker training is a form of positive reinforcement training using a conditioned secondary reinforcer, the "click" sound of a clicker, which serves as a time bridge between the strengthened behavior and an upcoming reward. The effective implementation of the clicker training protocol with a cohort of 12 BALB/c inbred mice of each sex proved to be uncomplicated. The mice learned rather quickly when challenged with tasks of the clicker training protocol, and almost all trained mice overcame the challenges they were given (100% of female mice and 83% of male mice). This study has identified that clicker training for mice strongly correlates with reduced fear in the mice during human-mice interactions, as shown by reduced anxiety-related behaviors (e.g., defecation, vocalization, and urination) and fewer depression-like behaviors (e.g., floating). By developing a reliable protocol that can be easily integrated into the daily routine of the keeping of laboratory mice, the lifetime experience of welfare in the mice can be improved substantially.

的最重要的步骤，第一和还一个是一个适当的食物奖励的确定。因此，将小鼠提供不同种类的螺母，糖溶液，果酱，和不同类型的巧克力在培养皿中（ 图1）。根据我们的经验，在小鼠表现为白巧克力明显偏好。因此，我们用白巧克力所有进一步的培训过程。 实际培训与男女各12只BALB / c近交系小鼠的队列来实现。所有的小鼠在训练中非常感兴趣。对于培训的成功的评价，我们检查所期望的行为的适当表现:"下面的目标棒"（ 图4）。绝大多数训练有素的老鼠，所有的雌性小鼠和雄性小鼠，跟随目标棒的83％（ 图8）。雌性小鼠显示高对于一般的训练器的动力与整个训练会话更高的频率进行各自的行为。完成4天的训练结束后，雌性小鼠跟着目标棒以每5分钟64次的平均，而雄性小鼠每5分钟显示这种行为只有50倍。在5分钟内，"以下的手掌"的任务是由雌性小鼠和雄性小鼠（ 图9）的35倍，平均55倍进行的。 要检查是否培养了对运动训练小鼠的福祉有积极的影响，我们在完成培训后评估的耐受性操作。因此，我们分析了焦虑相关的行为，而小鼠一手抑制（ 即，抓颈背和尾部的用一只手的基座）15秒。自发排尿，排便和发声的记录。未经训练，但轻拿轻放银鲑每次性生活的12只BALB / c近交系小鼠的RT作为对照组。训练小鼠显示比未受过训练的小鼠焦虑相关行为的显著较低的频率。 （ 图10）。记录链接到处理，同时执行Morris水迷宫试验的发声时，获得了类似的结果（ 图11和12）。训练有素的老鼠吱吱叫比未受过训练的老鼠（ 图11），并发出吱吱声每鼠显著减少吱吱总数显著少。为了进一步探讨这个问题，我们分析了莫里斯水迷宫试验中漂浮的行为。 Morris水迷宫试验中漂浮行为被描述为时间段时将小鼠不是游泳，但仅仅是漂浮在表面上。此抑郁相关浮动行为变成了训练组（ 图12）中显著降低。 图1 展示可能的奖励的。为奖励的呈现六个位置标记在培养皿中。 <img alt="图3" src="/files/ftp_upload/55415/55415fig2.jpg" /> 图2。 鼠标隧道位置。以提高进入隧道鼠标的概率，隧道旁边放置一个笼子壁。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig2large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图3" src="/files/ftp_upload/55415/55415fig3.jpg" /> 图3. 呈现奖励。呈现涂年底外的奖励适当的位置nnel被示出。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig3large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图3" src="/files/ftp_upload/55415/55415fig4.jpg" /> 图4.培训成功。一个训练有素的鼠标跟随目标棒正在受训。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig4large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图5" src="/files/ftp_upload/55415/55415fig5.jpg" /> 图5. 奖励。鼠标在训练过程中旁目标棒奖励。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig5large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> 图6.交流目标棒位置在培训的第二个星期。培训棒的位置，这个示意图中表示。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig6large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图7" src="/files/ftp_upload/55415/55415fig7.jpg" /> 图7. 培训成功。鼠标沿袭目标粘到教练的手中。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig7large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图8" src="/files/ftp_upload/55415/55415fig8.jpg" /> 图8. 培训协议的成功。每次性生活的12只BALB / c近交系小鼠的队列接受了培训。通过训练会话周2的端部:"继靶棒"，所有的雌性小鼠和雄性小鼠的83％成功地克服的挑战。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig8large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图8" src="/files/ftp_upload/55415/55415fig9.jpg" /> 图培训后一周9.所属行为重复。 12 BALB / C 在每次性生活中培育出的小鼠的队列接受了培训。在训练2周的最后一天:"经过一个目标棍"和3:"继目标粘在手"，各自的行为重复5分钟训练期间进行计数。在这两个星期，雌性小鼠显示终端ayed强化行为有显著频率高于雄性小鼠（"目标棒":63.92±3.72，P = 0.0300;"在手":54.92±4.01，P = 0.0069）。强化行为的频率没有显著雌性小鼠从两个每天都会有所改变到三个星期然而，雄性小鼠表现出重复三个星期显著下降两个周（"目标棒":50.42±4.48;"在手":35.92±5，P = 0.0408）。被执行的曼 - 惠特尼U检验。数据的结果表示为平均值±SEM <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig9large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图8" src="/files/ftp_upload/55415/55415fig10.jpg" /> 图10显示的行为由颈背控股触发。 12 BALB / c小鼠每个s近交系小鼠的队列<html>前练得继响片训练协议。 12只BALB / c每个性别的近交系小鼠的未受过训练的，但轻拿轻放队列作为对照组。小鼠一手抑制（ 即，抓颈背和尾部的用一只手的基座）15秒。自发排尿，排便，和发声的记录。有经训练的显示行为和对照组之间的深刻差。训练小鼠显示的所有行为，比未受过训练的小鼠显著较低的频率。 （"排尿":P &lt;0.001;"排便":P &lt;0.001;"发声":P &lt;0.001）。被执行的曼 - 惠特尼U检验。列被表示为所有受试小鼠的百分比。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig10large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> 图8"SRC ="/文件/ ftp_upload / 55415 / 55415fig11.jpg"/&gt; 图11显示的行为Morris水迷宫测试过程中。 12只BALB / c每个性别的近交系小鼠的队列接受了培训后的响片训练协议。 12只BALB / c每个性别的近交系小鼠的未受过训练的，但轻拿轻放队列作为对照组。 Morris水迷宫测试训练的第三个星期后所有小鼠进行的。联系到处理浮动行为和发声的记录。浮动的行为发生在训练小鼠（P &lt;0.001）显著少。另外，有一个在训练有素的发声和对照组深刻的差异。当比未受过训练的对照组（P &lt;0.001）处理的小鼠运动训练小鼠尖叫显著少。被执行的曼 - 惠特尼U检验。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig11large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> 图12.流行每只小鼠的尖叫声。 12只BALB / c每个性别的近交系小鼠的队列接受了培训后的响片训练协议。 12只BALB / c每个性别的近交系小鼠的未受过训练的，但轻拿轻放人群作为对照组。 Morris水迷宫测试训练的第三个星期后所有小鼠进行的。链接到小鼠的处理的发声被记录下来。未经训练的老鼠往往比训练小鼠显著尖叫。未经训练的老鼠显示发声1.167±0.7倍，未受过训练的老鼠4.071±0.83倍。进行非配对t检验与韦尔奇的校正。数据的结果表示为平均值±SEM <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig12large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> &lt;p系列="jove_content"FO: - together.within页保留="1"&gt; <img alt="图13" src="/files/ftp_upload/55415/55415fig13.jpg" /> 图13.进一步应用。鼠标跟随的目标棍子从一个笼子里过桥到另一个。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55415/55415fig13large.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

Watch this Scientific Journal Video about Introducing Clicker Training as a Cognitive Enrichment for Laboratory Mice at JoVE.com

Introducing Clicker Training as a Cognitive Enrichment for Laboratory Mice

The development of new refinement strategies for laboratory mice is a challenging task that contributes towards fulfilling the 3R principle. This protocol introduces clicker training as a cognitive enrichment program for laboratory mice.

引进响片训练为实验室老鼠认知富集

Establishing new refinement strategies in laboratory animal science is a central goal in fulfilling the requirements of Directive 2010/63/EU. Previous ...

introducing-clicker-training-as-cognitive-enrichment-for-laboratory

Nanyang Technological University

Research

JoVE Journal

Behavior

12.8K 次观看.  Johannes Gutenberg-Universität Mainz. The development of new refinement strategies for laboratory mice is a challenging task that contributes towards fulfilling the 3R principle. This protocol introduces clicker training as a cognitive enrichment program for laboratory mice. 

视频: Introducing Clicker Training as a Cognitive Enrichment for Laboratory Mice

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 ...

科研

行为学

A Fully Automated Rodent Conditioning Protocol for Sensorimotor Integration and Cognitive Control Experiments

Rodents have been traditionally used as a standard animal model in laboratory experiments involving a myriad of sensory, cognitive, and motor tasks. Higher cognitive functions that require precise control over sensorimotor responses such as decision-making and attentional modulation, however, are typically assessed in nonhuman primates. Despite the richness of primate behavior that allows multiple variants of these functions to be studied, the rodent model remains an attractive, cost-effective alternative to primate models. Furthermore, the ability to fully automate operant conditioning in rodents adds unique advantages over the labor intensive training of nonhuman primates while studying a broad range of these complex functions.
Here, we introduce a protocol for operantly conditioning rats on performing working memory tasks. During critical epochs of the task, the protocol ensures that the animal's overt movement is minimized by requiring the animal to 'fixate' until a Go cue is delivered, akin to nonhuman primate experimental design. A simple two alternative forced choice task is implemented to demonstrate the performance. We discuss the application of this paradigm to other tasks.

A fully automated protocol for rodent operant conditioning is proposed. The protocol relies on precise temporal control of behavioral events to investigate the extent to which this control influences neural activity underlying sensorimotor integration and cognitive control experiments.

为感觉运动整合与认知控制实验完全自动化的啮齿动物调理协议

Rodents have been traditionally used as a standard animal model in laboratory experiments involving a myriad of sensory, cognitive, and motor tasks. ...

The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice

Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain&#160;to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders. However, preclinical behavioral assays used to assess these deficits in mouse models which can be readily manipulated genetically and could provide the basis for studies of new treatment avenues have been underutilized. Here we describe the adaptation of a behavioral assay, the attentional set shifting task (AST), to be performed in mice to assess prefrontal cortex mediated cognitive deficits. The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents, providing excellent face, construct and predictive validity.

The goal of this protocol is to perform a behavioral assay such as the attentional set shifting task (AST) to assess prefrontal cortex-mediated cognitive flexibility in mice.

在注意定势转移任务:测量小鼠认知的灵活性

Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many ...

Operant Sensation Seeking in the Mouse

Operant methods are powerful behavioral tools for the study of motivated behavior. These 'self-administration' methods have been used extensively in drug addiction research due to their high construct validity. Operant studies provide researchers a tool for preclinical investigation of several aspects of the addiction process. For example, mechanisms of acute reinforcement (both drug and non-drug) can be tested using pharmacological or genetic tools to determine the ability of a molecular target to influence self-administration behavior1-6. Additionally, drug or food seeking behaviors can be studied in the absence of the primary reinforcer, and the ability of pharmacological compounds to disrupt this process is a preclinical model for discovery of molecular targets and compounds that may be useful for the treatment of addiction3,7-9. One problem with performing intravenous drug self-administration studies in the mouse is the technical difficulty of maintaining catheter patency. Attrition rates in these experiments are high and can reach 40% or higher10-15. Another general problem with drug self-administration is discerning which pharmacologically-induced effects of the reinforcer produce specific behaviors. For example, measurement of the reinforcing and neurological effects of psychostimulants can be confounded by their psychomotor effects. Operant methods using food reinforcement can avoid these pitfalls, although their utility in studying drug addiction is limited by the fact that some manipulations that alter drug self-administration have a minimal impact on food self-administration. For example, mesolimbic dopamine lesion or knockout of the D1 dopamine receptor reduce cocaine self-administration without having a significant impact on food self-administration 12,16. 
Sensory stimuli have been described for their ability to support operant responding as primary reinforcers (i.e. not conditioned reinforcers)17-22. Auditory and visual stimuli are self-administered by several species18,21,23, although surprisingly little is known about the neural mechanisms underlying this reinforcement. The operant sensation seeking (OSS) model is a robust model for obtaining sensory self-administration in the mouse, allowing the study of neural mechanisms important in sensory reinforcement24. An additional advantage of OSS is the ability to screen mutant mice for differences in operant behavior that may be relevant to addiction. We have reported that dopamine D1 receptor knockout mice, previously shown to be deficient in psychostimulant self-administration, also fail to acquire OSS24. This is a unique finding in that these mice are capable of learning an operant task when food is used as a reinforcer. While operant studies using food reinforcement can be useful in the study of general motivated behavior and the mechanisms underlying food reinforcement, as mentioned above, these studies are limited in their application to studying molecular mechanisms of drug addiction. Thus, there may be similar neural substrates mediating sensory and psychostimulant reinforcement that are distinct from food reinforcement, which would make OSS a particularly attractive model for the study of drug addiction processes. The degree of overlap between other molecular targets of OSS and drug reinforcers is unclear, but is a topic that we are currently pursuing. While some aspects of addiction such as resistance to extinction may be observed with OSS, we have found that escalation 25 is not observed in this model24. Interestingly, escalation of intake and some other aspects of addiction are observed with self-administration of sucrose26. Thus, when non-drug operant procedures are desired to study addiction-related processes, food or sensory reinforcers can be chosen to best fit the particular question being asked. 
In conclusion, both food self-administration and OSS in the mouse have the advantage of not requiring an intravenous catheter, which allows a higher throughput means to study the effects of pharmacological or genetic manipulation of neural targets involved in motivation. While operant testing using food as a reinforcer is particularly useful in the study of the regulation of food intake, OSS is particularly apt for studying reinforcement mechanisms of sensory stimuli and may have broad applicability to novelty seeking and addiction.

In this protocol we describe a method of operant learning using sensory stimuli as a reinforcer in the mouse. It requires no prior training or food restriction, and it allows the study of motivated behavior without the use of a pharmacological or natural reinforcer such as food.

在鼠标的操作性感觉寻求

Operant methods are powerful behavioral tools for the study of motivated behavior.  These 'self-administration' methods have been used extensively in drug ...

神经科学

Quantifying Social Motivation in Mice Using Operant Conditioning

In this protocol, social motivation is measured in mice through a pair of operant conditioning paradigms. To conduct the experiments, two-chambered shuttle boxes were equipped with two operant levers (left and right) and a food receptacle in one chamber, which was then divided from the second chamber by an automated guillotine door covered by a wire grid. Different stimulus mice, rotated across testing days, served as a social stimulus behind the wire grid, and were only visible following the opening of the guillotine door. Test mice were trained to lever press in order to open the door and gain access to the stimulus partner for 15 sec. The number of lever presses required to obtain the social reward progressively increased on a fixed schedule of 3. Testing sessions ended after test mice stopped lever pressing for 5 consecutive minutes. The last reinforced ratio or breakpoint can be used as a quantitative measure of social motivation. For the second paradigm, test mice were trained to discriminate between left and right lever presses in order to obtain either a food reward or the social reward. Mice were rewarded for every 3 presses of each respective lever. The number of food and social rewards can be compared as a measurement of the value placed upon each reward. The ratio of each reward type can also be compared between mouse strains and the change in this ratio can be monitored within testing sessions to measure satiation with a given reward type. Both of these operant conditioning paradigms are highly useful for the quantification of social motivation in mouse models of autism and other disorders of social behavior.

This article describes a new protocol for the quantitative measurement of social motivation in mice using operant conditioning for a social reward. The protocol is useful for the measurement of social motivation in mouse models of autism and other disorders of social behavior.

量化的社会动机小鼠使用操作条件反射

In this protocol, social motivation is measured in mice through a pair of operant conditioning paradigms. To conduct the experiments, two-chambered ...

A Fully Automated and Highly Versatile System for Testing Multi-cognitive Functions and Recording Neuronal Activities in Rodents

We have developed a fully automated system for operant behavior testing and neuronal activity recording by which multiple cognitive brain functions can be investigated in a single task sequence. The unique feature of this system is a custom-made, acoustically transparent chamber that eliminates many of the issues associated with auditory cue control in most commercially available chambers. The ease with which operant devices can be added or replaced makes this system quite versatile, allowing for the implementation of a variety of auditory, visual, and olfactory behavioral tasks. Automation of the system allows fine temporal (10 ms) control and precise time-stamping of each event in a predesigned behavioral sequence. When combined with a multi-channel electrophysiology recording system, multiple cognitive brain functions, such as motivation, attention, decision-making, patience, and rewards, can be examined sequentially or independently.

In this report, we present a fully automated and highly versatile system capable of simultaneously testing multi-cognitive behaviors and recording neuronal activities for rodents.

一个多认知功能测试，并记录在啮齿动物的神经元活动的完全自动化和高度灵活的系统

We have developed a fully automated system for operant behavior testing and neuronal activity recording by which multiple cognitive brain functions can be ...

Using Clicker Training and Social Observation to Teach Rats to Voluntarily Change Cages

Cage cleaning is a routinely performed husbandry procedure and is known to induce stress in laboratory rats. As stress can have a negative impact on well-being and can affect the comparability and reproducibility of research results, the amount of stress experienced by laboratory animals should be minimized and avoided when possible. Further, the direct contact between the rat and animal caretaker during the cage change bears hygiene risks and therefore possibly negatively impacts the well-being of the rats and the quality of the research. 
Our protocol aims to improve the routinely performed cage changing procedure. For this reason, we present a feasible protocol that enables rats to learn via clicker training and observation to voluntarily change to a clean cage. This training helps to reduce stress caused by the physical disturbance and handling associated with the cage changes and concurrently enables a reduction in direct contact between animal and animal caretaker after the training phase is completed.
The implementation of clicker training to rats is fast and easy. Rats are generally interested in the training and efficiently learn the desired behavior, which entails changing cages through a pipe. Even without training, the rats learn to perform the desired behavior by observation, as 80% of the observational learning group successfully changed cages when tested. The training further helps to establish a relationship of trust between trainer and animal. As hygiene and well-being are both very important in animal experiments, this protocol might also help to improve high-quality research.

This protocol introduces a method of cage change for rats via clicker training. Rats learn the desired behavior not only by direct training but also by observational learning. The implementation of this fast and easy protocol might help to improve well-being and hygiene in rodent facilities.

用小鼠训练和社会观察教老鼠主动改变笼子

Cage cleaning is a routinely performed husbandry procedure and is known to induce stress in laboratory rats. As stress can have a negative impact on ...

Evaluating Skilled Prehension in Mice Using an Auto-Trainer

We describe a method to introduce na&#239;ve mice to a novel prehension (reach-to-grasp) task. Mice are housed singly in cages with a frontal slot that permits the mouse to reach out of its cage and retrieve food pellets. Minimal food restriction is employed to encourage the mice to perform the food retrieval from the slot. As the mice begin to associate coming to the slot for food, the pellets are manually pulled away to stimulate extension and pronation of their paw to grasp and retrieve the pellet through the frontal slot. When the mice begin to reach for the pellets as they arrive at the slot, the behavioral assay can be performed by measuring the rate at which they successfully grasp and retrieve the desired pellet. They are then introduced to an auto-trainer that automates both the process of providing food pellets for the mouse to grasp, and the recording of successful and failed reaching and grasping attempts. This allows for the collection of reaching data for multiple mice with minimal effort, to be used in experimental analysis as appropriate.

Method to assess the impact of training on motor skills is a useful tool. Unfortunately, most behavioral assessments can be labor intensive and/or expensive.We describe here a robotic method of assessing prehension (reach-to-grasp) skill in mice.

使用自动训练器评估小鼠的熟练前向

We describe a method to introduce na&#239;ve mice to a novel prehension (reach-to-grasp) task. Mice are housed singly in cages with a frontal slot that ...

基于正强化的常规兔子饲养程序训练

Training Laboratory Rabbits to Refine Routine Husbandry Procedures

Non-aversive handling and training techniques for laboratory animals are required to facilitate experimental and routine husbandry procedures, improving both animal welfare and scientific quality. Clicker training was utilized to develop training protocols for rabbits to refine stressful routine husbandry procedures usually associated with lifting (i.e., being picked up from the floor)/restraining (i.e., being held in the arms of a human) them. Thirteen female New Zealand White rabbits were trained over three weeks. All rabbits learned the predefined goal behaviors: they followed the target stick, jumped onto the weighing scale, entered a transport box, and reared while placing their front paws onto the trainer&#39;s hand. In addition, ten animals jumped from the floor onto the sitting trainer&#39;s lap and allowed the trainer to lift their paws off the surface while sitting on the trainer&#39;s lap. For some individuals, the protocols had to be adapted by additional interim steps. At the end of the training, the rabbits reliably showed the expected goal behaviors, even after short and long training breaks. With few exceptions, a familiar person other than the trainer could elicit the goal behaviors from the rabbits (generalization), though further sessions were required for generalization. In the voluntary approach test, the rabbits preferred interacting with the trainer in the 1st trial but spent as much time with an unfamiliar person as with the trainer in the 2nd trial. The behavioral observations suggested that picking the rabbits up with the transport box, as described in the protocol, instead of restraining them with the scruff of their neck and lifting them on the arm, was less aversive. All in all, the training protocols were feasible and can serve as a refinement strategy in laboratory animal facilities. In the interest of animal welfare, the training protocols should be applied wherever possible.

作者聚焦：训练实验动物进行轻柔、无压力的处理

Training protocols involving positive reinforcement for routine husbandry procedures in rabbits were developed and proved to be successful, as the rabbits reliably showed the trained behaviors at the weekly general examination. Picking the rabbits up with the transport box was less aversive than the conventional handling technique.

训练实验兔改进常规饲养程序

Non-aversive handling and training techniques for laboratory animals are required to facilitate experimental and routine husbandry procedures, improving ...

引进响片训练为实验室老鼠认知富集

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此视频中的章节

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

为感觉运动整合与认知控制实验完全自动化的啮齿动物调理协议

在注意定势转移任务:测量小鼠认知的灵活性

在鼠标的操作性感觉寻求

量化的社会动机小鼠使用操作条件反射

一个多认知功能测试，并记录在啮齿动物的神经元活动的完全自动化和高度灵活的系统

用小鼠训练和社会观察教老鼠主动改变笼子

使用自动训练器评估小鼠的熟练前向

训练实验兔改进常规饲养程序

训练实验兔改进常规饲养程序