Summary

巴恩斯迷宫测试策略与小型和大型啮齿类动物模型

Published: February 26, 2014
doi:

Summary

在旱地巴恩斯迷宫被广泛用于测量响应于轻度厌恶刺激空间导航能力。连续多天,对照组的性能( 等待时间来寻找逃生笼)提高,表明正常的学习和记忆。大鼠和小鼠之间的差异必然要求,在这里详细的设备和方法的变化。

Abstract

空间学习和啮齿类实验动物的记忆往往是通过在迷宫,其中最流行的是水和旱地(巴恩斯)迷宫续航能力进行评估。在会话或试验改进的性能被认为是反映逃生笼/平台位置的学习和记忆。认为比水迷宫压力较小,巴恩斯迷宫是一个圆形的平台,上面一个相对简单的设计有几个洞在周边边缘等距。但所有的孔中的一个是假底或盲结束,而一个导致逃生笼。轻度厌恶刺激( 明亮的顶灯)提供动力,以找到逃生笼。潜伏期找到逃生笼可在会议期间进行测量,但额外的端点通常需要视频录制。从这些录像,使用自动跟踪软件可以生成各种端点类似于那些在水迷宫生产( 例如</ em>的行驶距离,速度/转速,时间在正确的象限中度过,花费的时间动/静息和确认延迟)。搜索策略( 随机的,串行,或直接)的类型可以分为好。巴恩斯迷宫建造和测试方法不同,可以为小型啮齿类动物,如小鼠和大啮齿动物,如老鼠。例如,在特迷宫的线索是有效的鼠,小的野生啮齿动物可能需要内部迷宫的线索与周围的迷宫视觉障碍。适当的刺激必须确定哪些激励啮齿动物找到逃生笼。双方巴恩斯和水迷宫可作为时间4-7测试试验通常需要检测改进学习和记忆能力( 较短的延迟或路径长度来寻找逃生平台或保持架)和/或实验组之间的差异耗时。即便如此,巴恩斯迷宫是一种广泛使用的行为评估测量空间的航行能力和他们受遗传,神经行为操作,或药物/毒物接触潜在干扰。

Introduction

空间学习和记忆的啮齿类实验动物首次评估与食品剥夺大鼠的导航小巷的迷宫找到食物增强剂1。几十年后,提出了一种空间参考记忆系统2。相反,工作记忆是指存储在测试会话或试验中,参考存储器是指存储器横跨测试阶段或临床试验,并更密切相关的长期记忆。

几种类型的迷宫已经发展成为在小型和大型啮齿动物这个海马依赖的空间学习和记忆( 例如水迷宫,多个T-迷宫,放射臂迷宫和旱地迷宫)3-6无创性评估。在这里,我们重点的圆形平台或Barnes迷宫,由卡罗尔·巴恩斯博士7于1979年首次描述上。这个迷宫已经被用来测试空间航行学习记忆在广泛啮齿类动物模型,包括大鼠(RAttus家鼠),老鼠( 小家鼠 ),鹿鼠(Peromyscus maniculatus bairdii),加州小鼠(Peromyscus加利福尼亚小 ),和hystricomorph啮齿类动物( degus [Octodon degus])8-13。使用巴恩斯迷宫评估的其他物种包括美国蟑螂( 美洲大蠊 )14,玉米蛇( 锦蛇雀雀 )15,  有鳞爬行动物( 边斑点蜥蜴[ stansburiana])16,和非人灵长类动物( 小鼠狐猴[Microcebus鼱 ])17。在我们的实验室,巴恩斯迷宫性能已被用作神经毒性的指标发育双酚A(BPA)或乙炔基雌二醇(EE2)曝光9-1113之后。它也被普遍用于各种小鼠品系18-21的老化效应7,22-28评估行为表型,和阿尔茨海默氏病相关的画质icits在动物模型3,29-33,以及锻炼和饮食,环境和代谢改变34-42的影响。

的巴恩斯迷宫利用一个主要优点是,它诱导少应力在相对 ​​于水迷宫,如Morris水迷宫43的主体,虽然两者都可以诱导急性增加血浆皮质酮的浓度在小鼠44上 。作为一个旱地迷宫,巴恩斯迷宫可能会更ethologically相关陆地啮齿动物45。虽然水迷宫性能已被证明是在小鼠3,46,47到遗传改变更敏感,巴恩斯迷宫性能是某些其他改动48,49更加敏感。在啮齿类动物模型在水迷宫的使用是不可能的,巴恩斯迷宫可以提供空间记忆保留31的微调评估。轻度厌恶刺激通常用于巴恩斯迷宫( 灯不亮),然而,可能无法提供足够的动力为啮齿动物,找到逃逸笼45。此外,啮齿动物可以学习,如果他们不进入笼逃生时没有处罚。而不是积极寻找逃生笼因此,一些啮齿类积极探索迷宫的每个试验的持续时间长。如由肯纳德和半圆-Pak的24评论,这增加了勘探可以延长等待时间来定位逃逸笼,路径长度,和增加错误数量。因此,对多个参数,包括时延,误码率,时间在正确的和不正确的象限,速度花了,时间移动,时间休息,和搜索战略测量,可以统称为每个主体的空间航行学习记忆能力8一个更好的指标-10。此外,性能可以测量的延迟先找到逃生笼(主要指标)或延迟进入逃生笼(总指标)。有些自变量主编的性能主要措施是空间学习的一个更准确地反映比总的措施50。大多数研究中,包括这里所描述的实施例中,使用延迟进入逃逸笼,以确定错误率和搜索策略。此外,一些跟踪的软件系统有三点体检测系统,可以测量嗅探正确不正确孔的频率。最后,迷宫必须彻底与审判之间的​​乙醇清洗,以除去嗅觉线索,可以提供线索或证明分心到后续的动物。

巴恩斯迷宫的设计而变化,但通常各具有12或20个潜在逃逸孔,其中只有一个引出到家庭或逃生笼。逃生笼可以是位于下方的迷宫顶部的逃生孔(用于迷宫没有围墙),或内置于迷宫周围的墙壁。该线索的大小从约16.5厘米的高度或宽度(米范围内变化阿塞拜疆)水平线21.6厘米宽放置从地板到房间墙上的迷宫外的天花板。 巴恩斯迷宫设计的Peromyscus品种1-5显示的例子( 图1)和老鼠( 图2-5)。插头或假底部必须覆盖nonescape孔,以防止动物掉落走出迷宫。试验室的大小可以变化(约20 平方米 ),但它必须足够大以提供足够的空间迷宫,habituating动物的房间,可容纳一台计算机与视频的建立(如果使用),和一个地方对于实验者从迷宫装置,使得它们的存在不与动物的表现干扰坐在一个距离(至少〜122厘米)。逃生笼位置分配应各治疗组之间和性别平衡。而此处所描述的具体程序不包括旋转试验,以阻止使用帧内迷宫气味线索,一些研究之间的迷宫把这个程序50。在我们的程序中,迷宫擦拭干净,用试验之间的乙醇,以消除异味的线索。

在寻 ​​找逃生笼,三种类型的检索策略已被定义(最初称为“模式”巴恩斯7):1)随机,操作上定义为通过孔穿越迷宫的中心路径分隔的局部搜索,2)串口,定义为系统的搜索连续孔在顺时针或反时针方向,以及3)直接或空间,定义为直接导航到正确的象限而不穿过迷宫中心多于一次,并与3个或更少的错误。一般情况下,反复试验,老鼠通常通过上市(随机,串行和直接)51的顺序搜索策略进展。而不逸出笼的探针试验也可以用来作为进一步的措施的存储器50。

该协议及代表此结果两种啮齿类(Peromyscus物种否则称为小型啮齿动物)和大鼠的开发工作。虽然这些一般的程序可能还持有近交系和/或远交系小鼠( 小家鼠 ),其他研究应征询那些后者的18-21种潜在的方法论差异。

Protocol

1。巴恩斯迷宫手术小鼠害打开顶灯的迷宫和地方上面的“不输入”在实验室门的外侧的迹象。 在正常的家庭笼带来小鼠试验室开始第一次审判,允许习惯之前大约30分钟到。如果房间很安静,它可能不是必要的,包括白噪声,否则预防措施可以考虑。 设置跟踪程序。 轻轻地从它的首页笼取出第一个鼠标,并放置在高大的盖塑料盒。将其转义(清洁家园)聚​​丙烯?…

Representative Results

性成熟的雄性鹿鼠依赖于找到潜在的合作伙伴繁殖,这是整个环境中广泛传播增强空间导航能力。既产前和成人接触的睾丸激素在组织和激活此以后的成年男性行为53是必不可少的。因此,有人推测,早期接触内分泌干扰物,可能会扰乱稍后性状的男性。为了检验这一假设,雄性和雌性鹿小鼠经产妇的饮食发育暴露于BPA的一种植物雌激素饮食,积极控制雌激素(炔雌醇[EE2])的一种?…

Discussion

在巴恩斯迷宫测试程序的关键步骤包括:1)提供适当的轻度厌恶刺激来激励动物找到逃生笼,2)确保统一的条件都能够维持相同的动物试验( 测试时间,测试人员,外部噪声控制,及可能影响性能等的刺激),3),如果试验是记录,优化,并确保适当的视频记录和文件备份和4)清洗,用70%乙醇的迷宫,以除去试验之间嗅觉视频。

确定激励对象以找到逃生笼最好?…

Disclosures

The authors have nothing to disclose.

Acknowledgements

作者承认埃尔丁Jašarević先生,斯科特·威廉姆斯先生,罗杰·W·麦森先生,莎拉·A·约翰逊,R·迈克尔·罗伯茨博士,马克河Ellersieck博士和David C.基尔博士在大学密苏里州和C德尔伯特罗先生和照顾动物的工作人员在国家毒理学研究中心/美国FDA。这项工作是支持由美国国立卫生研究院资助的挑战,授予中国南车(RC1 ES018195),一个密苏里大学优势格兰特(CSR和DCG),密苏里大学学院兽医学院奖(CSR),并在国家中心协议E7318毒理学研究/ FDA认证。

Materials

NOTE: Those items that are for small rodents only are bolded. Those items that are for large rodents only are italicized. Items neither bolded nor italicized are for both.
Barnes Maze platform with 12 or 20 escape holes every 30°. For rats, each hole is 10.5 cm in diameter and 4 cm from the maze top edge. For use with automated tracking programs, a black top for white rodents or a white top for pigmented rodents is needed. For mice and rats, this circular top is 95 and 122 cm in diameter, respectively. US Plastics Corp, Lima, OH 42625 This is the top of the Barnes Maze and the surface that the rodent is placed upon. It can be constructed from a variety of materials (e.g. Plexiglas), but for endocrine disruptor work, polypropylene BPA-free material is optimal. One of the holes leads to the an escape cage; all other holes are blind-ending or false-bottomed. For the rat maze, small slides on the underside of the maze platform allow the escape cage and false bottoms to slide in.
2" Polypropylene pipe plug (24)
2" 90° Black polypropylene elbow (12)
2" x 6" Polypropylene pipe nipple (1)
US Plastics Corp, Lima, OH 30724
32086
30712
These are only necessary for the small rodent (e.g. mouse) Barnes Maze. These adaptations are either blind-ending tubes/elbows or one of the tubes is connected to the pipe nipple that then leads to the escape cage.
False bottoms for rat Barnes Maze These were custom made of ABS plastic and vacuum molded for the rat maze apparatus.
Circular aluminum wall/barrier (50 cm high) around the maze Ace Hardware, Columbia, MO In the case of small rodents (e.g. mice), this barrier prevents them from falling off the maze; the rat apparatus generally does not require this. The wall may not be needed for laboratory mice that are relatively tame.
Support stand for maze platform top US Plastics Corp, Lima, OH 42625 The stand supports the maze platform top such that it is elevated above the floor (typically, 70-100 cm) to motivate the rodent to locate the escape cage. The stand can be constructed of any material.
White noise SleepMate Sound Conditioner,
Marpac, Rocky Point, NC
980A Background noise may be used to block out peripheral acoustic cues that may confound Barnes Maze testing across trials and animals
Light fixtures and 300-500 watt bulbs encased in aluminum shells. For example, Utilitech 500-watt halogen portable work lights. Ace Hardware or Lowes Bright lights provide a mildly aversive stimulus which motivate the rodent to locate the escape cage. The lights are generally suspended ~150 cm above the maze top.
Escape cage. For small rodents, this can be a polypropylene cage (27.8 x 7.5 x 13 cm). Ancare, Bellmore, NY N40 PP The rat escape cage here was custom built and has a ramp leading into the escape cage.
Opaque tube (rats only) (27 cm diameter; 23 cm height) with a piece of thick cardboard to cover the top. The tube is placed in the center of the maze and the rat is placed into the tube from the top which is covered with the cardboard. A handle on the outside of the tube allows easier lifting of the tube, which then begins the trial. The tube can be constructed of any material, but should be opaque.
High resolution video camera (e.g. Panasonic Digital Video Camera) Panasonic, Secaucus, NJ ICV19458 The video camera is positioned overhead and records trials for later analysis.
Extra- or intra-maze geometric cues made of high quality cardboard construction paper Any office supply store, such as Staples. These visual cues orient the animal within the maze environment, providing cues as to the spatial location of the escape cage; in rats, extra-maze cues on the walls work well, whereas in small rodents that require a wall around the maze, intra-maze cues must be used.
Black curtain to surround the maze (small rodents only) Any fabric and crafts store, such as Jo-Ann Fabrics A black curtain is used in small rodents (especially wild species, e.g. Peromyscus) to maintain attention within the maze confines.
70% ethanol Fisher Scientific BP2818-4 After each trial, the maze top and escape cage are cleaned to eliminate potential odor cues for consecutively tested rodents.
Tracking software program, such as Ethovision, and computer with appropriate video card and substantial (1 TB or more) hard-drive space. Alternatively, videos can be recorded directly to the computer for later analysis using a program such as Win TV (Hauppauge Computer Works, Inc.). Noldus (Leesburg, VA) Tracking software is required to analyze trials for latency to locate the escape cage, velocity, distance traveled, time spent resting, time spent moving, time spent in the correct versus incorrect quadrants, time spent around the escape hole, number of errors or entries into incorrect holes, and overall search strategy employed to find the escape cage.
External hard drives, such as Seagate or WD, with a minimum 1- 2 TB of memory Any office supply store, such as Staples. Videorecordings should be backed up in at least one separate location.
Videorecording program, e.g. WinTV program Hauppauge Computer Works, Inc.,
Hauppauge, NY
If tracking software is not available at the time of the testing,
the trials should be video-recorded for later analysis

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Cite This Article
Rosenfeld, C. S., Ferguson, S. A. Barnes Maze Testing Strategies with Small and Large Rodent Models. J. Vis. Exp. (84), e51194, doi:10.3791/51194 (2014).

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