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Neuroscienze

使用轻度创伤性脑损伤的清醒闭合性头部损伤模型评估突触可塑性的变化

Published: January 20, 2023
doi:
10.3791/64592
, , , , , , , ,
1Division of Medical Sciences,University of Victoria, 2Island Medical Program,University of British Columbia

Summary

在这里，展示了如何使用清醒闭合性头部损伤模型来检查反复轻度创伤性脑损伤（r-mTBI）对海马突触可塑性的影响。该模型在患者中复制了r-mTBI的重要特征，并与 体外 电生理学结合使用。

Abstract

轻度创伤性脑损伤（mTBIs）是北美普遍存在的健康问题。在临床前环境中利用生态有效的闭头mTBI模型来提高临床人群的可转化性的压力越来越大。清醒闭头损伤 （ACHI） 模型使用改进的受控皮质撞击器来传递闭头损伤，无需开颅或使用麻醉剂即可诱导临床相关的行为缺陷。

这种技术通常不会引起死亡、颅骨骨折或脑出血，并且更符合轻度损伤。事实上，ACHI程序的温和性质使其成为研究重复性mTBI（r-mTBI）的理想选择。越来越多的证据表明，r-mTBI可导致累积性损伤，产生行为症状、神经病理改变和神经变性。r-mTBI在参加体育运动的年轻人中很常见，这些损伤发生在突触重组和髓鞘形成的时期，使年轻人群特别容易受到r-mTBI的长期影响。

此外，r-mTBI发生在亲密伴侣暴力的病例中，这种情况很少有客观的筛查措施。在这些实验中，使用ACHI模型评估了经历过r-mTBI的幼鼠海马的突触功能。受伤后，使用组织切片机制作海马切片，以评估r-mTBI后1天或7天海马体中的双向突触可塑性。总体而言，ACHI模型为研究人员提供了一个生态学上有效的模型来研究mTBI和r-mTBI后突触可塑性的变化。

Introduction

创伤性脑损伤（TBI）是一个重大的健康问题，加拿大和美国每年有~200万例1，2。TBI 影响所有年龄组和性别，发病率高于任何其他疾病，特别是包括乳腺癌、艾滋病、帕金森病和多发性硬化症 3。尽管 TBI 患病率很高，但其病理生理学仍知之甚少，治疗选择有限。部分原因是85%的TBI被归类为轻度（mTBI），而mTBI以前被认为只产生有限和短暂的行为改变，没有长期的神经精神后果4，5。现在人们认识到，mTBI恢复可能需要数周到5，6年，诱发更严重的神经系统疾病4，甚至反复的“亚脑震荡”撞击也会影响大脑7。这是令人震惊的，因为曲棍球/>足球等运动的运动员每场比赛/练习赛有10 次头部亚脑震荡冲击 7、8、9、10。

青少年的mTBI发病率最高，在加拿大，每年约有十分之一的青少年会因运动相关的脑震荡而寻求医疗护理11，12。实际上，任何亚脑震荡头部撞击或mTBI都会对大脑造成弥漫性损伤，这也可能为随后的伤害和/或更严重的神经系统疾病创造更脆弱的状态13，14，15，16，17。在加拿大，通过罗文定律在法律上承认，先前的损伤会增加大脑对进一步损伤的脆弱性18，但对r-mTBI的机制理解仍然严重不足。然而，很明显，单一和r-mTBI会影响学年的学习能力19，20，具有性别特异性结果21，22，23，24，并损害以后生活中的认知能力16，25，26。事实上，队列分析将生命早期的r-mTBI与27，28的后期痴呆密切相关。r-mTBI还可能与慢性创伤性脑病（CTE）有关，其特征是过度磷酸化tau蛋白的积累和进行性皮质萎缩，并由显着炎症诱发27，29，30，31。尽管r-mTBI和CTE之间的联系目前存在争议32，但该模型将允许在临床前环境中更详细地探索它们。

mTBI通常被描述为“看不见的损伤”，因为它发生在闭合的颅骨内，即使使用现代成像技术也很难检测到33，34。mTBI的准确实验模型应遵循两个原则。首先，它应该概括通常在临床人群中观察到的生物力学力35。其次，该模型应该诱导异质性行为结果，这在临床人群中也非常普遍36，37，38。目前，大多数临床前模型往往更严重，涉及开颅术、立体定位头枕、麻醉和控制皮质冲击（CCI），这些模型会产生明显的结构损伤和比临床上正常观察到的更广泛的行为缺陷33。许多涉及开颅术的脑震荡临床前模型的另一个问题是，该程序本身会在大脑中产生炎症，这可能会加剧任何后续损伤引起的mTBI症状和神经病理学39，40。麻醉还引入了几种复杂的混杂因素，包括减少炎症41，42，43，调节小胶质细胞功能44，谷氨酸释放45，通过NMDA受体进入Ca2+46，颅内压和脑代谢47。麻醉通过增加血脑屏障 （BBB） 通透性、tau过度磷酸化和皮质类固醇水平进一步引入混杂，同时降低认知功能48，49，50，51。此外，弥漫性闭头损伤占临床mTBI的绝大多数52。它们还允许人们更好地研究可能影响行为结果的众多因素，包括性别21，年龄53，损伤间隔15，严重程度54和受伤次数23。

加速/减速力的方向（垂直或水平）也是行为和分子结果的重要考虑因素。Mychasiuk及其同事的研究比较了弥漫性闭头mTBI的两种模型：重量下降（垂直力）和横向冲击（水平力）55。行为和分子分析均揭示了mTBI后异质的模型和性别依赖性结局。因此，有助于避免外科手术的动物模型，同时包含线性和旋转力，更能代表这些损伤通常发生的生理条件33，56。ACHI模型是为了满足这一需求而创建的，允许在大鼠中快速和可重复地诱导mTBI，同时避免已知会偏向性别差异的程序（即麻醉）57。

Protocol

维多利亚大学动物护理委员会根据加拿大动物护理委员会（CCAC）标准批准了所有动物程序。所有雄性Long-Evans大鼠都是在内部繁殖或购买的（见 材料表）。 1. 饲养和繁殖条件 让动物适应其住房环境 1 周，然后在产后断奶日 （PND） 21. 将大鼠保持在22.5°C±2.5°C的标准笼舍中， 随意获取食物 和水，在12小时的光照/黑暗循环中。…

Representative Results

清醒闭合头部损伤模型是在幼鼠中诱导r-mTBI的可行方法。使用ACHI模型暴露于r-mTBI的大鼠没有表现出明显的行为缺陷。这些实验中的受试者在r-mTBI手术过程中的任何时候都没有表现出右潜伏期或呼吸暂停，这表明这确实是一个轻微的TBI手术。在国家行动方案中确实出现了微妙的行为差异;如上所述，对大鼠的四个感觉运动任务（惊吓反应，肢体伸展，光束行走和旋转光束）进行评分，范围从0到3，其…

Discussion

大多数临床前研究都使用了mTBI模型，这些模型不能概括临床人群中观察到的生物力学力。在这里，展示了如何使用ACHI模型在幼年大鼠中诱导r-mTBI。这种封闭式 r-mTBI 模型比更具侵入性的手术具有显着优势。首先，ACHI通常不会导致颅骨骨折，脑出血或死亡，所有这些都是临床人群中“轻度”TBI的禁忌症61。其次，ACHI不需要使用开颅术，这很重要，因为已知它们会引起炎症反应，?…

Divulgazioni

The authors have nothing to disclose.

Acknowledgements

我们感谢维多利亚大学克里斯蒂实验室的所有成员，无论过去还是现在，他们为制定该协议做出了贡献。该项目得到了加拿大卫生研究所（CIHR：FRN 175042）和NSERC（RGPIN-06104-2019）的资金支持。 图 1 的头骨图形是使用 BioRender 创建的。

Materials

3D-printed helment  Designed and constructed by Christie laboratory (See Specifications in Christie et al. (2019), Current Protocols in Neuroscience) 
Agarose  Fisher Scientific (BioReagents) BP160500
Anesthesia chamber Home Made N/A Plexiglass Container
Automatic Heater Controller Warner Electric TC-324B
Axon Digidata Molecular Devices 1440A Low-noise Data Acquisition System
Balance beam  Can be constructed or purchased (100 cm long x 2 cm wide x 0.75 cm thick)
Calcium Chloride Bio Basic Canada Inc.  CD0050 For aCSF
Camera Dage MTI NC-70
Carbogen tank Praxair MM OXCD5C-K Carbon Dioxide 5%, Oxygen 95%
Clampex Software Molecular Devices Clampex 10.5 Version
Compresstome Vibrating Microtome Precisionary VF 310-0Z
Concentric Bipolar Electrode FHC Inc. CBAPC75
Dextrose (D-Glucose) Fisher Scientific (Chemical) D16-3 aCSF
Digital Stimulus Isolation Amplifier   Getting Instruments, Inc.  Model 4D
Disodium Phosphate Fisher Scientific (Chemical) S373-500 PBS
Dissection Tools
Feather Double Edge Blade Electron Microscopy Sciences 72002-10
Filter Paper Whatman 1 1001-055
Flaming/Brown Micropipette Puller Sutter Instrument P-1000
Hair Claw Clip Can be obtained from any department store
Home and Recovery Cages Normal rat cages from animal care unit.
Hum Bug Noise Eliminator Quest Scientific  726300
Isoflurane USP Fresenius Kabi CP0406V2
Isotemp 215 Digital Water Bath Fisher Scientific  15-462-15
Leica Impact One CCI unit Leica Biosystems Tip is modified to hold 7mm rubber impact tip
Long-Evans rats, male Charles River Laboratories (St. Constant, PQ)
Low-Density Foam Pad 3" polyurethane foam sheet 
Magnesium Chloride Fisher Scientific (Chemical) M33-500 aCSF
Male Long Evans Rats Charles River Laboratories Animals ordered from Charles River Laboratories, or pups bred at the University of Victoria
MultiClamp 700B Amplifier Molecular Devices Model 700B
pH Test Strips VWR Chemicals BDH BDH83931.601
Potassium Chloride Fisher Scientific (Chemical) P217-500 aCSF, PBS
Potassium Phosphate Sigma P9791-500G PBS
Push Button Controller Siskiyou Corporation  MC1000e Four-axis Closed Loop Controller Push-Button
Sample Discs ELITechGroup SS-033 For use with Vapor Pressure Osmometer
Small towel
Sodium Bicarbonate Fisher Scientific (Chemical) S233-500 aCSF
Sodium Chloride Fisher Scientific (Chemical) S271-3 For aCSF, PBS
Sodium Phosphate Fisher Scientific (Chemical) S369-500 aCSF
Soft Plastic Restraint Cones Braintree Scientific model DC-200
Stopwatch Many lab members use their iPhone for this
Table or large cart with raised edges  For NAP and ACHI
Thin Wall Borosilicate Glass (with Filament) Sutter Instrument BF150-110-10 Outside diameter: 1.5 mm; Inside diameter: 1.10 mm; Length: 10 cm
Upright Microscope Olympus Olympus BX5OWI 5x MPlan 0.10 NA Objective lens
Vapor Pressure Osmometer Vapro Model 5600 aCSF should be 300-310 mOSM
Vetbond Tissue Adhesive 3M 1469SB
Vibraplane Vibration Isolation Table Kinetic Systems 9101-01-45
DOWNLOAD MATERIALS LIST

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Synaptic PlasticityAwake Closed-head Injury ModelMild Traumatic Brain Injury (mTBI)Transverse Hippocampal SlicesNeurological Assessment Protocol (NAP)Electrophysiological RecordingsBrain DissectionSlice Preparation
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Christie, B. R., Gross, A., Willoughby, A., Grafe, E., Brand, J., Bosdachin, E., Reid, H. M. O., Acosta, C., Eyolfson, E. Assessing Changes in Synaptic Plasticity Using an Awake Closed-Head Injury Model of Mild Traumatic Brain Injury. J. Vis. Exp. (191), e64592, doi:10.3791/64592 (2023).
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