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Neurociência

軽度外傷性脳損傷の覚醒閉鎖頭部損傷モデルを用いたシナプス可塑性変化の評価

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

Summary

ここでは、海馬のシナプス可塑性に対する軽度の外傷性脳損傷(r-mTBI)の繰り返しの影響を調べるために、覚醒閉鎖頭部損傷モデルをどのように使用できるかを示しています。このモデルは、患者におけるr-mTBIの重要な特徴を再現し、 in vitro 電気生理学と組み合わせて使用 されます。

Abstract

軽度の外傷性脳損傷(mTBI)は、北米で一般的な健康問題です。臨床集団への翻訳可能性を高めるために、前臨床環境でクローズドヘッドmTBIの生態学的に有効なモデルを利用するという圧力が高まっています。覚醒閉鎖頭損傷(ACHI)モデルは、修正された制御された皮質インパクターを使用して閉鎖頭損傷を提供し、開頭術や麻酔薬の使用を必要とせずに臨床的に関連する行動障害を誘発します。

この技術は通常、死亡、頭蓋骨骨折、または脳出血を誘発せず、軽度の傷害であることとより一致しています。実際、ACHI手順は軽度であるため、反復mTBI(r-mTBI)を調査する研究に最適です。r-mTBIは、行動症状、神経病理学的変化、および神経変性を引き起こす累積損傷を引き起こす可能性があることを示す証拠が増えています。r-mTBIはスポーツをしている若者によく見られ、これらの損傷は強力なシナプス再編成と髄鞘形成の期間中に発生し、若い人口をr-mTBIの長期的な影響に対して特に脆弱にします。

さらに、r-mTBIは、客観的なスクリーニング手段がほとんどない状態である親密なパートナーの暴力の場合に発生します。これらの実験では、ACHIモデルを使用してr-mTBIを経験した幼若ラットの海馬のシナプス機能を評価しました。損傷後、組織スライサーを使用して海馬スライスを作成し、r-mTBIの1日後または7日後の海馬の双方向シナプス可塑性を評価しました。全体として、ACHIモデルは、mTBIおよびr-mTBI後のシナプス可塑性の変化を研究するための生態学的に有効なモデルを研究者に提供します。

Introduction

外傷性脳損傷(TBI)は重大な健康問題であり、カナダと米国では毎年~200万件の症例があります1,2。TBIはすべての年齢層と性別に影響を及ぼし、特に乳がん、エイズ、パーキンソン病、多発性硬化症など、他のどの疾患よりも発生率が高くなっています3。TBIの有病率にもかかわらず、その病態生理学は十分に理解されておらず、治療の選択肢は限られています。部分的には、これはすべてのTBIの85%が軽度(mTBI)に分類されており、mTBIはこれまで、長期的な神経精神医学的影響なしに限定的で一時的な行動変化のみを引き起こすと考えられていたためです4,5。現在、mTBIの回復には数週間から数年かかることがあり、5,6、より深刻な神経学的状態を引き起こし4、繰り返される「脳震盪下」の影響でさえ脳に影響を与えることが認識されています7。ホッケー/サッカーなどのスポーツのアスリートは、ゲーム/練習セッションごとに>10頭の脳震盪の影響があるため、これは憂慮すべきことです7,8,9,10。

青年はmTBIの発生率が最も高く、カナダでは、10代の若者の約10人に1人が毎年スポーツ関連の脳震盪の治療を求めています11,12。実際には、脳震盪以下の頭部衝撃またはmTBIは、脳にびまん性損傷を引き起こす可能性があり、これはまた、その後の損傷および/またはより深刻な神経学的状態に対してより脆弱な状態を作り出す可能性があります13、14、15、16、17。カナダでは、ローワンの法則により、以前の損傷が脳のさらなる損傷に対する脆弱性を高める可能性があることが法的に認められていますが18、r-mTBIの機構的理解は依然としてひどく不十分です。しかし、シングルおよびr-mTBIは、学年19,20の学習能力に影響を与え、性別固有の結果21,22,23,2 4を持ち、後年の認知能力を損なう可能性があることは明らかです16,25,26。実際、コホート解析では、r-mTBIの早期性と認知症の後期が強く関連している27,28。r-mTBIはまた、高リン酸化タウタンパク質の蓄積と進行性の皮質萎縮を特徴とし、重大な炎症によって沈殿する慢性外傷性脳症(CTE)に関連している可能性があります27,29,30,31。r-mTBIとCTEの関係は現在議論の余地がありますが32、このモデルにより、前臨床環境でより詳細に調査できるようになります。

mTBIは、閉じた頭蓋骨内で発生し、最新のイメージング技術でも検出が難しいため、「目に見えない損傷」とよく説明されます33,34。mTBIの正確な実験モデルは、2つの原則に従う必要があります。第1に、臨床集団35において通常観察される生体力学的力を要約すべきである。第二に、モデルは異質な行動結果を誘発するはずであり、これは臨床集団でも非常に普及している36,37,38。現在、前臨床モデルの大部分はより重症である傾向があり、開頭術、定位固定術、麻酔、および制御された皮質衝撃(CCI)が含まれ、臨床的に通常観察されるよりも重大な構造的損傷とより広範な行動障害を引き起こします33。開頭術を伴う脳震盪の多くの前臨床モデルの別の懸念は、この手順自体が脳に炎症を引き起こし、これがその後の損傷からmTBI症状と神経病理を悪化させる可能性があることです39,40。麻酔はまた、炎症の軽減41、42、43、ミクログリア機能の調節44、グルタミン酸放出45、NMDA受容体を介したCa2+侵入46、頭蓋内圧、および脳代謝47を含むいくつかの複雑な交絡因子を導入する。麻酔はさらに、認知機能を低下させながら、血液脳関門(BBB)透過性、タウ過剰リン酸化、およびコルチコステロイドレベルを増加させることによって交絡を導入します48,49,50,51。さらに、びまん性の閉鎖性損傷は、臨床mTBIの大部分を占めています52。また、性別21、53歳、負傷間隔15、重症度54、負傷数23など、行動の結果に影響を与える可能性のある多数の要因をよりよく研究することもできます。

加速力/減速力(垂直または水平)の方向も、行動的および分子的結果にとって重要な考慮事項です。Mychasiukらの研究では、拡散性閉鎖頭mTBIの2つのモデル、重量減少(垂直方向の力)と横方向の衝撃(水平方向の力)を比較しました55。行動解析と分子解析の両方で、mTBI後のモデルおよび性別依存の不均一な結果が明らかになりました。したがって、直線力と回転力を組み込んでいる間、外科的処置を回避するのに役立つ動物モデルは、これらの損傷が通常発生する生理学的条件をより代表しています33,56。ACHIモデルはこのニーズに応えて作成され、性差を偏らせることが知られている手順(すなわち麻酔)を回避しながら、ラットにおけるmTBIの迅速かつ再現性のある誘導を可能にしました57。

Protocol

すべての動物の手順の承認は、カナダ動物管理評議会(CCAC)の基準に準拠して、ビクトリア大学動物管理委員会によって提供されました。すべてのオスのLong-Evansラットは、社内で飼育または購入されました( 資料表を参照)。 1.住居と繁殖条件 動物が生後(PND)21で離乳する前に、動物を1週間住居環境に順応させます。 ラットを22.5°C±2…

Representative Results

覚醒閉鎖頭部損傷モデルは、幼若ラットにおいてr-mTBIを誘導する実行可能な方法である。ACHIモデルでr-mTBIに曝露されたラットは、明白な行動障害を示さなかった。これらの実験の被験者は、r-mTBI手順中のどの時点でも右への潜時または無呼吸を示さず、これが実際に軽度のTBI手順であったことを示しています。NAPでは微妙な行動の違いが現れました。上記のように、ラットは、0から3までの?…

Discussion

ほとんどの前臨床研究では、臨床集団に見られる生体力学的力を再現しないmTBIのモデルを利用しています。ここでは、ACHIモデルを使用して幼若ラットにr-mTBIを誘導する方法が示されています。r-mTBIのこのクローズドヘッドモデルは、より侵襲的な手順に比べて大きな利点があります。第一に、ACHIは通常、頭蓋骨骨折、脳出血、または死亡を引き起こさず、これらはすべて臨床集団における?…

Declarações

The authors have nothing to disclose.

Acknowledgements

ビクトリア大学のクリスティ研究所のすべてのメンバーに、過去と現在のこのプロトコルの開発への貢献に感謝します。このプロジェクトは、カナダ健康研究所(CIHR:FRN 175042)およびNSERC(RGPIN-06104-2019)からの資金提供を受けて支援されました。 図1 の頭蓋骨グラフィックは、BioRenderで作成されました。

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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Keywords: 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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