This research was supported by the Israel Science Foundation (grant No. 592/12) to DJ

注:所有的实验方案符合特拉维夫大学，以色列的机构动物护理和使用委员会的指导方针，并在NIH的指导方针。所作的所有努力，尽量减少使用动物和他们的痛苦的数量。 1.动物准备<ol><li>房子只在一个房间里有12小时的光/暗周期。 </li><li>在实验过程保持大鼠与免费提供水22小时的食物限制的时间表。 </li><li>每周称重大鼠两次，以确保他们的体重不减少到90％以下的自由喂养的大鼠的重量的基础上，生长曲线（ 例如，哈兰， <a href="http://www.harlan.com/models/spraguedawley.asp" target="_blank">http://www.harlan.com/models/spraguedawley。 ASP</a> ）。排除老鼠的体重减少。 </li></ol> 2.建立<ol><li>使用两个相邻的房间。一个被用作"候车室"F或之前保持大鼠行为测试，另一个用于实施该过程。这间客房将房子的操作性商会。 注:确保只在候车室都没有接触到的操作性商会产生的音调。 </li><li>使用操作室与电网地板和美食杂志，它提供了通过铰链有机玻璃面板访问1 45毫克的食物颗粒。 注:打开的铰链的激活微动开关;一个3瓦的光照亮食品杂志; 2伸缩杆（4厘米宽，位于2.8厘米从侧壁，7.5厘米的食品盒每侧和5厘米的层）;位于天花板上的一所房子的光来照亮腔室;音频信号设备产生80分贝2.8 kHz音频。 </li><li>座位声音衰减箱操作室与换气扇安装在每个盒子的侧面。 </li><li>在实验前的开始时，预先计划的所有训练与精确的会话参数的阶段S表示每个阶段使用一个指定的软件，该计算机控制和激活操作室以及自动相关记录在实验运行过程中积累的所有相关数据。 注意:参数为每个训练阶段（杂志训练，杠杆压训练，信号衰减，试验）都充分详述如下。确切的方式中，这些参数被预编程取决于软件和硬件的使用。 </li></ol> 3.处理和食品的限制<ol><li>处理的大鼠进行约2分钟，每日，之前的实验程序的开始5天。 </li><li>推出了22小时的食品限制的时间表开始在处理的第一天。让大鼠处理/行为训练结束后，早于半个小时在他们的家笼没有获得食物2小时。 注:确保有老鼠的时候在他们的家笼，特别是在2小时feedi水自由采食吴时期，因为他们不会好好吃饭不喝水。 </li><li>在处理的最后3天，放置20 - 30食物颗粒在一个小托盘并将在大鼠家笼的托盘。从笼中取出托盘后才每只大鼠已经观察到消耗的至少两个颗粒。 注:后来，使用颗粒作为加固操作性的培训。 </li></ol> 4.培训过程<ol><li>为了使大鼠获得适应于测试环境中，运输将大鼠在其家笼中至少15分钟前行为测试在候车室。 </li><li> 杂志培训（天1 - 3）。 <ol><li>弹匣训练的第1天，把食物颗粒足够量的在食品杂志，以便它们是可见的老鼠。 注意:这样做的一种方式是使它们所造成的铰接有机玻璃面板保持稍微打开以放置粒料。 </li><li>计算该杂志的训练计划，这样的房子LIGHT在每个试验和单个食物丸的开始自动开启落入食品杂志以下一个5秒的可变延迟，与化合物的刺激选自由杂志光和音的开始同时进行。 </li><li>计算复合刺激和房屋光关闭老鼠的头部进入食品杂志（收集试行）或15秒（未收试行），以先到者为准之后后。定义每个试验应遵循的一个30秒的试验间隔。 </li><li>将老鼠进入操作室，5分钟后手动验证所有的老鼠都收集到的颗粒。如果是这样，启动培训计划。如果不是，允许额外的5分钟。 </li><li>节目杂志训练停止运行后，无论是鼠已完成30所收集的试验或总共40试验后，已经实现。 </li><li>在杂志的训练的第三天确保老鼠进行30试验收集了共32的t里亚尔在最。返回老鼠未能在训练一天结束时达到这一标准的操作性商会的另一个完整的培训课程。 注:运行老鼠无法达到这个标准以下的在杠杆记者培训的第一天上午的训练杂志的最后一天，一个额外的会话。排除老鼠无法达到标准。 </li></ol></li><li> 杠杆记者培训-前培训阶段（4天）:在一个自由操作性的时间表杆压。 <ol><li>把老鼠的操作性商会前启动的培训计划。计算程序，以便在加强杆是存在于室内，整个训练期间，非增强杆总是缩回屋内灯亮。 注:抗衡杆（左/右）横跨鼠的侧，并保持恒定在整个实验过程中的每个鼠。 </li><li>把一些小球上的杠杆，并把一只老鼠进入室中。 </li><li>允许大鼠探索杠杆面积，直到它捎带按压杠杆同时收集粒料，触发单个食物颗粒的递送和化合物刺激的发作。 </li><li>计算使该化合物刺激老鼠的头部后，关闭进入食品杂志（建成试）或15秒（未完成的试验）后，以先到者为准程序。 </li><li>程序会停止运行后，老鼠已经达到了30完成试验。 </li><li>如果一只老鼠没有在30分钟内达到这一标准，把3 - 4球团矿的杠杆，并等待20分钟。如果一只老鼠未能完成30次试验，在每天训练结束就返回操作性室进行额外的培训。 注:运行老鼠无法达到这一标准对杠杆记者培训的第一天上午再次下额外的预培训。排除老鼠无法达到标准。一般情况下，几乎所有的RATS收购杆压前培训3届之后（最要做的第一届内）。但是，如果动物有收购杠杆压，利用整形更多的困难。 </li><li>在塑造，保持声音衰减箱的门打开，观察大鼠在操作性室。当大鼠接近杆用软件来激活一个食物丸的递送和化合物刺激的发作。如此反复做。 </li><li>在开始时，加强大鼠时，它是在杆的附近，但逐渐开始增强它，只有当它与杠杆实际物理接触，最后加强仅试图按下。 注:整形可能需要一段时间。要尽量保持安静。 </li></ol></li><li> 杠杆记者培训（天5 - 7）:在离散审判时间表杆压。 <ol><li>计算程序，使每个试验的开始是由家光，5秒的发作信号后，无论是杆被引入室中。 </li><li>确保在非增强杆（NRL）的反应对加固杆没有编程的后果，并引发印刷机的单一食物颗粒进入该杂志的交付，与化合物刺激的呈现在一起。 </li><li>后大鼠的头进入食物杂志或之后15秒已经过去了杆缩回和化合物的刺激和房子光截止。 </li><li>定义每个试验，以便它后面是30秒试验间隔。上的杠杆压训练（第5天）定义的化合物刺激的第一天，以进行15秒后，以促进采集杆压响应的关闭。在随后两天（天6 - 7）定义的化合物的刺激，以仅持续10秒，以确保暗盒条目紧随杠杆压响应。 </li><li>放置在操作室的老鼠，然后启动培训计划。 </li><li&gt;程序杠杆压训练会话停止运行或者后大鼠按压了增强杆（RL）和收集的食物小丸（已完成试验）的40倍或总共60试验已经实现之后。 </li><li>对杠杆记者培训的最后一天，确保完成老鼠最40试验在总共42总试验的。如果大鼠无法达到该标准，在一天结束时将其返回到操作性室额外训练会话。 注:排除老鼠是无法达到这个标准以下的杠杆，按培训的最后一天额外的会话。 </li><li>对杠杆记者培训记录的最后一天unrewarded杠杆压力机每次试验的数量， 即印刷机之后的RL（额外杠杆压力机）的第一个响应的数量。 </li><li>随机分配的大鼠的实验组。 </li><li>当在试验阶段的时间进行的实验操作（ 例如，在研究测试药物的急性作用），使用方差（ANOVA）与操控的主要因素（与操作分析/无操作）和过程（培训后的信号衰减，PTSA /常规灭绝，RE， 见4.5）来分析过度杠杆压力机随后沉淀收集的数目（称为过度杠杆压力机完成的，ELP-C）和上杆压训练信号衰减阶段开始前的最后一天未压制试验。 </li><li>保证有在这一措施的组间差异无统计学差异显著。 注意:通常情况下，只有少数的大鼠具有高数目的额外的杠杆压力机，所以比较各组在没有这些影响。此外，确保老鼠接受额外的培训分布在组之间尽可能均匀。 </li></ol></li><li> 信号衰减/常规灭绝（天8 - 10）。 <ol><li>运行过程中一个IDEntical方式周刊培训天1 - 3有两个例外: <ol><li>清空粒料分配器，使得以下的化合物刺激的发生没有食物丸被输送到食物杂志。 </li><li>程序有关的阶段，使化合物刺激10秒后关闭，并且不经过1​​5秒。 </li></ol></li><li>确保两个RL和NRL的训练过程中保持缩回。 </li><li>确保每个信号衰减的培训会议，包括30次试验。在培训的最后一天，确保老鼠试图收集食物颗粒（ 即，将其头部进入食品杂志社继复合刺激发病）不超过14次。 </li><li>返回老鼠失败在这一天结束时达到这一标准的操作性商会额外训练。 注:不排除老鼠未能在这个阶段要达到的标准。 </li><li>把接受正规灭绝的老鼠"等待室"，离开他们在他们的家笼的期间相当于该信号的衰减阶段的平均持续时间。 </li><li>使用混合ANOVA与操控的主要因素（与操作/无操作）和过程（PTSA / RE）和会话的重复测量因子（会话1 - 3）来分析信号的三个交易日完成试验的次数衰减阶段。 </li><li>确保在测试阶段中的性能差异不是较早差异的结果。 </li></ol></li><li> 测试（11天）:运行以相同的方式，以杠杆压训练方法，但消光的条件下，也就是说 ，按压RL结果中的化合物刺激的呈现，但没有食物被输送到食物杂志，因为球团分配器是空的。 <ol><li>计算测试环节，以包括50试验的男性和60试验的女性，因为通常女性仍然respo次后50次试验。然而，如果两种性别均在同一研究中（推荐）使用，然后再给60试验的所有受试者。 </li><li>收集的过度杠杆压力机没有后跟杂志条目（命名为过度杠杆压力机-未完成，ELP-U）的数量;过度杠杆压力机其次是杂志的条目（ 即 ELP-C）的数量;对NRL杠杆按压的次数;和鼻捅数（ 即，多少次的大鼠插入其头部进入食品杂志。 </li><li>分析大鼠上采用方差（ANOVA）与操控的主要因素的分析测试阶段的表现（与操作/无操作）和过程（PTSA / RE）在ELP-C，ELP-U，数数进行完成后，未完成的和未压制的试验，以及鼻捅和压力机对非增强杆的数目。 </li><li>按照与事后分析比较，治疗组的Wi显著的相互作用TH未处理/对照组中，每个过程内。 注意:当不知道该操作的确切参数（ 例如，相关的药物剂量，电刺激的参数），并且为了减少动物的数量，测试该操纵PTSA过程中的作用只，采用不同的参数（ 例如，使用多个药物剂量）。 </li><li>找到最优的参数，即，施加ELP-U的数目的影响最大的参数，而不消除行为响应，并且然后运行一个完整的实验设计（PTSA和RE）。 </li></ol></li></ol>

The authors have nothing to disclose.

强迫症的信号衰减大鼠模型是一个强大的行为模式的强迫样行为的研究。该模型显示较高的脸，预测和构想效度20,21，并已被广泛用于研究的这种行为39,43-45,48神经基板，其应对药理操纵38,39,43,47,53， 54和深部脑刺激40,46,50和调制卵巢激素51。因此，这种模式是一种有用的动物模型，强迫症的研究。 强迫杆压在信号衰减模型比其他实验性重复行为（如消爆和固着行为）几个优点。首先，强迫性杠杆按压到强迫行为在人类中已经确立，而其他的重复行为，它们通常被称为强迫状，有效性相关性是低的，或从来没有过测试20-22。值得注意的是，行为重复/ perseveration是一种现象，各种精神疾病55-62，因此共享，目标行为强迫般的适当的验证是至关重要的。此外，PTSA过程中收集到的各种行为的措施（ 即在非增强杆或一般数量印刷机的数量鼻子戳老鼠在测试阶段执行）消除替代解释为强迫性的差异帮助杆按压在组之间进行测试。例如，过度的杠杆按压可以反映一个普遍增加运动活动，在这种情况下，将最有可能伴随着增加的非增强杠杆压力机的数量（因而，该措施也消除了需要测试大鼠在附加程序，例如旷场试验）。另一方面，操纵这导致在鼻p的数​​目的普遍增加澳克士老鼠进行可能导致减少强迫杆压，即使他们不具备真正的抗强迫作用。甚至在测试收集额外的措施（在过度杠杆压训练阶段杠杆压力机，在信号的衰减阶段完成试验）允许实验者消除的可能性，在测试阶段，源于以前的不同群体之间的差异学习。值得注意的是，在该过程的不同阶段所收集的全部措施是定量的，并因此无偏，不给予主观解释，不受间实验者变性。 信号衰减模型的一个缺点是它需要特殊的设备（计算机操作的操作性盒，对于这些框的操作适当软件等 ）的事实。这使得既昂贵又有点复杂来执行，需要技能型人才，精通无论是在广告典当排除故障，并在每天的日常维护设备。另外，因为该模型基于学习而不是自发行为，并且因为它是由多个阶段的，它是相对耗时的（11天）相比，一些OCD的其它动物模型。然而，在我们的经验，用适当的培训需要执行的程序是很容易获得的专业知识。此外，因为所有的设备是计算机控制的，几乎完全自动的，大组大鼠可以有效地和同时运行，从而减少它的时间成本。此外，结果很容易计算出来，并且不需要人工编码或任何特殊的处理。最后，操作性框是高度通用的，一旦获得，它们可用于各种行为的程序，除了信号衰减，这使得它们非常具有成本效益。 另一个要考虑的，它应在使用被考虑模型，是由于它的冗长的和多级的性质，它可能不适合用于慢性治疗或发育的研究。为了不影响大鼠的学习，在行为过程的初始阶段中，慢性治疗的给药要求中的步骤，这使得该过程更加耗时的休息。此外，这种断裂不能立即测试阶段之前发生，因此，大鼠施用的慢性治疗将经历信号衰减阶段，而治疗的影响，甚至在测试阶段可以改变他们的行为，使的任何解释下结果有问题。关于发育研究，同样，由于模型的冗长的性质，就不可能将其用于极幼鼠（ 例如，年龄小于46天龄的大鼠上的测试天）。此外，老鼠不能被重新测试，使得必须培养新的老鼠在每个年龄研究，不包括possibilitŸ采用纵向设计。 以上已经提及的信号衰减模型的一个重要方面是，强迫杠杆按压由在卵巢激素水平沿大鼠发情周期51的波动调制。这一方面是对研究者兴趣研究由雌性性腺激素影响强迫行为的机制很重要。虽然对强迫杆压未经测试的男性性腺激素的影响，这些或其他因素的影响男性表现的模型，在模型中的不同应对措施的变化是在雄性和雌性大鼠51相似。因此，研究人员，不打算研究性腺激素的作用，谁可以使用雄性和雌性大鼠没有测量这些激素的水平。 总之，尽管强迫症的信号衰减的大鼠模型的一些缺点，例如它的长度和事实上，它需要特殊的设备和一些技术知识，它提供了评估在大鼠强迫行为的敏感和可靠的方式。此外，它可以将这些行为和其他重复性/固着的行为，这是不本质上真正强迫区分。因此，它是用于推定抗强迫治疗评估的优良模型，研究采用它可以用来扩大强迫症的神经基质，这仍不能很好地理解的知识。

强迫症（OCD）是一个主要的精神病学障碍是体现在1 -一般人群1,2的3％。人患强迫症有反复，侵入和不必要的想法（执着）和/或重复的仪式行为（强迫）3。基本OCD的具体病理机制尚不完全清楚。然而，血清素4-7，多巴胺8,9和谷氨酸10系统的参与已被证明在这混乱。此外， 眶额皮质，扣带皮质，基底节和地区顶叶内有牵连其病理生理学7,11-13。最后，在卵巢激素水平相关的波动生活事件（ 例如，生育，排卵）已经报道以触发或加剧的OCD女性患者14-16，这表明&lt;EM&gt;卵巢激素发挥OCD 17的调节作用。 因为底层OCD机制知之甚少，使用合适的动物模型，密切模仿其行为和神经表现为推进我们的生物学基础知识是必不可少的。此外，这些模型有助于治疗的新行的开发。这是在强迫症的情况下，特别是相关的，因为许多患者要么治疗性或经验的症状18,19只有部分减轻。事实上，在最近几年，强迫症（在20-28综述）的遗传，药理和行为动物模型已经扩大，提高了我们这种疾病的知识。 一个OCD的最广泛使用的行为动物模型的信号衰减大鼠模型（综述见29）。该模型背后的理论假设是，在反馈的赤字相关与目标导向行为的成功表现导致强迫性的响应30-37。该模型由乔尔和他的同事28开发的，是基于对大鼠操作行为。在最初的培训，只奖励与按杠杆后的食物颗粒。另外一个成功的杠杆压触发的一本杂志光线和色调的发作。这提供了反馈，该杠杆压响应，导致食品的交付大鼠。接着，将刺激信号的奖励的递送的能力被有意降低反复呈现它而不奖励（重要的是，也有在箱子没有杠杆在此阶段）。强迫式的行为出现在训练的最后阶段。在此测试阶段，这是消光条件下进行，杆压榨之后是刺激的呈现，但不是食物奖励。 "强迫"行为表现为多个杠杆印刷机之后，老鼠母鹿不是尝试收集奖励。抗/亲强迫效果表示为减少/增加的"强迫"杠杆按压次数。由于信号衰减包括消光，它和之间的消光本身的信号衰减的影响，以区分是重要的。因此，在对照组（正常消光基团）的化合物的刺激之前不测试阶段衰减。治疗具有抗/亲强迫效果不应该改变的"强迫"杠杆压力机在该组中的号。 （了解更多详细信息，请参阅第29）。 "强迫"杠杆压力机通过模仿强迫症患者显示的强迫行为的夸张和不必要的性质。因此，信号衰减模型显示良好的表面效度。此外，在该模型进行的研究表明，它具有良好的预测和建构效度（在20,21中综述）。该模型的P从研究表明该强迫杠杆按压通过已知改善强迫症状38,39，以及由底丘脑核40，其已被发现的高频刺激药物减毒redictive有效性导出到具有抗强迫在人类强迫症患者41,42的效果。此外，一些药物，是低效强迫症的治疗中已经发现没有施加在模型38,39抗强迫作用。该模型还显示良好的结构效度，因为研究表明，类似的神经机制参与无论是在强迫症症状，并在大鼠信号衰减引起的强迫式的行为。因此，血清素能43-46，多巴胺39,46和谷氨酸能系统47的参与，以及强迫症有关的大脑区域的40,44,48-50已被证明在强迫杠杆按压的参与。此外，卵巢激素已被发现调节强迫杆压在女性51。因此，信号的衰减模型是一个功能强大的工具，探索强迫症的神经基质和用于筛选新的抗强迫疗法。对于信号衰减模型的临床相关性以及它的实用性和应用OCD研究的深入讨论，请参阅20-22,29。

<table><tbody><tr><td>Modular test chamber for rats</td><td>Campden Instruments Ltd.</td><td>Model 80003M</td><td></td></tr><tr><td>Pellet trough for modular chamber</td><td>Campden Instruments Ltd.</td><td>Model 80210M-R</td><td>with head entry and door</td></tr><tr><td>Low profile retractable response lever</td><td>Campden Instruments Ltd.</td><td>Model CI4460-M</td><td>2 levers per chamber</td></tr><tr><td>Stimulus lights</td><td>Campden Instruments Ltd.</td><td>Model 80221</td><td></td></tr><tr><td>Pellet dispenser</td><td>Campden Instruments Ltd.</td><td>Model 80209-45</td><td>with 45 mg interchangeable pellet size wheel</td></tr><tr><td>Mouse nosepoke</td><td>Campden Instruments Ltd.</td><td>Model 80116S</td><td>with stimulus light</td></tr><tr><td>Sonalert audible stimulus system</td><td>Campden Instruments Ltd.</td><td>Model SC628</td><td></td></tr><tr><td>ABET II Complete Starter Package</td><td>Campden Instruments Ltd.</td><td>Model 88501*C</td><td>with 220 VAC/50 Hz power supply</td></tr><tr><td>Sound attenuating chamber</td><td>Campden Instruments Ltd.</td><td>Model 80600A-SAC</td><td>Equipped with a peephole and a 28 VDC ventilation fan panel</td></tr><tr><td>Animal Behavior Environment Test system (ABET) II</td><td>Lafayette Instrument Neuroscience, Indiana, USA</td><td>Model 89501</td><td></td></tr><tr><td>Personal computer</td><td></td><td></td><td>with a minimum 1.8 GHz Processor, running Microsoft Windows XP (SP3), or Win7</td></tr><tr><td>45 mg dust-free precision pellets</td><td>PMI Nutrition International, Indiana, USA</td><td>Formula. P/AlN-76A</td><td>Keep the containers tightly closed to protect from moisture.</td></tr></tbody></table>

signal attenuation as a rat model of obsessive compulsive disorder

在强迫症（OCD）的信号衰减大鼠模型中，杠杆按压食品后跟的化合物刺激其用作反馈提示的呈现。这种反馈是由刺激政策的反复演示，没有食物（不发光的杠杆记者回应鼠）后减弱。在下一阶段，杠杆压在灭绝的条件下，评估（ 即，没有食物交付）。在此阶段的大鼠显示两种类型的杠杆压力机，那些随后试图收集奖励的是，和那些没有。后者是在模型强迫样行为的量度。的控制程序，其中大鼠不会遇到反馈提示的衰减提供消光的信号衰减和的效果来区分。信号衰减模型是强迫症的一种高度有效的模型，并强迫样行为和行为是区分重复，但ñOT强迫。另外在此过程中收集的措施消除对被测试的组间差异替代的解释，而且是定量的，公正的，不受跨实验者变化。这种模式的主要缺点是昂贵的设备，它需要一定的技术知识和事实，即它是耗时相比其他车型OCD（11天）的事实。可用于检测的药理学和非药理学操作的抗或促强迫效应和用于研究的强迫行为的神经基底模型。

下面的结果是基于Brimberg 等人，2007年52。所有数据都重新印刷与爱思唯尔的权限。 在这项研究中，我们测试只SD（SD）雄性大鼠，在信号衰减模型的行为。首先，在实验1中，我们测试了3个剂量的选择性血清素再摄取抑制剂（SSRI）帕罗西汀的PTSA过程中的作用（正每组10只）。在测试中，帕罗西汀剂量依赖性地降低ELP-C的数量（ 图1A; ANOVA产生剂量，F（3,22）= 5.15，P &lt;0.01的显着的主效应）和ELP-U（ 图1B; ANOVA产生剂量，F（3,22）= 7.99，P &lt;0.001）的显着主要作用。 <img alt="图1" src="/files/ftp_upload/52287/52287fig1highres.jpg" /> 图1.该图显示了一个典型的剂量反应EXPeriment比较SSRI帕罗西汀上ELP-C和雄性大鼠的ELP-U为下列信号衰减各种剂量的效应。平均数和额外的杠杆数的标准误差按压使（A），其次是杂志条目（额外杠杆压力机在完成试验; ELP-C）及（B）没有跟随杂志条目（在未完成试验的额外杠杆压力机进行;大鼠车辆或1，5或10毫克治疗/ kg的帕罗西汀对考试当天ELP-U）的PTSA程序。重新印有许可52。 在实验2中，我们测试的药物剂量，这是最有效的在实验1（5毫克/千克），同时在PTSA和RE程序（正每组10只）。在测试中，帕罗西汀下降ELP-C的数量都PTSA和RE程序（ 图2A;双向方差分析，程序主要作用，F（1,32）= 6.50，P &lt;0.05;药物的主要作用，F（1,32）= 8.69，P &lt;0.01;程序X药物相互作用，F（1,32）= 0.43，P = 0.52），并在另外施加的抗强迫作用，也就是说 ，ELP-U的数目减少，在PTSA但不是对RE过程中（ 图2B;主效应药物的主效应，F（1,32）= 5.75，P &lt;0.05;步骤，F（1,32）= 9.60，P &lt;0.005的方法X药物相互作用，F（1,32）= 4.83，P &lt; 0.05）。 <img alt="图2" src="/files/ftp_upload/52287/52287fig2highres.jpg" /> 图2.该图显示了一个代表性的实验进行比较的信号衰减和定期消上ELP-C和的了生理盐水ELP-U和帕罗西汀暴露雄性大鼠的影响。平均数和（A）的 ELP-C中的数的标准误差和（B）与车辆或5mg / kg的帕罗西汀对PTSA和RE程序的测试一天处理的大鼠的ELP-U。重新印有许可52。

Watch this Scientific Journal Video about Signal Attenuation as a Rat Model of Obsessive Compulsive Disorder at JoVE.com

Signal Attenuation as a Rat Model of Obsessive Compulsive Disorder

在本文中描述的协议的目的是诱导大鼠强迫样行为的强迫症（OCD）的研究。此行为是由一个衰减指示的杠杆压响应，有效地生产食品的信号沉淀。

信号衰减为强迫症的大鼠模型

In the signal attenuation rat model of obsessive-compulsive disorder (OCD), lever-pressing for food is followed by the presentation of a compound stimulus ...

signal-attenuation-as-a-rat-model-of-obsessive-compulsive-disorder

Universidad de Cartagena UDEC

Research

JoVE Journal

Behavior

15.4K 次观看.  Tel-Aviv University. 在本文中描述的协议的目的是诱导大鼠强迫样行为的强迫症（OCD）的研究。此行为是由一个衰减指示的杠杆压响应，有效地生产食品的信号沉淀。 

视频: Signal Attenuation as a Rat Model of Obsessive Compulsive Disorder

Marble Burying and Nestlet Shredding as Tests of Repetitive, Compulsive-like Behaviors in Mice

Obsessive-compulsive disorder (OCD) and autism spectrum disorders (ASD) are serious and debilitating psychiatric conditions and each constitutes a significant public health concern, particularly in children. Both of these conditions are highlighted by the repeated expression of meaningless behaviors. Individuals with OCD often show checking, frequent hand washing, and counting. Children with ASDs also engage in repetitive tapping, arm or hand flapping, and rocking. These behaviors can vary widely in intensity and frequency of expression. More intense forms of repetitive behaviors can even result in injury (e.g.&#160;excessive grooming, hand washing, and self-stimulation). These behaviors are therefore very disruptive and make normal social discourse difficult. Treatment options for repetitive behaviors in OCD and ASDs are somewhat limited and there is great interest in developing more effective therapies for each condition. Numerous animal models for evaluating compulsive-like behaviors have been developed over the past three decades. Perhaps the animal models with the greatest validity and ease of use are the marble burying test and the nestlet shredding test. Both tests take advantage of the fact that the target behaviors occur spontaneously in mice. In the marble burying test, 20 marbles are arrayed on the surface of clean bedding. The number of marbles buried in a 30 min session is scored by investigators blind to the treatment or status of the subjects. In the nestlet shredding test, a nestlet comprised of pulped cotton fiber is preweighed and placed on top of cage bedding and the amount of the nestlet remaining intact after a 30 min test session is determined. Presently, we describe protocols for and show movie documentation of marble burying and nestlet shredding. Both tests are easily and accurately scored and each is sensitive to small changes in the expression of compulsive-like behaviors that result from genetic manipulations, disease, or head injury.

Disease, head injury, genetic modifications, and treatment of mice with drugs can have profound effects on behavior. Utilizing well-characterized and validated approaches such as marble burying and nestlet shredding, compulsive-like behaviors can be documented accurately in mice as models of human obsessive-compulsive disorder and autism spectrum disorder.

Obsessive-compulsive disorder (OCD) and autism spectrum disorders (ASD) are serious and debilitating psychiatric conditions and each constitutes a ...

科研

行为学

Biomarkers in an Animal Model for Revealing Neural, Hematologic, and Behavioral Correlates of PTSD

Identification of biomarkers representing the evolution of the pathophysiology of Post Traumatic Stress Disorder (PTSD) is vitally important, not only for objective diagnosis but also for the evaluation of therapeutic efficacy and resilience to trauma. Ongoing research is directed at identifying molecular biomarkers for PTSD, including traumatic stress induced proteins, transcriptomes, genomic variances and genetic modulators, using biologic samples from subjects' blood, saliva, urine, and postmortem brain tissues. However, the correlation of these biomarker molecules in peripheral or postmortem samples to altered brain functions associated with psychiatric symptoms in PTSD remains unresolved. Here, we present an animal model of PTSD in which both peripheral blood and central brain biomarkers, as well as behavioral phenotype, can be collected and measured, thus providing the needed correlation of the central biomarkers of PTSD, which are mechanistic and pathognomonic but cannot be collected from people, with the peripheral biomarkers and behavioral phenotypes, which can.
Our animal model of PTSD employs restraint and tail shocks repeated for three continuous days - the inescapable tail-shock model (ITS) in rats. This ITS model mimics the pathophysiology of PTSD 17, 7, 4, 10. We and others have verified that the ITS model induces behavioral and neurobiological alterations similar to those found in PTSD subjects 17, 7, 10, 9. Specifically, these stressed rats exhibit (1) a delayed and exaggerated startle response appearing several days after stressor cessation, which given the compressed time scale of the rat's life compared to a humans, corresponds to the one to three months delay of symptoms in PTSD patients (DSM-IV-TR PTSD Criterian D/E 13), (2) enhanced plasma corticosterone (CORT) for several days, indicating compromise of the hypothalamopituitary axis (HPA), and (3) retarded body weight gain after stressor cessation, indicating dysfunction of metabolic regulation.
The experimental paradigms employed for this model are: (1) a learned helplessness paradigm in the rat assayed by measurement of acoustic startle response (ASR) and a charting of body mass; (2) microdissection of the rat brain into regions and nuclei; (3) enzyme-linked immunosorbent assay (ELISA) for blood levels of CORT; (4) a gene expression microarray plus related bioinformatics tools 18. This microarray, dubbed rMNChip, focuses on mitochondrial and mitochondria-related nuclear genes in the rat so as to specifically address the neuronal bioenergetics hypothesized to be involved in PTSD.

We describe a rat model of post traumatic stress disorder (PTSD) that reveals the persistent alterations in neuroendocrine function and the delayed long-term, exaggerated fear response, characteristic of PTSD patients. The animal model and methods described here are useful for correlating biomarkers in brain nuclei, which are mechanistic but cannot be measured in patients, with biomarkers in peripheral white blood cells, which can.

在动物模型揭示神经，血液，创伤后应激障碍和行为相关因素的生物标志物

Identification of biomarkers representing the evolution of the pathophysiology of Post Traumatic Stress Disorder (PTSD) is vitally important, not only for ...

医学

Novel Object Exploration as a Potential Assay for Higher Order Repetitive Behaviors in Mice

Restricted, repetitive behaviors (RRBs) are a core feature of autism spectrum disorder (ASD) and disrupt the lives of affected individuals. RRBs are commonly split into lower-order and higher-order components, with lower order RRBs consisting of motor stereotypies and higher order RRBs consisting of perseverative and sequencing behaviors. Higher order RRBs are challenging to model in mice. Current assays for RRBs in mice focus primarily on the lower order components, making basic biomedical research into potential treatments or interventions for higher-order RRBs difficult. Here we describe a new assay, novel object exploration. This assay uses a basic open-field arena with four novel objects placed around the perimeter. The test mouse is allowed to freely explore the arena and the order in which the mouse investigates the novel objects is recorded. From these data, patterned sequences of exploration can be identified, as can the most preferred object for each mouse. The representative data shared here and past results using the novel object exploration assay illustrate that inbred mouse strains do demonstrate different behavior in this assay and that strains with elevated lower order RRBs also show elevated patterned behavior. As such, the novel object exploration assay appears to possess good face validity for higher order RRBs in humans and may be a valuable assay for future studies investigating novel therapeutics for ASD.

Higher order restricted, repetitive behaviors (RRBs) disrupt the lives of affected individuals. These behaviors are challenging to model in rodents, making basic biomedical research into potential treatments or interventions for RRBs difficult. Here we describe novel object exploration as a potential assay for higher order RRBs in mice.

新对象的探索在小鼠电位测定高阶重复的行为

Restricted, repetitive behaviors (RRBs) are a core feature of autism spectrum disorder (ASD) and disrupt the lives of affected individuals.  RRBs are ...

Stress-Enhanced Fear Learning, a Robust Rodent Model of Post-Traumatic Stress Disorder

Fear behaviors are important for survival, but disproportionately high levels of fear can increase the vulnerability for developing psychiatric disorders such as post-traumatic stress disorder (PTSD). To understand the biological mechanisms of fear dysregulation in PTSD, it is important to start with a valid animal model of the disorder. This protocol describes the methodology required to conduct stress-enhanced fear learning (SEFL) experiments, a preclinical model of PTSD, in both rats and mice. SEFL was developed to recapitulate critical aspects of PTSD, including long-term sensitization of fear learning caused by an acute stressor. SEFL uses aspects of Pavlovian fear conditioning but produces a distinct and robust sensitized fear response far greater than normal conditional fear responses. The trauma procedure involves placing a rodent in a conditioning chamber and administering 15 unsignaled shocks randomly distributed over 90 minutes (for rat experiments; for mouse experiments, 10 unsignaled shocks randomly distributed over 60 minutes are used). On day 2, rodents are placed in a novel conditioning context where they receive a single shock; then, on day 3 they are placed back in the same context as on day 2 and tested for changes in freezing levels. Rodents that previously received the trauma display enhanced levels of freezing on the test day compared to those that received no shocks on the first day. Thus, with this model, a single highly stressful experience (the trauma) produces extreme fear of the stimuli associated with the traumatic event.

Here we describe the detailed methodology required to conduct stress-enhanced fear learning (SEFL) experiments, a preclinical model of post-traumatic stress disorder, in both rats and mice. The model utilizes aspects of Pavlovian fear conditioning and freezing as an index of enhanced fear in rodents.

压力增强恐惧学习--创伤后应激障碍的健壮啮齿动物模型

Fear behaviors are important for survival, but disproportionately high levels of fear can increase the vulnerability for developing psychiatric disorders ...

A Conflict Model of Reward-seeking Behavior in Male Rats

The present protocol describes a novel conflict task as a model of inhibitory control in rats. In this model, a natural rewarding stimulus (sexual stimulus) that represents a high-value reward, and the aversive stimuli (pins), are concurrently presented. The male rats have to climb or jump over the obstacle full of pins to approach and investigate the sexual partner. If the animal persists in their approaching behavior regardless of the aversive stimuli, it is considered as a maladaptive or risky reward-seeking behavior. The conflict task permits the evaluation of deficit in inhibitory control resulting from exposure to abused drug, such as morphine, or a stressful event. 
The main advantage of this model is that it provides a simple and quick way to discover the deficit in inhibitory control after exposure to opiate drugs or other stressful events. In addition to opiates, this behavioral model would also be useful for quickly discovering the inhibitory control deficits induced by other addictive drugs. However, the limitation is that the male rats' performance may be subject to exercising effects with repeated testing under this conflict task. In the future, one can hope that the individuals with the compulsive phenotype of reward-seeking behavior after exposure to opiates will be identified based on modifying this conflict model.

This conflict model is used to measure the impairment of inhibitory control after exposure to addictive drugs, or other factors that may influence inhibitory control. A sexual stimulus and an aversive obstacle are concurrently presented, thus male rats have to conquer the obstacle to approach the sexual reward.

雄性大鼠寻救行为的冲突模型

The present protocol describes a novel conflict task as a model of inhibitory control in rats. In this model, a natural rewarding stimulus (sexual ...

An Inescapable Cat Odor Exposure Protocol for Studying Innate and Contextual Threat Conditioning in Rats

Animals respond to threatening situations by exhibiting a number of defensive behaviors, including avoidance, freezing, and risk assessment. An animal model with an ethological approach offers a deeper insight into the biological mechanisms underlying threat responses. This paper describes a methodology to measure defensive behaviors toward both innate and learned aversive stimuli in rats. Animals were individually exposed to predator odor in an inescapable chamber to elicit a measurable, sustained, defensive state. The experimental design involved placing a rat in a familiar chamber for 10 min followed by exposure to cat odor for another 10 min in the same context. The next day, the rats were re-exposed for 10 min to the same context chamber where cat odor exposure occurred. Sessions were video-recorded and defensive behaviors were assessed on both days. 
The behavioral test was coupled with reversible functional inactivation and c-Fos immunohistochemistry techniques to determine the role of the interoceptive cortex in threat responses. Rats exposed to cat odor on the first day and re-exposed to the context chamber on the second day displayed higher levels of defensive behaviors, and that cat odor elicited a robust increase in the neural activity of the interoceptive cortex. Moreover, muscimol inactivation of the interoceptive cortex reduced the expression of defensive behaviors in response to cat odor and impaired contextual threat memory. These results show that this behavioral assay is a useful tool for studying neural mechanisms of defensive behaviors and may offer insight into mechanisms that mediate fear in humans and its related disorders.

Cat skin/fur odor exposure provides a reliable method to investigate neural circuits and mechanisms of defensive responses in rodents and may offer insight into mechanisms that mediate fear in humans. Here, we describe a protocol for investigating the role of the interoceptive cortex in threat responses in rats.

Animals respond to threatening situations by exhibiting a number of defensive behaviors, including avoidance, freezing, and risk assessment. An animal ...

<meta charset="utf8"></head><body>小鼠模型中自闭症谱系障碍的行为检测

Strategies for Assessing Autistic-Like Behaviors in Mice

Autism spectrum disorder (ASD) is a neurobiologically complex condition with a heterogeneous genetic etiology. Clinically, ASD is diagnosed by social communication impairments and restrictive or repetitive behaviors, such as hand flapping or lining up objects. These behavioral patterns can be reliably observed in mouse models with ASD-linked genetic mutations, making them highly useful tools for studying the underlying cellular and molecular mechanisms in ASD. Understanding how genetic changes affect the neurobiology and behaviors observed in ASD will facilitate the development of novel targeted therapeutic compounds to ameliorate core behavioral impairments. Our lab has employed several protocols encompassing well-described training and testing procedures that reflect a wide range of behavioral deficits related to ASD. Here, we detail two assays to study the core features of ASD in mouse models: self-grooming (a measure of repetitive behavior) and the three-chamber social interaction test (a measure of social interaction approach and preference for social novelty).

<meta charset="utf8"></head><body>评估小鼠自闭症样行为的策略

Rodent models are valuable tools for studying core behaviors related to autism spectrum disorder (ASD). In this article, we expound on two behavioral tests for modeling the core features of ASD in mice: self-grooming, which assesses repetitive behavior, and the three-chamber social interaction test, which documents social impairments.

评估小鼠自闭症样行为的策略

Autism spectrum disorder (ASD) is a neurobiologically complex condition with a heterogeneous genetic etiology. Clinically, ASD is diagnosed by social ...

Developing a Rat Model for Bipolar Disorder

Bipolar disorder is a mental health condition characterized by extreme mood swings, including periods of emotional highs (mania) and lows (depression). While the exact underlying neurobiology is not yet fully understood, imbalances in neurotransmitter systems, particularly dopamine, appear to play a central role. For this reason, manipulations of dopaminergic pathways have been used to model mania or depression in rodents. However, models that accurately represent the typical switch between these two episodes are rare, limiting face validity. In a unique model, modern techniques are used to temporarily increase dopamine D1 receptor expression, which has been implicated in the pathology of bipolar disorder. A tetracycline-inducible lentiviral construct that expresses the dopamine D1 receptor under the control of the calmodulin kinase II alpha promoter is stereotactically injected into the medial prefrontal cortex of adult rats. Dopamine D1 receptor overexpression is achieved by adding the tetracycline analog doxycycline to the animals&#39; drinking water, leading to an increase in reward-related, impulsive, and risk-taking behaviors and a decrease in anxiety. These behaviors resemble a mania-like phenotype. By removing doxycycline from the drinking water, a depressive-like phenotype, characterized by increased helplessness and anhedonia, can be induced within the same animal. This article provides a step-by-step protocol for performing the surgery, as well as procedures for inducing the bipolar disorder-like phenotype. Additionally, considerations for assessing behavioral changes associated with mania-like and depressive-like behavior are described. This promising model, which demonstrates good construct and face validity, offers a valuable tool for further investigating the pathophysiological mechanisms of bipolar disorder.

This article presents a protocol for the induction of a unique rat model of bipolar disorder that captures both mania-like and depressive-like behavior.

开发双相情感障碍的大鼠模型

Bipolar disorder is a mental health condition characterized by extreme mood swings, including periods of emotional highs (mania) and lows (depression). ...

信号衰减为强迫症的大鼠模型

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Marble Burying and Nestlet Shredding as Tests of Repetitive, Compulsive-like Behaviors in Mice

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新对象的探索在小鼠电位测定高阶重复的行为

压力增强恐惧学习--创伤后应激障碍的健壮啮齿动物模型

雄性大鼠寻救行为的冲突模型

An Inescapable Cat Odor Exposure Protocol for Studying Innate and Contextual Threat Conditioning in Rats

评估小鼠自闭症样行为的策略

评估小鼠自闭症样行为的策略

评估小鼠自闭症样行为的策略

开发双相情感障碍的大鼠模型