Summary
痕量经典条件反射 (ECC) 用于评估了的成年大鼠海马依赖联想学习管理高 (11.9 %v / v) 乙醇浓度早期新生儿大脑发育。ECC 程序一般声音诊断工具检测脑功能障碍跨越心理和生物医学的许多设置。
Abstract
新生大鼠进行问卷调查期间产后天 4-9，相对较高浓度的乙醇 （酒精） (11.9 %v / v) 一段时间当胎儿的大脑经历了快速的组织变革是类似于加速大脑在人类妊娠期间发生的变化。这个型号的胎儿酒精谱系障碍 (FASDs) 产生严重的脑损伤，模仿的数量和模式的酗酒，发生在一些酒精孕妇。我们描述了使用的跟踪经典条件反射 (ECC)，高阶 variant 类型的联想学习，以评估长期海马的功能障碍，通常看到酒精暴露的成年子女。在 90 日龄，啮齿类动物是手术准备好录音和刺激电极，测量肌电图 (EMG) 眨眼从左的眼睑肌肉的活动，并分别交付轻微冲击后的左眼。经过 5 天恢复时间，他们经历了跟踪确定酒精暴露与控制大鼠联想学习差异的 ECC 6 各届会议。痕量 ECC 是可以轻松地修改使用相同的设备和软件，以便可以评估不同的神经系统的许多可能的 ECC 程序之一。ECC 程序一般情况下，可以被用于作为诊断工具检测神经病理学侮辱大脑的不同条件，不同的大脑系统。
Representative Results
眨眼软件是能够提供一套大型和全面的数据对于许多类型的测量。为简洁起见，我们在此研究中，报告代表结果学习和性能包括自适应 CR 百分比、 自适应的 CR 振幅、 UR 百分比和 UR 振幅的措施。之所以选择自适应的 CR 期间，因为它代表着收购时宜眨眼反应过度重复训练，由于期间跟踪 ECC50，，5152海马增强突触可塑性。UR 措施被选为澄清是否在新生儿酒精所致的学习赤字跟踪 ECC 的原因是联想学习中断或中断响应冲击我们-这可能表明动机或电机的差异，而不是学习处理群体之间的差异。为每个度量值的数据分析采用 2 （性别） x 3 （新生儿组） x 6 （会话） 混合不明，与会话作为重复测量因素。采用配对 t 检验的事后测试分析重要影响新生儿的治疗和显著的交互作用分析了使用简单效果测试。使用 0.05 最低 alpha 级别进行了所有的统计分析和图中的结果是平均 ± 镜
开始与自适应的 CR 百分比量值，方差分析表明显著的主效应，新生儿组， F(2，21) = 11.69， p < 0.001，但性没有显著的主效应 (p = 0.71) 或显著的交互作用，这些因素之间 (p = 0.20)。不出所料，自适应的 CR 百分比增加培训， F（5，105） 六届 = 81.15， p < 0.001 和新生儿群体之间的差异是依赖在某种程度上的会话， F（10，105） = 4.58， p < 0.001。没有其他显著的交互作用涉及会话因素。同样为自适应的 CR 振幅，那里又显著的主效应，新生儿组， F(2，21) = 22.32， p < 0.001，但性没有显著的主效应 (p = 0.21) 或显著的交互作用，这些因素之间 (p = 0.48)。CR 振幅也大大增加培训， F（5，105） 六届 = 59.27， p < 0.001 和新生儿群体之间的差异是依赖在某种程度上的会话， F（10，105） = 4.31， p < 0.001。总体来看，这两个 CR 措施有显着差异组和这些手段明显分隔在不同的会话的培训。若要确认哪些组差别很大，配对 t 检验的事后测试表明，酒精插管 (AI) 大鼠表现明显差于这两个 CR 措施比 unintubated-控制 (UC) 和深水插管 (SI) 大鼠 (p < 0.01 CR 百分比;p < CR 振幅为 0.001)，其中没有不与彼此不同 (p> 0.05)。重大的新生儿组 x 两个 CR 措施，确认 AI 大鼠显著更显著受损获取的 CRs 开始在会话 2 和贯彻会议 6 相比，大鼠 UC 和 SI 的会话交互执行简单的效果测试 (所有p< 0.05)，在六届会议期间不做从彼此不同。唯一的例外是自适应的 CR 振幅为寺大鼠才开始 AI 大鼠直到会话 3 相差很大。这些结果都显示在图 5A、 5B。
没有显著的差异，在 UR 措施由于性别、 新生儿组或与会话因素这些因素的交互。这些负面的结果表明，每个组能够发出对休克的眨眼反应我们同样，AI 大鼠模型观察学习赤字并不受激励或电机的闪烁 （图 6A、 6B） 的差别。
图 5： 跟踪采集条件响应 (平均 ± SEM)。早期的酒精暴露 （组 AI） 显著影响采集的自适应条件反应 (CR) 百分比 （A） 和 (B) 振幅。跟踪 ECC 是天生难以获得，因此这些措施是为所有的组-ECC 时滞相对较低，百分比可能会达到 80-85%的胎儿酒精紊乱症21，53啮齿动物模型中。尽管如此，ECC 过程跟踪是征税对海马，这早期的脑发育过程中易受酒精影响的更多。* = p < 0.05，* * = p < 0.01，* * * = p < 0.001 之间 UC 和 AI 的大鼠;中括号提供了样本。请点击这里查看此图的大版本。
图 6： 无条件反应 （意思是 ± SEM） 采集。眨眼 （UR 百分比和 UR 振幅） 表现不组间差异显著。缺乏的差异表明在采集培训过程中使用的激波强度差异没有改变 AI 大鼠的动机或他们能够生产防御眨眼休克，相比两个对照组 （UC 和 SI） 的答复。中括号提供了样本。请点击这里查看此图的大版本。
Discussion
在产后天 4 9 期间收到乙醇 （酒精） 的新生大鼠幼仔展出跟踪眨眼空调在成年后的损伤。这些发现支持酒精是致畸与持久对海马功能的有害影响的观点。总体而言，条件响应在跟踪过程中是大鼠暴露于酒精与两个对照组大鼠相比要低。联想学习障碍酒精暴露大鼠都不受激励或电机的差异 (即.，闪烁对美国冲击强度无差异)。
虽然跟踪 ECC 是阐明挑战诱导海马神经病理学会有用的诊断工具，这种方法的结果必须放入适当的上下文。第一，在本演示中的关键程序元素涉及酒精靶向的递送到发育中的大脑，允许录制的肌电活动和提供休克、 手术植入术的上述硬件，和随后的动物测试使用评估认知功能的兴趣学习范式的电极硬件制造漏洞已知窗口期间。在每个阶段的过程中，必须注意对啮齿动物的科目不造成不必要无意的伤害，并定期监测其健康体征。他们行为的结果向认知提供了"窗口"，准确地只是一个心理建构描述当他们的健康不会受到包括酒精加药，硬件缺陷或外科手术植入的实验误差。因此，在研究过程中的每个程序元素必须执行以声音的方式，以确保外推结果从 ECC 的同时，还可以到人体的研究结果。其次，ECC 范式提供了联想学习的性质，但必须小心不扩展使用这种方法的结果，大致所赋予它们到其他认知域-工作记忆、 短期长期记忆，等意识 — — 除非一已纳入这些域内 ECC 研究某些方面的实验设计。例如，此演示审查的追踪 ECC 学习，采集阶段，但未审查大鼠记忆保持他们完成培训后。内存因而是独立的心理过程，应该评估除了学习。按照设计，一个可能纳入记忆的保留间隔，以评估任何短期或长期的记忆能力。第三，有可能与动机、 经验性的和荷尔蒙因素促成的行为，同时工作的并行存储器系统54的认识是必不可少的 （在 ECC) 相关性是的理解但揭示了什么是"好"或"差"关于学习的许多过程之一。最后，跟踪 ECC 不是纯粹海马依赖任务，其他的大脑区域可能介导 CR 的某些组件。因此，对不同的神经回路和/或在研究中，利用的刺激参数的类型之间相互作用的认识，必须考虑到当制作基于离散结果的影响。例如，小脑，也有助于跟踪 ECC，在那里它影响铬和铬时机，特别是三军情报局短时间的地形特点。痕量 ECC 在小脑受损的人用长的跟踪时间间隔 （1,000 女士），测试不受影响，但在那些接受较短的跟踪间隔 （400 毫秒）34，影响。此外，背内侧前额叶皮层 （律） 的小鼠，前扣带回和内侧嗅沟地区为目标的双侧病变防止采集跟踪 CRs55，而破坏的兔尾律产生类似结果46。这些发现也突出考虑物种差异在小脑脑前额叶贡献阀杆驱动的联想学习，如跟踪 ECC 的重要性。而在 500 ms 跟踪 CRs 成人 PD 4 9 不利影响采集新生儿酒精暴露大鼠在这项研究和其他47，56，这不是经验 300 ms 跟踪时间间隔，即使在较高剂量的酒精 （5 克/公斤）57，暗示酒精染毒大鼠的微量损害依赖于跟踪间隔的挑战的新生儿酒精暴露大鼠的同一理由。
在此研究中，海马被强调是非常重要的调解 ECC，跟踪和新生儿酒精暴露受到挑战时展出相关神经损伤的缺陷跟踪 CRs 习得中可见一斑。但是，它必须告诫，小脑脑干电路，特别是间位核，是 ECC，包括采集、 表达式和地形特征的 CR，ECC 任务包括跟踪 ECC36，，4055，，5859类型的许多方面的必要条件。事实上，这种神经电路与海马的驾驶中 ECC，如跟踪 ECC60的高阶形式表达的 CRs 进行交互。是否早期大脑发育过程中的酒精暴露专门影响跟踪 ECC 中的海马功能尚不完全清楚。许多不同的大脑区域是易受早期酒精侮辱，包括律、 小脑、 海马18，19，，2347，61，62，和很可能酒精扰乱跨许多 ECC 程序运作这些结构不同程度和不同，但功能上重要的差异。尽管关于从跟踪 ECC 研究结果解释的陷阱，跟踪 CRs 成功收购已被证明至少依靠完整的海马，动物病变研究42，44，63，，6465所支持的。此过程因此仍然是非常有价值地演示之间发展酒精暴露于跟踪条件响应因为底层 it，神经回路要好得多的联系比其他海马相关的任务，如在 Morris 水迷宫，地方学习理解新物体再认，和上下文和跟踪担心空调。
ECC 作为行为法"测定"认知、 发展 neuroteratology 领域具有广泛的适用性。事实上，最近的调查结果，从我们的实验室支持发展中国家海马是酒精作用，可能通过不同的介入策略18，47缓解对高度敏感的概念。这里的关键的好处是与酒精所致的微量 ECC 学习赤字更好地了解，他们可能是预测中海马基于功能联想学习-以外的其他问题的特别是那些已知的由同一海马神经介导。
应用微量 ECC 和及其其他变体 （例如，延迟、 逆转、 歧视、 复合） 澄清的神经生物学机制和神经系统参与的联想学习，还可以扩展超出了胎儿酒精研究领域。例如，这种范式在人类病例及动物模型，精神疾病如精神分裂症66，67、 神经退行性疾病，如老年痴呆症68，69，以及药物的滥用70，，7172关注。它作为一种研究方法来评估认知功能和功能障碍的好处也由此明显横跨许多心理和生物医学的学科，包括神经科学。
Disclosures
作者没有透露。
Acknowledgments
这项工作被支持由格兰特到 TDT 从酒精饮料医疗研究基金会 (ABMRF)。
Materials
| Name | Company | Catalog Number | Comments |
| Neonatal Alcohol Exposure | |||
| 190 Proof Ethyl Alcohol (USP) | Pharmco-AAPER | 225-36000 [ECU Medical Storeroom] | Can be substituted; should be USP; avoid using 200 proof ethyl alcohol |
| Container/Basket for Pups | Any | ||
| Corn Oil | Any | Food grade | |
| Heated Water Therapy Pump w/ Pads | Gaymar | TP-500 | To keep pups warm; can be substituted |
| Hypodermic Needles 22G x 1 in, Sterile | Any | ||
| Hypodermic Needles 30G x 1/2 in, Sterile | Any | ||
| Isopropyl Alcohol 70% | EMD Millipore | PX1840-4 [Fisher Scientific] | Can be substituted; reagent grade www.fishersci.com |
| Long-Evans Rats (Female and Male Breeders) | Charles River Laboratories | N/A [ECU Dept. of Comparative Medicine] | Age and weight need to be specified; pricing varies by these factors www.criver.com |
| Micro Dissecting Scissors, 3.5 in, 23 mm Blades | Biomedical Research Instruments | 11-2200 | For cutting PE tubing brisurgical.com |
| Polyethylene 10 Tubing (0.011 in. I.D.; 0.024 in. O.D.) | BD Diagnostic Systems | 22-204008 [Fisher Scientific] | Can be substituted www.fishersci.com |
| Polyethylene 50 Tubing (0.023 in. I.D.; 0.038 in. O.D.) | BD Diagnostic Systems | 22270835 [Fisher Scientific] | Can be substituted www.fishersci.com |
| Regulated water heater or baby milk bottle warmer | Any | Optional; helps with warming up cold milk solutions | |
| Tuberculin Syringes, Sterile, 1.0 ml | Any | ||
| Tuberculin Syringes, Sterile, 10 ml | Any | Can be used to draw out ethyl alcohol or use appropriate size micropipet | |
| Weigh Scale | Any | Should have good resolution (in gram units) | |
| Name | Company | Catalog Number | Comments |
| EMG Headstage Fabrication and Bipolar Electrode Modification | |||
| Bipolar Electrode, 2 Channel SS Twisted | Plastics One, Inc. | MS303/2-B/SPC ELECT SS 2C TW .008" | Must specify custom length of 20 mm below pedestal www.plastics1.com |
| Centi-Loc Strip Socket Insulator (aka, Micro Strip) | ITT Cannon / ITT Interconnect Solutions | CTA4-IS-60* or CTA4-1S-60* | *Depends on vendor; see www.onlinecomponents.com or www.avnetexpress.avnet.com |
| Dental Pliers, Serrated | CMF Medicon | 390.20.05 | Can be substituted; use to crimp wires to male contact pins www.medicon.de |
| Micro Dissecting Scissors, 3.5 in, 23 mm Blades | Biomedical Research Instruments | 11-2200 | Only use to cut 3T wires; cutting 10T wires will damage the blade - use the blade of the wire stripper instead brisurgical.com |
| PTFE-Coated Stainless Steel Wire, 10T (Bare Diameter .010 in) | Sigmund Cohn-Medwire | 316SS10T | www.sigmundcohn.com |
| PTFE-Coated Stainless Steel Wire, 3T (Bare Diameter 0.003 in) | Sigmund Cohn-Medwire | 316SS3T | www.sigmundcohn.com |
| Razor Blade | Any | To strip 1 mm from prongs of bipolar electrode | |
| Relia-Tac Socket Contact Pin, Male | Cooper Interconnect | 220-P02-100 | See Allied Electronics Cat # 70144761 www.alliedelec.com |
| Tweezers, High Precision, Serrated, 4 3/4 in | Electron Microscopy Sciences | 78314-00D | To grasp 10T wire firmly while stripping PTFE with smooth tweezers www.emsdiasum.com |
| Tweezers, High Precision, Smooth, 4 3/4 in | Electron Microscopy Sciences | 78313-00B | www.emsdiasum.com |
| Tweezers, Ultra Fine Tips, 4 3/4 in | Electron Microscopy Sciences | 78510-0 | To strip 1 mm of PTFE from one end of 3T wire; grasp shielded portion with smooth tweezers www.emsdiasum.com |
| Wire Stripper, 16-26 AWG | Any | Use the blade end to cut micro strips | |
| Name | Company | Catalog Number | Comments |
| Eyelid Surgery | |||
| Surgical Instruments (High Quality Stainless Steel) | |||
| 2 x Dressing Forceps, 4 in Serrated | Biomedical Research Instruments | 30-1205 | Can be substituted; extra forceps for grasping electrodes/screws outside of surgery tray brisurgical.com |
| Dressing Forceps, 3 in Serrated | Biomedical Research Instruments | 30-1200 | Can be substituted brisurgical.com |
| Instrument Tray | Biomedical Research Instruments | 24-1355 | Can be substituted brisurgical.com |
| Knife Handle No. 3, 5 in | Biomedical Research Instruments | 26-1000 | Can be substituted brisurgical.com |
| Micro Dissecting Forceps, 3.5 in, Fine Points | Biomedical Research Instruments | 10-1630 | Can be substituted brisurgical.com |
| Micro Dissecting Forceps, 3.5 in, Smooth Platform (0.3 x 5 mm) | Biomedical Research Instruments | 10-1720 | brisurgical.com |
| Micro Dissecting Scissors, 3.5 in, Extremely Delicate, 15 mm Blades | Biomedical Research Instruments | 11-2000 | Can be substituted brisurgical.com |
| Plain Splinter Forceps, 3.5 in | Biomedical Research Instruments | 30-1600 | Can be substituted brisurgical.com |
| #10 Stainless Steel Surgical Blade for #3 Handle, Sterile | Any | Can be substituted | |
| 0-80 x 0.125 in Stainless Steel Screws | Plastics One, Inc. | 0-80 x 0.125 | Can be substituted www.plastics1.com |
| Alcohol Prep Pads, Sterile | Fisher Scientific | 22-363-750 [Fisher Scientific | Can be substituted www.fishersci.com |
| Betadine Povidone-Iodine | Purdue Frederick Co. | 6761815101 [Fisher Scientific] | Can be substituted www.fishersci.com |
| Betadine Povidone-Iodine Prep Pads | Moore Medical | 19-898-946 [Fisher Scientific] | Can be substituted www.fishersci.com |
| Cotton-Tipped Swabs, Autoclavable | Any | Typically 7.6 cm or 15.2 cm length | |
| Drill Bit for Pin Vise, #55 (0.052 in) | Any | Metal should resist rusting and corrosion | |
| Gauze Pads, 2 in x 2 in | Fisher Scientific | 22-362-178 [Fisher Scientific] | Can be substituted www.fishersci.com |
| General Purpose Latex/Nitrile/Vinyl Gloves | Any | ||
| Glass Bead Sterilizer | Any | Sterilize instruments between surgeries | |
| Heated Water Therapy Pump w/ Pads x 2 | Gaymar | TP-500 | Can be substituted; separate pumps are recommended - 1 for surgery, 1 for recovery |
| Hypodermic Needles 26G x 3/8 in, Sterile | Any | ||
| Isoflurane | Vedco | NDC 50989-150-12 | Manfacturer can be substituted; veterinary approval may be required |
| Isoflurane Vaporizer System, Tabletop, Non-Rebreathing | Parkland Scientific | V3000PK | Can be substituted www.parklandscientific.com |
| Jewelers Screwdriver w/ 1.8-2 mm Blade | Any | Metal should resist rusting and corrosion | |
| Ortho-Jet BCA Package (Dental Cement) | Lang Dental | B1334 | Contains powder (1 lb) and liquid www.langdental.com |
| Oxygen Tank with Pressure Regulator, Large | Local supplier | ||
| Porcelain Crucible, High-Form, Glazed, 10 ml | CoorsTek, Inc. | 07-965C [Fisher Scientific] | Can be substituted with Fisher FB-965-I Wide-Form Crucible www.fishersci.com |
| Puralube Veterinary Ophthalmic Ointment, Sterile | Henry Schein Company | NC0144682 [Fisher Scientific] | Can be substituted www.fishersci.com |
| Quatricide PV-15 | Pharmacal | PV-15 | Antimicrobial disinfectant; can be substituted www.pharmacal.com |
| Rat Gas Anesthesia Masks for Stereotaxic Surgery | Stoelting Company | 51610 | www.stoeltingco.com |
| Rat Stereotaxic Apparatus w/ Ear Bars (45 Degree) | Any | 45 degree bars are recommended to prevent damaging eardrums | |
| Roboz Surgical Instrument Milk | Roboz Surgical | NC9358575 [Fisher Scientific] | Can be substituted; for lubricating instruments during autoclaving www.fishersci.com |
| Rodent Hair Trimmer | Any | ||
| Sodium Chloride | Fisher Scientific | S641-500 [Fisher Scientific] | To make 0.9% saline; reagent grade; USP www.fishersci.com |
| Stainless Steel Microspatula (Blade: 0.75 L x 0.18 in. W) | Fisher Scientific | 21-401-15 [Fisher Scientific] | Can be substituted www.fishersci.com |
| Starrett Pin Vise, 0.000 in - 0.055 in | Any | Nickel-plated or equivalent recommended to resist rusting and corrosion | |
| Sterile Surgical Gloves | Any | ||
| Sterilization Wraps, 20 in x 20 in, Autoclavable | Propper Manufacturing | 11-890-8C [Fisher Scientific] | Useful for wrapping autoclavable supplies and on sterile field during surgery www.fishersci.com |
| Surgical Drape, Sterile/Autoclavable | Any | May need to cut to size for rats | |
| Surgical Gown* | Any | *If required by IACUC | |
| Surgical Mask | Any | ||
| Tuberculin Syringes, Sterile, 1.0 ml | Any | ||
| Weigh Scale | Any | Should have good resolution (in gram units) | |
| Name | Company | Catalog Number | Comments |
| Eyeblink System and Components (assuming 4-rodent system) | |||
| 5 Channel Commutator x 4 | Plastics One, Inc. | SL2 + 3C | www.plastics1.com |
| Bipolar Electrode Cable, Dual 305 x 4 | Plastics One, Inc. | 305-305 80CM TT2 (C) | Provides plug end to bipolar electrode on rat and to commutator; must be modified www.plastics1.com |
| Cable, 5 Channel, Shielded, 26 AWG x 4 | Any | To fabricate commutator cable; this must be made from scratch | |
| Chamber for Operant Test Box (Inside: 24 H x 23 W x 14 D in) x 4 | Med-Associates | Can be substituted; inner dimensions should fit operant test box comfortably, with room for acoustical foam; fit with fan - 55-60 dB www.med-associates.com |
|
| Eyeblink System and Software | JSA Designs | N/A | Proprietary and customized for research lab |
| Heat Shrink Tubing (3/16 in, 1/4 in, 3/8 in, 1/2 in Diameters) | Any | To protect modified commutator cable soldered ends and splices | |
| Melamine Triple Peak Acoustical Foam w/Black Hypalon (24 x 48 in) | McMaster-Carr | 9162T5 | Can be substituted; cut to fit 4 housing chambers www.mcmaster.com |
| Operant Test Box (Exterior 12.5 L x 10 W x 13.5 in H), Complete x 4 | Med-Associates | ENV-007 Custom Package | With stainless steel grid floor and custom top (3 in hole in center for commutator cable) www.med-associates.com |
| Oscilloscope (Optional) | Any | Recommended minimum specs: 200 MHz analog bandwidth, 1 GS/s real-time sampling, 4 channels; see www.picotech.com /td> |
|
| Piezo Tweeters (Speakers) x 4 (7 x 3 in) | MCM Electronics | 53-805 | Must match frequency range specifications for eyeblink system (2500 Hz - 25 KHz) www.mcmelectronics.com |
| Soldering Station, Solder, Flux, Tinner | Any | For soldering 26 AWG cables to female sockets (that fit male relia-tac contact pins) and bipolar plugs | |
| Stimulus Isolators x 4 | WPI International | A365 | These units run on 16-9V alkaline batteries; a suitable rechargeable version (A365R) is available www.wpiinc.com |
| Tripolar Electrode Cable for SL3C Commutator x 4 | Plastics One, Inc. | 335-335 80cm TT3 C | Provides plug end to EMG headstage on rat and to commutator; must be modified www.plastics1.com |
| USB LED Lights x 4 | Any | USB-based lights do not cause electrical "noise" with the EMG signals from the rats www.plastics1.com |
|
| Webcams x 4, Surveillance Software | Any | ||
| PC Computer Running MS Windows OS | Any |
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