The authors would like to thank Irene Ma, Rose Tobais, and Jong Rho for their technical assistance. Funding was provided to MJE by the Department of Pediatrics at the University of Calgary, the Alberta Children&#8217;s Hospital Foundation (ACHF) and the Alberta Children&#8217;s Hospital Research Institute (ACHRI). The Postdoctoral fellowship for RM was provided by ACHF.

注：全ての実験は、動物管理のカナダ人評議会に合わせて実施し、カルガリー大学、動物ケア倫理委員会によって承認された。 1.繁殖と動物の準備<ol><li>標準繁殖プロトコルに従って、社内標準の実験動物のサプライヤーや品種の仔から妊娠ラットを注文。 </li><li>暗サイクル：食物および水を自由摂取アクセスハウスのすべての動物を、温度制御されたラット収容室（21℃）で、そのは、12：12時間の明に維持されている。 </li><li>子犬は生後21日目（P21）に到達すると、3または4の同性グループで母親と家から子犬を離乳させる。 </li></ol>軽度外傷性脳損傷（MTBI）装置の2.セットアップ<ol><li>所望の質量（ 例えば、150グラム）の手順、ミル重みの開始前。安全に釣り糸が第ことを可能にする重量の上端に金属ループを取り付ける重みにXED。 </li><li>鋭利なカミソリの刃でスズ箔のスコア。得点スズ箔は、ラットの体重をサポートしていますが、重量が頭部衝撃後のラットの加速に干渉しないことを確認してください。 </li><li>それはピンと張っているように、コレクションのスポンジ（38×25×15 cm 3）で（ 図1）を含むテープ透明なプラスチック（38のx 27 xは27センチメートル3）からなるU字形の段階にスコア化スズ箔。 </li><li>透明なプラスチック製のガイドチューブの下の正しい位置にU字型のプラスチック製のステージを置く。 </li><li>クランプスタンド付きの場所にプラスチック製のガイドチューブ（X 1.5メートル2.2センチメートル径）を持ち、それが3.5センチメートル得点スズ箔の上になるようにガイドチューブを配置する。 </li><li>体重の底が自由に2.5センチメートル得点スズ箔の上にハングアップすることを確実に重量に金属ループを通して釣り糸を取り付けます。 </li><li>確実にクランプスタンドに釣り糸を添付。 注：ハマグリに重みをテザリングラットは、コレクションスポンジへの影響）から落下している間スズ箔上2.5センチメートルの高さでのpスタンドは再ヒットを防ぎます。 </li><li>釣り糸でプラスチック製のガイドチューブを通して体重を引き上げ、1.0メートルで、六角レンチピンで所定の位置にそれを保持する。 </li></ol> MTBIの3誘導<ol><li>ラットは、手続きの部屋にP30の移動ケージに達すると。 </li><li>イソフルランチャンバー内にラットを置き、足や尾ピンチに非応答になるまで軽くラットを麻酔。 </li><li>すばやく落錘のパスで直接その頭を放ちスズ箔上のラットの胸ダウンを置く。 図2を参照してください。ラットが移動したり、ウェイクアップ、それが得点スズ箔上に配置することができる前に、足や尾ピンチに非応答するまで、イソフルラン室に戻り、再び開始するために開始されます。 </li><li>重量はプラスチック製のガイドチューブを垂直に落下し、頭の上にラットを打つできるように、アレンキーピンを引き。目Eラットは急速に仰臥位で180°回転し、土地を受けることになる。 </li><li>すぐに収集スポンジからラットを削除し、綿先端アプリケーターでラットの頭部への局所リドカインを適用します。 </li><li>市販の加熱パッド上にそれを設定することによって加熱されるクリーンケージ内の仰臥位でラットを置きます。 </li><li>ストップウォッチを使用して、またはデジタルタイマーは、「時間から右へ」を取得する。タイム·トゥ·右は、麻酔から覚ますと発生しやすい位置に仰臥位から​​フリップやウォーキングを開始するために、ラットに要する時間である。 </li><li>それは通常の動作（グルーミング、ウォーキング、探検など ） を回復した後にそのホームケージにラットを返す。 </li><li>繰り返しますMTBIを必要とする追加の各ラットについて3.2から3.8を繰り返します。 </li><li>繰り返しのMTBI実験のために複数の時点で同じラットに手順を繰り返します。 </li></ol>シャム傷害の4誘導<ol><li>軽くアネスト岩田それは足や尾のピンチに非応答になるまで、イソフルランでラットをhetize。 </li><li>すばやく落錘のパスで直接その頭を放ちスズ箔上のラットの胸ダウンを置く。 </li><li>プラスチック製のガイドチューブからアレンキーピンを引いたことなく、スズ箔からラットを取り出し、綿先端アプリケーターでラットの頭部への局所リドカインを適用します。 </li><li>市販の加熱パッド上にそれを設定することによって加熱されるクリーンケージ内の仰臥位でラットを置きます。 </li><li> 「時間から右へ」を取得するためにストップウォッチやデジタルタイマーを使用してください。 </li><li>それは通常の動作（グルーミング、ウォーキング、探検など ） を回復した後にそのホームケージにラットを返す。 </li></ol>ビームによるMTBI 5.実証試験8ウォーキング <ol><li>手続き部屋にMTBIまたは偽傷害の戻り動物の誘導後24時間。 </li><li>クリーン保持ケージにラットを転送と家庭ケージのオープンエンド部分はビームの狭い側を向くように165センチメートルテーパービームの狭い最後にラットのホームケージを置く。 注：テーパービーム165センチです。ビームの中心プラットフォームは、ワイド端で6センチ狭い端1.75センチ幅を有する。中心ビームが時ラットの足スリップ安全性を提供する棚部（幅2cmとセンタービーム2以下cm）を有している。テスト中にビームから落ちる可能性ラットへの傷害の危険を減らすために、ビーム下のフォームパッドを配置します。 </li><li>テーパー梁のワイド端でビデオカメラを置き、位置/ビデオを見て研究者が明らかにテーパービームの全長のためにラットの動きを見ることができることを保証するためにビデオカメラをズーム。 </li><li>テーパー梁のワイド端にラットを置き、そのホームケージにビームを歩いて渡ることをお勧めします。ラットがテーパー状ビームを横切ると、レイに少なくとも60秒間そのホームケージにラットを残すターゲットの場所をのnForce。これは試験＃1であり、分析には含まれていません。 </li><li>上のビデオカメラの電源を入れ、ラットは、ビーム歩行タスクを4回追加（ホームケージで60秒の強化期間を維持する）を完了することができます。ラットはすべての試験を完了すると、そのホームケージにラットを返す。 </li><li>スコアに、発生し、時間/期間は、個々の試験のために、ビームを横断する後肢の足-スリップの数を記録。各ラットについて、ビームを横切るように後肢足グラスと時間の平均数を計算するためにこのデータを使用する。 </li></ol>

<ol>
	<li>DeWitt, D., Perez-Polo, R., Hulsebosch, C., Dash, P., Robertson, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Challenges+in+the+development+of+rodent+models+of+mild+traumatic+brain+injury.">Challenges in the development of rodent models of mild traumatic brain injury.</a> Journal of Neurotrauma. 30, 688-701 (2013).</li><li>Xiong, Y., Mahmood, A., Chopp, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Animal+models+of+traumatic+brain+injury.">Animal models of traumatic brain injury.</a> Nature Reviews Neuroscience. 14, 128-142 (2013).</li><li>Zhang, Z., Lerner, S., Kobiessy, F., Hayes, R., Wang, K., Yan, Q. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Systems+biology+and+the+anostic+approach+to+drug+discovery+and+development+to+treat+traumatic+brain+injury.">Systems biology and the anostic approach to drug discovery and development to treat traumatic brain injury.</a> Systems Biology in Drug Discovery and Development: Methods and Protocols, Methods in Molecular Biology. , .</li><li>Viano, D., Casson, I., Pellmen, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Concussion+in+profession+football:+Biomechanics+of+the+struck+player+-+Part+14.">Concussion in profession football: Biomechanics of the struck player - Part 14.</a> Neurosurgery. 61, 313-327 (2007).</li><li>Marmarou, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+new+model+of+diffuse+brain+injury+in+rats:+Part+1+-+Pathophysiology+and+biomechanics.">A new model of diffuse brain injury in rats: Part 1 - Pathophysiology and biomechanics.</a> Journal of Neurosurgery. 80, 291-300 (1994).</li><li>Mychasiuk, R., Farran, A., Esser, M. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+an+experimental+rodent+model+of+pediatric+mild+traumatic+brain+injury.">Assessment of an experimental rodent model of pediatric mild traumatic brain injury.</a> Journal of Neurotrauma. 31 (8), (2014).</li><li>Kane, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+mouse+model+of+human+repetitive+mild+traumatic+brain+injury.">A mouse model of human repetitive mild traumatic brain injury.</a> Journal of Neuroscience Methods. 203, 41-49 (2012).</li><li>Schallert, T., Woodlee, M., Fleming, S., Krieglstein, J., Klumpp, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Disentangling+multiple+types+of+recovery+from+brain+injury.">Disentangling multiple types of recovery from brain injury.</a> Pharmacology of Cerebral Ischemia. , (2002).</li><li>Mychasiuk, R., Hehar, H., Farran, A., Esser, M. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mean+Girls:+Sex+differences+in+the+effects+of+mild+traumatic+brain+injury+on+the+social+dynamics+of+juvenile+rat+play+behaviour.">Mean Girls: Sex differences in the effects of mild traumatic brain injury on the social dynamics of juvenile rat play behaviour.</a> Behavioural Brain Research. 259, (2014).</li><li>Centers for Disease Control and Prevention. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Report to congress on mild traumatic brain injury in the United States: Steps to prevent a serious public health problem. , 1-47 (2003).</li></ol>

No competing financial interests exist.

Reliable modelling systems are needed to effectively cultivate basic science research that has significant translational validity. In response to rising occurrences and popular media, the investigation of mTBI and concussion has become a priority in many disciplines. However, despite increased research, there have been only incremental improvements in therapeutic strategies and treatment options 3. This lack of progress may be partially due to a discrepancy between the modeling systems employed and actual injury etiology. The majority of studies utilized rodent models that failed to reproduce the important biomechanical forces and appropriate post-injury symptomology. The current human definition of mTBI specifies that the injury results from acceleration and deceleration forces associated with a blunt trauma 10. The modified weight drop technique described here is therefore an ideal model for the study of mTBI and concussion because it uses a glancing impact to cause rapid rotational acceleration and deceleration to the head of an unrestrained animal, mimicking the biomechanical forces identified in sports-related injuries and automobile accidents. In addition, this model is easily adapted to examine repetitive mTBI, a phenomena that is emerging as a serious medical and socioeconomic issue. Studies indicate that rodents may be exposed to a series of 10 distinct mTBIs with minimal mortality 7. Finally, the method is inexpensive and can be carried out rapidly, allowing for high-throughput examination of a many therapeutic compounds and treatment regiments. 
Just as with any procedural technique, certain aspects of the protocol are particularly important to the generation of reliable results. First, the tin foil needs to be scored effectively. If the tin foil is not properly scored, the force imparted by the weight during the glancing impact will not be enough to propel the juvenile rat through the tin foil onto the collection sponge. In these situations, the rat will remain in the starting position (chest down on the tin foil) and the mTBI will result from the blunt trauma from the weight impacting the stationary head, not the rotational acceleration and deceleration desired. Second, during the induction of the mTBI and the sham injury, the level of anesthetic applied to each rat should be consistent. Owing to the fact that time-to-right is used as marker of mTBI, the researcher should try to ensure that animals receiving a mTBI and animals receiving a sham injury are exposed to similar levels of anesthetic. A major advantage to this technique over many other TBI procedures is the low level and duration of anesthesiology. However, the juvenile rat needs to be non-responsive to a toe or tail pinch to ensure they do not wake-up on the stage before the injury is induced. Finally, in order to maintain a consistent injury etiology, the positioning of the rat&#8217;s head is particularly important. Ideally the weight should impact the center of the dorsal surface of the head. Caution should be taken to avoid positioning the path of the weight too near the caudal/posterior portion of the head, as impacting the brainstem and cerebellum is associated with increased mortality and seizure activity. 
Based upon the biomechanical pathophysiology of injury induction and the behavioural outcomes examined, the modified weight-drop technique appears to be a reliable model for the investigation of paediatric mTBI and concussion. Although preliminary studies of this novel model have assessed some basic molecular and structural changes 7 future studies will be needed to ascertain how the brain responds to a mTBI with this injury etiology. An in-depth analysis of the neuroanatomical and biological changes that occur at the cellular and epigenetic level would increase model validity and translational applicability. In addition to stimulating the generation of targeted pharmacological therapies, understanding the pathophysiological changes that occur in the brain in response to mTBI and concussion would also direct the research related to clinical biomarkers that have the ability to predict outcomes following injury.

中等度から重度の外傷性脳損傷（TBI）の生成のための多くの広く使用されている方法があるが、非常に少数の技術は穏やかな誘導するために開発されており、げっ歯類における頭部外傷を閉じた。軽度の外傷性脳損傷（MTBI）は1を組み合わせた中等度および重度の脳損傷の3倍一般的であるという事実のために、MTBIの信頼性モデルは、病態生理、神経生物学および行動の結果、および治療 ​​戦略に関する研究を促進するために必要とされる。たとえば、200の上にありました、過去10年間で、現在の動物モデル2の制限などの理由では、TBI 3の治療のための臨床薬物試験を失敗した。モデリングシステムはトランスレーショナルリサーチ研究のために生成される場合、調査結果の適用が実装モデルの妥当性に依存している。 MTBI /脳震盪の研究のために、信頼性の高い動物モデルは、生体力学的な力のresponを模倣していないだろう傷害の病因のためsibleするだけでなく、臨床的に関連する人口によって報告されたものと一致する症状を誘発するだろう。子供はMTBI特に高い危険にさらされているので、また、最適なモデリングシステムは、成人同等に加えて、若い少年げっ歯類に適用可能である。 選手がmTBIsまたは震とう脳損傷を負っているような状況の生体力学的分析は怪我のために最も重要な予測因子は、急速なヘッド加速と高速の影響4であることを示している。現在TBIの誘導のために用いられるげっ歯類モデルの大部分は、ヘッド5（総説については2を参照）のほとんど又は全く動きを可能にする。ここで概説モデルは、被験者の頭と体に加速/減速力を加える180°回転し、自由落下を伴う物理的に拘束されていない幼若ラットの頭部に高速のインパクトを実現します。 Tここでは、MTBIの誘導のため、この修正された重量損失の技術に関連する2つの主要な利点である。まず、モデルは（6を参照の行動の結果の完全な説明のために）は、脳への明白な損傷を与えることなく、症状のような震とう臨床的に関連を生成します。また、この修正された重量ドロップ技術が異質な成果をポスト震とう症候群の臨床報告と一致して生成します。 MTBIの影響が有意であるが、複数のアウトカム指標に検討したときにMTBIを経験したげっ歯類の間に実質的な変動がある。第二に、この方法は、反復MTBI 7の研究を可能にします。既存のTBIモデルの大部分は重篤な傷害を負わせるように、全体の皮質への広範​​な損傷を与えることなく、反復的なTBIを研究するために第二の損傷、およびほぼ不可能を誘導することがしばしば困難である。 したがって、寄り付きために改変重量ドロップ技術を使用する主な根拠MTBIのctionはより密接に脳震盪と少年集団における反復的なTBIの病態生理と症状を表してけがを生成することである。スポーツに関連するMTBIの発生率の増加により、落下し、自動車事故、特に小児期に、MTBIのこのユニークなげっ歯類モデルが簡単に複数のヒットに適用することができ震とうのような脳損傷の研究のための貴重なツールと研究者を提供していますパラダイム。

<table><tbody><tr><td>Brass Weights</td><td>Ginsberg Scientific</td><td>7-2500-2</td><td>Need to have metal loop attached to base</td></tr><tr><td>Alluminum Foil</td><td>Alcan</td><td></td><td>Available at most grocery stores</td></tr><tr><td>Masking Tape</td><td></td><td></td><td>Commercially available&amp;nbsp;</td></tr><tr><td>U-Shaped Plastic Stand</td><td></td><td></td><td>Constructed by Laboratory</td></tr><tr><td>Clamp Stand</td><td>Sigma-Aldrich</td><td>Z190357</td><td></td></tr><tr><td>Plastic Guide Tube</td><td></td><td></td><td>Could be constructed or purchased at a hardware store</td></tr><tr><td>Fishing Line</td><td>Angler 10lb&amp;nbsp;</td><td></td><td>Purchased from a sporting goods retailer&amp;nbsp;</td></tr><tr><td>Isoflurane</td><td>Pharmaceutical Partners of Canada</td><td>DIN 02237518</td><td>Inhalation Anesthetic</td></tr><tr><td>Topical Lidocaine (30ml)</td><td>Astra Zeneca</td><td>DIN 0001694</td><td>Xylocaine Jelly 2%&amp;nbsp;</td></tr><tr><td>Cotton Swabs</td><td></td><td></td><td>Commercially available&amp;nbsp;</td></tr><tr><td>Heating Pad - 3 heat setting</td><td></td><td></td><td>Commercially available&amp;nbsp;</td></tr><tr><td>Stop Watch</td><td>Sportline</td><td>L303</td><td>Purchased from a sporting goods retailer&amp;nbsp;</td></tr><tr><td>Video Camera</td><td>Sony</td><td>HDR-CX260V</td><td></td></tr><tr><td>Sprague Dawley Rats</td><td>Charles River Laboratories</td><td>SAS SD 40</td><td>Male and females ordered from Charles River Laboratories and pups bred in-house</td></tr><tr><td>Balance Beam</td><td></td><td></td><td>Constructed by Laboratory</td></tr></tbody></table>

a novel model of mild traumatic brain injury for juvenile rats

Despite growing evidence that childhood represents a major risk period for mild traumatic brain injury (mTBI) from sports-related concussions, motor vehicle accidents, and falls, a reliable animal model of mTBI had previously not been developed for this important aspect of development. The modified weight-drop technique employs a glancing impact to the head of a freely moving rodent transmitting acceleration, deceleration, and rotational forces upon the brain. When applied to juvenile rats, this modified weight-drop technique induced clinically relevant behavioural outcomes that were representative of post-concussion symptomology. The technique is a rapidly applied procedure with an extremely low mortality rate, rendering it ideal for high-throughput studies of therapeutics. In addition, because the procedure involves a mild injury to a closed head, it can easily be used for studies of repetitive brain injury. Owing to the simplistic nature of this technique, and the clinically relevant biomechanics of the injury pathophysiology, the modified weight-drop technique provides researchers with a reliable model of mTBI that can be used in a wide variety of behavioural, molecular, and genetic studies.

上述の修正された重量ドロップ手法は幼若ラットにおける軽度の外傷性脳損傷（MTBI）の誘導のために信頼できる方法である。 150グラムの影響の重みを利用して、この技術は、成功して50〜120グラムの範囲幼若ラットに適用されている。また、手順が簡単に反復MTBIの研究のために同じ動物で繰り返すことができる。 （ 図3）シングルMTBIの展示の時間から右への増加を経験すると思われる動物は起床時に唖然とするが、それらは急速に正常な活動を再開し、シャム損傷動物からの視覚的に区別できない。傷害がかすめる影響に関連するすべての痛みがなくなり、穏やかな、局所リドカインであることを考えると、必要な唯一の鎮痛薬である。鎮痛剤は、一般的な炎症性および回復プロセスを妨害することが知られているように、この研究のために重要である。明白な症状がないため、ビーム歩行タスクがに信頼性があるMTBIの誘導を検証するために使用することができるオール。それは、MTBIを経験していないすべての動物は、ビーム歩行タスク上の欠損を示すことが、注意することが重要であるが、偽の負傷と少年ラットと比較した場合、グループとして、MTBIを持つ少年ラットは、かなり多くの後肢の足-スリップを実証する（ 図4）。 この修​​正された重量ドロップ技術のもう一つの重要な特徴は、傷害の誘導中幼若ラットに適用される拘束の欠如である。急速な回転加速と減速が続くヘッドにかすめる打撃を提供することにより、このモデルは、より密接にMTBIと脳震盪に起因する生体力学的な力を表している。この手順は、若年ラットまたは成体マウスに適用した場合、死亡率は極めて低い（202分の7幼若動物〜3.4％の死亡率）、及び頭蓋骨骨折および頭蓋内の出血は6,7非常に稀である。さらに、このモデルは、臨床的に関連SYを生成mptomology。シングルMTBIを経験した少年げっ歯類は、抑う ​​つ様行動の増加実行機能の欠損、および変更された社会的相互作用6,9と一緒に、バランスとモーター行動の赤字を示した。同様に、成体マウスは、時間7で回復する軽度のバランスと協調赤字を表示します。最後に、このモデルを用いてMTBIの誘導が最小限の麻酔薬を必要とする外科的調製を含むか、頭蓋骨に穴を掘るしない。結果は、したがって、手術や麻酔薬によってトリガ交絡炎症や免疫学的効果によってバイアスされていません。さらに、急速な回復時間と開放創の欠如は、げっ歯類がMTBIを体験した直後に発生する追加試験パラダイムの開始を可能にします。 <img alt="図1" fo:content-width="5in" src="/files/ftp_upload/51820/51820fig1highres.jpg" width="500" /> 図1： </strong<html> &gt; すべての適切な寸法のU字型のプラスチックステージと収集スポンジの Cのアートゥーン表現。10cmの距離は、幼若ラットを確保するために、コレクションスポンジとプラスチックステージの上面との間に維持されなければならない180を完了するのに十分な時間がある°回転。 <img alt="図2" fo:content-width="5in" src="/files/ftp_upload/51820/51820fig2highres.jpg" width="500" /> 図2：傷害誘導プラットフォームの（A）写真表現。ヘッドが直接落錘以下になるように幼若ラットを獲得スズ箔上の胸ダウンに配置される。傷害誘導プラットフォームの（B）側面図。MTBIの誘導に使用される量（C）写真デモ。 アップロード/ 51820 / 51820fig3highres.jpg &quot;幅=&quot; 500 &quot;/&gt; 図3：MTBIの出品に有意な増加を受けているシングルMTBIと偽の負傷を経験した若年ラット（* P &lt;0.01）ラットを経験した時から右への幼若ラットの間での平均の違いのグラフィカル表現仰臥位から​​身を正すのに必要な時間の長さ。 <img alt="図4" fo:content-width="5in" src="/files/ftp_upload/51820/51820fig4highres.jpg" width="500" /> 図4：シングルMTBIと偽の負傷を経験した若年ラット（* p &lt;0.05）を経験した若年ラットによるビームウォーキングタスクに展示後肢足-スリップの平均数のグラフ表示。

Watch this Scientific Journal Video about A Novel Model of Mild Traumatic Brain Injury for Juvenile Rats at JoVE.com

A Novel Model of Mild Traumatic Brain Injury for Juvenile Rats

The modified weight-drop technique is an easy, cost-effective procedure used for the induction of mild traumatic brain injury in juvenile rats. This novel technique produces clinically relevant symptomology that will advance the study of mild traumatic brain injury (mTBI) and concussion.

少年ラット用マイルド外傷性脳損傷の新規モデル

Despite growing evidence that childhood represents a major risk period for mild traumatic brain injury (mTBI) from sports-related concussions, motor ...

a-novel-model-of-mild-traumatic-brain-injury-for-juvenile-rats

Universidad de Cartagena UDEC

Research

JoVE Journal

Medicine

23.5K ビュー.  University of Calgary. The modified weight-drop technique is an easy, cost-effective procedure used for the induction of mild traumatic brain injury in juvenile rats. This novel technique produces clinically relevant symptomology that will advance the study of mild traumatic brain injury (mTBI) and concussion. 

ビデオ: A Novel Model of Mild Traumatic Brain Injury for Juvenile Rats

Detecting Behavioral Deficits in Rats After Traumatic Brain Injury

With the increasing incidence of traumatic brain injury (TBI) in both civilian and military populations, TBI is now considered a chronic disease; however, few studies have investigated the long-term effects of injury in rodent models of TBI. Shown here are behavioral measures that are well-established in TBI research for times early after injury, such as two weeks, until two months. Some of these methods have previously been used at later times after injury, up to one year, but by very few laboratories. The methods demonstrated here are a short neurological assessment to test reflexes, a Beam-Balance to test balance, a Beam-Walk to test balance and motor coordination, and a working memory version of the Morris water maze that can be sensitive to deficits in reference memory. Male rats were handled and pre-trained to neurological, balance, and motor coordination tests prior to receiving parasagittal fluid percussion injury (FPI) or sham injury. Rats can be tested on the short neurological assessment (neuroscore), the beam-balance, and the Beam-Walk multiple times, while testing on the water maze can only be done once. This difference is because rats can remember the task, thus confounding the results if repeated testing is attempted in the same animal. When testing from one to three days after injury, significant differences are detected in all three non-cognitive tasks. However, differences in the Beam-Walk task were not detectable at later time points (after 3 months). Deficits were detected at 3 months in the Beam-Balance and at 6 months in the neuroscore. Deficits in working memory were detected out to 12 months after injury, and a deficit in a reference memory first appeared at 12 months. Thus, standard behavioral tests can be useful measures of persistent behavioral deficits after FPI.

The goal of the behavioral tests presented here is to detect functional deficits in rats after traumatic brain injury. Four specific tests are presented that detect deficits in behaviors to reflect the damage to specific brain areas at times extending to one year after injury.

外傷性脳損傷後のラットの行動の赤字を検出

With the increasing incidence of traumatic brain injury (TBI) in both civilian and military populations, TBI is now considered a chronic disease; however, ...

行動学

Assessing Dominant-Submissive Behavior in Adult Rats Following Traumatic Brain Injury

Competition over resources such as food, territory, and mates significantly influences relationships within animal species and is mediated through social hierarchies that are often based on dominant-submissive relationships. The dominant-submissive relationship is a normal behavioral pattern among the individuals of a species. Traumatic brain injury is a frequent cause of social interaction impairment and the reorganization of dominant-submissive relationships in animal pairs. This protocol describes submissive behavior in adult male Sprague-Dawley rats after the induction of traumatic brain injury using a fluid-percussion model compared to naive rats through a series of dominant-submissive tests performed between 29 days and 33 days after induction. The dominant-submissive behavior test shows how brain injury can induce submissive behavior in animals competing for food. After traumatic brain injury, the rodents were more submissive, as indicated by them spending less time at the feeder and being less likely to arrive first at the trough compared to the control animals. According to this protocol, submissive behavior develops after traumatic brain injury in adult male rats.

The present protocol describes a rat model of fluid percussion-induced traumatic brain injury followed by a series of behavioral tests to understand the development of dominant and submissive behavior. Using this model of traumatic brain injury in conjunction with specific behavioral tests enables the study of social impairments following brain injury.

外傷性脳損傷後の成体ラットにおける優性服従行動の評価

Competition over resources such as food, territory, and mates significantly influences relationships within animal species and is mediated through social ...

A Mouse Model of Single and Repetitive Mild Traumatic Brain Injury

Mild Traumatic Brain Injury (mTBI) can result in the acute loss of brain function, including a period of confusion, a loss of consciousness (LOC), focal neurological deficits and even amnesia. Athletes participating in contact sports are at high risk of exposure to large number of mTBIs. In terms of the level of injury in a sporting athlete, a mTBI is defined as a mild injury that does not cause gross pathological changes, but does cause short-term neurological deficits that are spontaneously resolved. Despite previous attempts to model mTBI in mice and rats, many have reported gross adverse effects including skull fractures, intracerebral bleeding, axonal injury and neuronal cell death. Herein, we describe our highly reproducible animal model of mTBI that reproduces clinically relevant symptoms. This model uses a custom made pneumatic impactor device to deliver a closed-head trauma. This impact is made under precise velocity and deformation parameters, creating a reliable and reproducible model to examine the mechanisms that contribute to effects of single or repetitive concussive mTBI.

Athletes absorb several hundred mild traumatic brain injuries (mTBI)/concussions every year; however, the consequence of these on the brain is poorly understood. Therefore, an animal model of single and repetitive mTBI that consistently replicates clinically relevant symptoms provides the means to advance the study of mTBI and concussion.

片性および反復性軽度外傷性脳損傷のマウスモデル

Mild Traumatic Brain Injury (mTBI) can result in the acute loss of brain function, including a period of confusion, a loss of consciousness (LOC), focal ...

医学

A Novel and Translational Rat Model of Concussion Combining Force and Rotation with In Vivo Cerebral Microdialysis

Persistent cognitive and motor symptoms are known consequences of concussions/mild traumatic brain injury (mTBIs) that can be partly attributable to altered neurotransmission. Indeed, cerebral microdialysis studies in rodents have demonstrated an excessive extracellular glutamate release in the hippocampus within the first 10 min following trauma. Microdialysis offers the clear advantage of in vivo neurotransmitter continuous sampling while not having to sacrifice the animal. In addition to the aforementioned technique, a closed head injury model that exerts rapid acceleration and deceleration of the head and torso is needed, as such a factor is not available in many other animal models. The Wayne State weight-drop model mimics this essential component of human craniocerebral trauma, allowing the induction of an impact on the head of an unrestrained rodent with a falling weight. Our novel and translational rat model combines cerebral microdialysis with the Wayne State weight-drop model to study, in lightly anesthetized and unrestrained adult rats, the acute changes in extracellular neurotransmitter levels following concussion. In this protocol, the microdialysis probe was inserted inside the hippocampus as region of interest, and was left inserted in the brain at impact. There is a high density of terminals and receptors in the hippocampus, making it a relevant region to document altered neurotransmission following concussion. When applied to adult Sprague-Dawley rats, our combined model induced increases in hippocampal extracellular glutamate concentrations within the first 10 min, consistent with the previously reported post-concussion symptomology. This combined weight-drop model provides a reliable tool for researchers to study early therapeutic responses to concussions in addition to repetitive brain injury, since this protocol induces a closed-head mild trauma.

Neurotransmitter alteration is a mechanism of neural dysfunction that occurs after concussion and contributes to the sometimes-catastrophic long-term consequences. This rat model combines microdialysis, allowing in vivo neurotransmitter quantification, with a weight-drop technique exerting rapid acceleration and deceleration of the head and torso, an important factor of human craniocerebral trauma.

生体内脳微小透析における力と回転を組み合わせた脳震盪の新規および翻訳ラットモデル

Persistent cognitive and motor symptoms are known consequences of concussions/mild traumatic brain injury (mTBIs) that can be partly attributable to ...

神経科学

Advanced Diffusion Imaging in The Hippocampus of Rats with Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is the most common type of acquired brain injury. Since patients with traumatic brain injury show a tremendous variability and heterogeneity (age, gender, type of trauma, other possible pathologies, etc.), animal models play a key role in unraveling factors that are limitations in clinical research. They provide a standardized and controlled setting to investigate the biological mechanisms of injury and repair following TBI. However, not all animal models mimic the diffuse and subtle nature of mTBI effectively. For example, the commonly used controlled cortical impact (CCI) and lateral fluid percussion injury (LFPI) models make use of a craniotomy to expose the brain and induce widespread focal trauma, which are not commonly seen in mTBI. Therefore, these experimental models are not valid to mimic mTBI. Thus, an appropriate model should be used to investigate mTBI. The Marmarou weight drop model for rats induces similar microstructural alterations and cognitive impairments as seen in patients who sustain mild trauma; therefore, this model was selected for this protocol. Conventional computed tomography and magnetic resonance imaging (MRI) scans commonly show no damage following a mild injury, because mTBI induces often only subtle and diffuse injuries. With diffusion weighted MRI, it is possible to investigate microstructural properties of brain tissue, which can provide more insight into the microscopic alterations following mild trauma. Therefore, the goal of this study is to obtain quantitative information of a selected region-of-interest (i.e., hippocampus) to follow up disease progression after obtaining a mild and diffuse brain injury.

The overall goal of this procedure is to obtain quantitative microstructural information of the hippocampus in a rat with mild traumatic brain injury. This is done using an advanced diffusion-weighted magnetic resonance imaging protocol and region-of-interest based analysis of parametric diffusion maps.

軽度の外傷性脳損傷を有するラットの海馬における高度な拡散イメージング

Mild traumatic brain injury (mTBI) is the most common type of acquired brain injury. Since patients with traumatic brain injury show a tremendous ...

Electromagnetic Controlled Closed-Head Model of Mild Traumatic Brain Injury in Mice

Highly reproducible animal models of traumatic brain injury (TBI), with well-defined pathologies, are needed for testing therapeutic interventions and understanding the mechanisms of how a TBI alters brain function. The availability of multiple animal models of TBI is necessary to model the different aspects and severities of TBI seen in people. This manuscript describes the use of a midline closed head injury (CHI) to develop a mouse model of mild TBI. The model is considered mild because it does not produce structural brain lesions based on neuroimaging or gross neuronal loss. However, a single impact creates enough pathology that cognitive impairment is measurable at least 1 month after injury. A step-by-step protocol to induce a CHI in mice using a stereotaxically guided electromagnetic impactor is defined in the paper. The benefits of the mild midline CHI model include the reproducibility of the injury-induced changes with low mortality. The model has been temporally characterized up to 1 year after the injury for neuroimaging, neurochemical, neuropathological, and behavioral changes. The model is complementary to open skull models of controlled cortical impact using the same impactor device. Thus, labs can model both mild diffuse TBI and focal moderate-to-severe TBI with the same impactor.

The protocol describes mild traumatic brain injury in a mouse model. In particular, a step-by-step protocol to induce a mild midline closed head injury and the characterization of the animal model is fully explained.

マウスにおける軽度外傷性脳損傷の電磁制御クローズドヘッドモデル

Highly reproducible animal models of traumatic brain injury (TBI), with well-defined pathologies, are needed for testing therapeutic interventions and ...

Assessing Changes in Synaptic Plasticity Using an Awake Closed-Head Injury Model of Mild Traumatic Brain Injury

Mild traumatic brain injuries (mTBIs) are a prevalent health issue in North America. There is increasing pressure to utilize ecologically valid models of closed-head mTBI in the preclinical setting to increase translatability to the clinical population. The awake closed-headed injury (ACHI) model uses a modified controlled cortical impactor to deliver closed-headed injury, inducing clinically relevant behavioral deficits without the need for a craniotomy or the use of an anesthetic.
This technique does not normally induce fatalities, skull fractures, or brain bleeds, and is more consistent with being a mild injury. Indeed, the mild nature of the ACHI procedure makes it ideal for studies investigating repetitive mTBI (r-mTBI). Growing evidence indicates that r-mTBI can result in a cumulative injury that produces behavioral symptoms, neuropathological changes, and neurodegeneration. r-mTBI is common in youths playing sports, and these injuries occur during a period of robust synaptic reorganization and myelination, making the younger population particularly vulnerable to the long-term influences of r-mTBI.
Further, r-mTBI occurs in cases of intimate partner violence, a condition for which there are few objective screening measures. In these experiments, synaptic function was assessed in the hippocampus in juvenile rats that had experienced r-mTBI using the ACHI model. Following the injuries, a tissue slicer was utilized to make hippocampal slices to evaluate bidirectional synaptic plasticity in the hippocampus at either 1 or 7 days following the r-mTBI. Overall, the ACHI model provides researchers with an ecologically valid model to study changes in synaptic plasticity following mTBI and r-mTBI.

Here, it is demonstrated how an awake closed-head injury model can be used for examining the effects of repeated mild traumatic brain injury (r-mTBI) on synaptic plasticity in the hippocampus. The model replicates important features of r-mTBI in patients and is used in conjunction with in vitro electrophysiology.

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

Mild traumatic brain injuries (mTBIs) are a prevalent health issue in North America. There is increasing pressure to utilize ecologically valid models of ...

mTBIラットモデルにおける傷害反応と行動評価の検証

Rat Model of Closed-Head Mild Traumatic Injury and its Validation

Animal models are crucial for advancing our understanding of mild traumatic brain injury (mTBI) and guiding clinical research. To achieve meaningful insights, developing a stable and reproducible animal model is essential. In this study, we report a detailed description of a closed-head mTBI model and a representative validation method using Sprague-Dawley rats to verify the modeling effect. The model involves dropping a 550 g mass weight from a height of 100 cm directly onto the head of a rat on a destructible surface, followed by a 180-degree turn. To assess the injury, rats underwent a series of neurobehavioral assessments 10 min post-injury, including time of loss of consciousness, first seeking-behavior time, escape ability, and beam balance ability test. During the acute and subacute stages following the injury, behavioral tests were conducted to assess motor coordination ability (Beam task), anxiety (Open Field test), and learning and memory abilities (Morris Water Maze test). The closed-head mTBI model produced a consistent injury response with minimal mortality and replicated real-life situations. The validation method effectively verified the model development and ensured the stability and consistency of the model.

著者スポットライト:外傷性脳損傷研究の進歩 - 正確な複製と迅速な評価のためのクローズドヘッドモデル 

Here, we present a closed-head mild traumatic brain injury (mTBI) rat model and its validation exhibiting remarkable similarity to human mTBI concerning behavioral manifestations during the acute and subacute stages.

閉鎖性軽度外傷のラットモデルとその検証

Animal models are crucial for advancing our understanding of mild traumatic brain injury (mTBI) and guiding clinical research. To achieve meaningful ...

少年ラット用マイルド外傷性脳損傷の新規モデル

要約

さらに動画を探す

外傷性脳損傷後のラットの行動の赤字を検出

外傷性脳損傷後の成体ラットにおける優性服従行動の評価

片性および反復性軽度外傷性脳損傷のマウスモデル

生体内脳微小透析における力と回転を組み合わせた脳震盪の新規および翻訳ラットモデル

軽度の外傷性脳損傷を有するラットの海馬における高度な拡散イメージング

マウスにおける軽度外傷性脳損傷の電磁制御クローズドヘッドモデル

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

閉鎖性軽度外傷のラットモデルとその検証

閉鎖性軽度外傷のラットモデルとその検証

閉鎖性軽度外傷のラットモデルとその検証