This method paper was funded by Eranet Neuron Neuvasc (Badaut), Agence Nationale de la Recherche Nanospace (Badaut), CNRS IRP IINOVAtion (Badaut) and NIH NINDS Grant No. 1R01NS119605 (Obenaus, Badaut) and 1RF1NS138032 (Obenaus, Territo).&#160;Figure 1 is created with BioRender.com.

Experiments were reproduced on 2 sites, the University of Bordeaux (France) and the University of California Riverside (CA, USA).
In Bordeaux, all experiments were performed on male and female P17 C57Bl6J mice bred in the University animal facility. Initial breeders were obtained from a commercial source and raised under standard conditions with a 12/12-h dark/light cycle, a temperature of 21 &#176;C &#177; 1 &#176;C, and a humidity of 55% &#177; 10%, and food and water provided ad libitum. Experimental procedures are in accordance with the University of Bordeaux Animal Care Committee regulations, French laws governing laboratory animal use (authorization #29324-2021012118549817 v3), the European Council directives (86/609/EEC), and the ARRIVE guidelines. This protocol, being a mild model of traumatic brain injury, does not produce pain or distress. As such, it does not necessitate any specific pain management outside of regular pain management. Weaning of the pups (TBI, Shams) was effective at P25.
At Riverside, E13 pregnant C57Bl6J female mice were commercially obtained, and all experiments were performed on the resultant litters in both male and female pups aged P17. Animals were raised with an automated 12/12-h dark/light cycle and a temperature of 21 &#176;C. Dams and pups had ad libitum access to food and water. All experimental procedures were approved by the University of California, Riverside Institutional Animal Care and Use Committee and complied with the Animal Welfare Act and Public Health Service policy. All pups (TBI, Sham) in that facility were weaned on P21.
The details of the animals, reagents, and equipment used in this study are listed in the Table of Materials.
1. Preliminary steps
<ol>
	<li>To prevent hypothermia, warm up the chamber for anesthesia induction and the recovery cages in advance with warming pads.</li>
	<li>Set the stereotaxic apparatus with the impactor mounted at a 90&#176; angle.</li>
	<li>Verify that all parts are properly tightened and secured and that the piston is firmly screwed to the impactor.</li>
	<li>Cut an aluminum sheet that will fit the stereotaxic apparatus (in this case, 18 cm x 30 cm). The aluminum used here is of standard aluminum quality. Wrap the stereotaxic frame with the foil to form a pad on which the animal will be laid on. Secure the position and tension of the foil with regular lab tape in order to sustain the weight of the animal.</li>
	<li>Turn on the impactor controller and, in the function of the severity of the injury, set the speed of impact to 2 m.s-1 for grade 1 (G1) or 3 m.s-1 for grade 2 (G2) for a more severe impact (modifying this parameter will impact the severity of the concussion).</li>
	<li>Weight out the animals. At P17, the weight of the animals must be over 5.9 g for C57Bl6 mice. Animals that fall under that weight are excluded. 
	NOTE: For some studies, CD1 mice were used, and for P17, the threshold was fixed to be over 6.5 g (personal data).</li>
</ol>
2. Juvenile mild traumatic brain injury procedure
<ol>
	<li>Anesthetize the mouse with a 5 min exposure to isoflurane. Set the gas composition to a 2.5% mixture (in this case, the carrier is a synthetic air mixture with 21% oxygen) with a flow rate of 1.5 L/min. 
	NOTE: From this step, all the actions must be done swiftly, as unimpacted animals will wake up within 5 min.</li>
	<li>Position the mouse head under the impactor. The pup should be spread out at all lengths. The tip is 3 mm in diameter and covered with rubber to minimize the effect of the metal on the skull.</li>
	<li>Lower the impactor by switching the knob to the Extend position.</li>
	<li>Roughly lower the impactor and position the mouse so that the impactor is just between the ears. Then, slide the mouse so that the piston tip is moved forward to the equivalent of one piston tip, and one piston tip to the left of the animal (see Figure 1). 
	NOTE: Sham animals are positioned slightly away from the piston (no part of the animal should be impacted).</li>
	<li>Lower the impactor so that it contacts the head of the animal (Figure 1E2).</li>
	<li>Set the impactor to Retract (Figure 1E3).</li>
	<li>In order to determine the severity of the injury, move the piston 1 mm down for grade 1 (G1). For more severe impact grade 2 (G2), move the piston 3 mm down (Figure 1E4).</li>
	<li>Set the dwell time to 0.1 s regardless of the severity (modifying this parameter will not impact the severity of the concussion).</li>
	<li>Press Impact on the right knob (Figure 1E5).</li>
	<li>Rapidly set the left knob to the off position so that the system doesn&#39;t overheat. See the flow chart for more information (Figure 2).</li>
</ol>
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/67667/67667fig01.jpg" /> 
Figure 1: Positioning of the impactor tip. (A) The impactor tip is first positioned on the midline between the ears. (B) The tip is then moved 3 mm forward (the equivalent of a tip diameter). (C) Finally, the piston tip is moved 3 mm on the left side of the mouse. (D,E) Possible positions of the impactor tip in regard to the magnetic barrel. (D) The impactor has 3 positions in relation to the piston body (neutral, retracted, or extended/impact) with 5 mm range between them. (E) Positions of the impactor tip in relation to the skull surface at the different stages of the procedure. (1) Position of the impactor in the neutral position; (2) the piston is moved to gently touch the skull of the animal (step 2.5); (3) the impactor is then set to retract (step 3.6); (4) the whole body of the impactor is moved of x mm down (step 2.7). For G1 grade, a speed of impact (y) of 2 m.s-1 with 1 mm depth (x) for G1 or a speed of impact (y) of 3 m.s-1 with 3 mm (x) depth for G2. (5) Once the lever impact is pressed, the impactor tip moves x mm below the skull surface at a y speed during dwell time upon moving back to the neutral position. <a href="https://www.jove.com/files/ftp_upload/67667/67667fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/67667/67667fig02.jpg" /> 
Figure 2: CHILD flow chart. Flow chart detailing the steps to induce CHILD in PND17 mice color-coded to denote different phases of concussion induction. Photographs of the setup include (A) the entire CHILD induction setup (anesthesia device is not visible), including the Impact controller, the stereotactic device with the impactor and tip positioned above taut tin foil, and the recovery box located on top of a heating pad. (B) Rubber impact tip (3 mm) with scale. (C) The stereotactic device with tin foil stretched across the stereotactic frame and the impactor solenoid with the impact tip positioned above the foil. (D) Recovery chamber sitting on the heat pad. (E) The impact controller with two control switches, highlighted as in the flow chart (red box = extend/retract/off; purple box= impact toggle). <a href="https://www.jove.com/files/ftp_upload/67667/67667fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
3. Post-trauma follow-up
NOTE: The following steps can be videorecorded for offline analysis, allowing the experimenter to perform CHILD on multiple animals in a row. Nonetheless, regular and repeated assessments of animal well-being should be performed.
<ol>
	<li>Note the duration of apnea, if present (immediately after impact), and if there was a head rotation during impact.</li>
	<li>Position the mouse on its right flank in a recovery cage.</li>
	<li>Note the righting time of the mouse (rearing on 4 legs) and the time of resuming an exploratory behavior. Typically, sham mice awake within 3-4 min and resume an exploratory behavior 3-4 min later (Figure 3). CHILD mice awake within 7-12 min after impact (Figure 3A) and resume exploration within 12-18 min after impact (Figure 3B), according to the sex and impact severity (Figure 3A,B). 
	NOTE: If the impacted animal doesn&#39;t resume its exploratory behavior within 30 min, the animal is excluded.</li>
	<li>Once fully recovered, return the animals to their home cage. At this point, the behavior of sham and CHILD mice (G1 or G2 severity) should be exactly similar, and animal groups shouldn&#39;t be distinguishable within the litter. 
	NOTE: The animals can be maintained up to 18 months post-injury14 in conditions indicated at the beginning of the methods. Behavioral outcomes assessments can be performed using a battery of tests in association with MRI measurements, miniscope imaging, histology, and immunohistochemistry12. Immunohistochemistry for GFAP and NeuN can be used at early time points to validate the model and the presence of tissue changes.</li>
</ol>
4. Immunohistochemistry
NOTE: One day post-injury, animals from the G2 and sham groups (n = 4 mice for G2 and n = 4 for Sham) were anesthetized and transcardially perfused with 4% paraformaldehyde (PFA) prepared in phosphate-buffered saline (PBS) 0.1 M, pH 7.4 at 4 &#176;C. Brains were extracted10 from the skull and immersed in the same PFA solution overnight, and then transferred to PBS with sodium azide (0.1%) before cutting. Coronal sections were then prepared at 50 &#181;m thickness using a vibratome. For long storage, sections were placed in cryoprotective medium (30% ethylene glycol and 20% glycerol in PBS) at -20 &#176;C until use. To characterize the impact of the concussion on brain gliosis and neuronal loss, immunohistochemistry targeting GFAP and NeuN was performed as described here below.
<ol>
	<li>Wash the brain sections 4 times for 10 min in PBS.</li>
	<li>Transfer the sections in blocking solution (1% BSA, 0,3% Triton X-100 in PBS) for 10 min at room temperature (RT).</li>
	<li>Incubate sections overnight at 4 &#176;C with the following primary antibodies diluted in blocking solution: chicken anti-GFAP (1:3000) and rabbit anti-NeuN (1:500).</li>
	<li>Wash the slices 4 times for 10 min in PBS under agitation.</li>
	<li>Then, transfer the sections in blocking solution containing the secondary fluorescent antibodies diluted 1:1000 for 1 h at RT, Alexa-Fluor-488-nm goat anti-rabbit, and Alexa-Fluor-568-nm goat anti-chicken.</li>
	<li>Wash then the sections 4 times for 10 min in PBS under agitation.</li>
	<li>Mount the sections on slides using a mounting medium and add a cover slip. Keep the slides at 4 &#176;C until the image acquisition.</li>
	<li>Aquire immunofluorescence using an epifluorescence microscope and micromanager software. Use a stitching plugin with a 10x lens to obtain tiled images of ipsilateral and contralateral hemispheres. 
	NOTE: Negative control staining where the primary antibody or secondary antibody was omitted showed no detectable labeling. For more detailed image analysis, Fiji software15 can be used to quantify the immunostaining parameters in various regions of interest16.</li>
</ol>

CHILD Model &#8212; Recapitulating Juvenile Concussion and Long-Term Outcomes in Mice

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The authors have nothing to disclose.

Critical steps in the protocol 
The CHILD protocol described here requires the use of an electromagnetic impactor (Figure 2A) that (1) standardizes the impact parameters (speed, depth, duration), (2) ensures reproducibility within and across laboratories, and (3) is readily available commercially. Another critical component is the impactor tip that strikes the rodent&#39;s head. A variety of possibilities can be used, ranging from silicone to metal tips, but this protoc...

Pediatric Traumatic Brain Injury (TBI) is a major health concern as it represents the leading cause of pediatric emergency medical care visits and is associated with debilitating health outcomes later in life. Even mild TBI (mTBI), which makes up 75% of all TBI cases1, leads to long-term abnormalities, including physiological, psychological, neurological, and cognitive dysfunctions2. Despite the high occurrence of pediatric mTBI and its significant associated health risks, the pathological, cellular, and molecular mechanisms that precede the chronic deficits are still underexplored. This gap in knowledge impedes the development of effective treatments and diagnostic methods for pediatric mTBI.
Adult rodent TBI models include weight drop, controlled cortical impact, and fluid percussion injury and can be titrated to elicit moderate to severe injuries (dependent upon outcome measures)3,4. Many of these adult models have been adapted for pediatric TBI5,6. During the last decade, models of mTBI have been developed in rodents with closed head injury as well as with rotational models7. However, implementation of these models in developing rodents is sparse compared to the adult TBI literature8. To address the clinical relevance, encompassing a wide range of severities that model pediatric clinical heterogeneity, this study developed the Closed Head Injury with Long-term Disorder (CHILD) TBI model. CHILD is a non-surgical, unrestrained concussion model using P17 mice, a developmental age that corresponds to the peak of myelination observed in 2-3-year-old children9. A concussive force is delivered using an electromagnetic impactor over the somatosensory cortex of a lightly isoflurane-anesthetized mouse. Impacting the unrestrained head results in rotational forces on the brain10, as reported in many clinical concussion reports. Consistent with clinical mTBI, the CHILD model does not lead to skull fracture or visible abnormality on conventional neuroimaging.
The CHILD model has several advantages. First, both early and long-term pathological features have been observed in CHILD, mimicking the pathological clinical features observed in juvenile concussion patients. It has been observed at late time points gliosis, altered diffusion tensor MRI, and progressive behavioral perturbations with age10,11, modified neuronal activity, and plasticity11,12. Interestingly, unsuspected peripheral consequences were also found with cardiac abnormalities in the long term after a single pediatric injury13. Second, this model is replicable and showed comparable results between researchers and between labs13. Third, the CHILD model is flexible and can be expanded to encapsulate the heterogeneous nature of TBIs. For instance, previous studies have shown that different speeds and depths of impact result in different severities10,11. Finally, an additional strength of this model is that CHILD can be administered repeatedly and can be easily applied to differential locations to probe responses to repeated injury and identify vulnerable brain regions.
Overall, the CHILD model replicates clinical pediatric mTBI and concussion and serves as a research tool to facilitate the understanding of the pathophysiological characteristics of pediatric mTBI. While no model encapsulates every aspect of the features described in real-life TBI cases, this model can address many of the outstanding research questions that remain unanswered.

<table><tbody><tr><td>BSA</td><td>Sigma Aldrich Chimie S.a.r.l&lt;br/&gt; 80 Rue de Luzais&lt;br/&gt; L&#039;lsle-d&#039;Abeau Chesnes - BP701&lt;br/&gt; 38297 Saint-Quentin-Fallavier Cedex&lt;br/&gt; France</td><td>A7030</td><td></td></tr><tr><td>C57Bl6J mice&amp;nbsp;</td><td>Charles River Laboratory France CRLF 9 All. Moulin Berger, 69130 &amp;Eacute;cully, France</td><td></td><td>Bordeaux</td></tr><tr><td>Electromagnetic impactor</td><td>Leica Biosystems, Richmond, IL USA</td><td>Impact One stereotaxic impactor</td><td></td></tr><tr><td>Epifluorescence microscope</td><td>Olympus, BX41, Center Valley, PA</td><td></td><td></td></tr><tr><td>Ethylen glycol</td><td>Sigma Aldrich Chimie S.a.r.l&lt;br/&gt; 80 Rue de Luzais&lt;br/&gt; L&#039;lsle-d&#039;Abeau Chesnes - BP701&lt;br/&gt; 38297 Saint-Quentin-Fallavier Cedex&lt;br/&gt; France</td><td>102466</td><td></td></tr><tr><td>GFAP primary antibody</td><td>Millipore, Billerica, MA</td><td>AB5541</td><td>chicken anti-GFAP</td></tr><tr><td>GFAP secondary antibody</td><td>Molecular Probes, Invitrogen</td><td>A11034</td><td>goat anti-rabbit AlexaFluor&amp;nbsp; 488</td></tr><tr><td>Glycerol</td><td>Sigma Aldrich Chimie S.a.r.l&lt;br/&gt; 80 Rue de Luzais&lt;br/&gt; L&#039;lsle-d&#039;Abeau Chesnes - BP701&lt;br/&gt; 38297 Saint-Quentin-Fallavier Cedex&lt;br/&gt; France</td><td>G5516</td><td></td></tr><tr><td>Heavy duty aluminium foil</td><td>Kirkland</td><td>RK611</td><td>obtained at Cosco</td></tr><tr><td>Micromanager software&amp;nbsp;</td><td>(NIH, USA</td><td></td><td></td></tr><tr><td>NeuN primary antibody</td><td>AbCam, Discovery Drive, Cambridge&lt;br/&gt; Biomedical Campus,&lt;br/&gt; Cambridge, CB2 0AX, UK</td><td>AB128886</td><td>rabbit anti-NeuN</td></tr><tr><td>NeuN secondary antibody</td><td>Molecular Probes, Invitrogen</td><td>A11041</td><td>goat anti-chicken AlexaFluor 568</td></tr><tr><td>PBS</td><td>Sigma Aldrich Chimie S.a.r.l&lt;br/&gt; 80 Rue de Luzais&lt;br/&gt; L&#039;lsle-d&#039;Abeau Chesnes - BP701&lt;br/&gt; 38297 Saint-Quentin-Fallavier Cedex&lt;br/&gt; France</td><td>P5493</td><td></td></tr><tr><td>PFA</td><td>Sigma Aldrich Chimie S.a.r.l&lt;br/&gt; 80 Rue de Luzais&lt;br/&gt; L&#039;lsle-d&#039;Abeau Chesnes - BP701&lt;br/&gt; 38297 Saint-Quentin-Fallavier Cedex&lt;br/&gt; France</td><td>1.04003</td><td></td></tr><tr><td>Sodium azide</td><td>Sigma Aldrich Chimie S.a.r.l&lt;br/&gt; 80 Rue de Luzais&lt;br/&gt; L&#039;lsle-d&#039;Abeau Chesnes - BP701&lt;br/&gt; 38297 Saint-Quentin-Fallavier Cedex&lt;br/&gt; France</td><td>26628-22-8</td><td></td></tr><tr><td>Stereotaxic frame - base</td><td>KOPF instruments 7324 Elmo St, Tujunga, CA 91042, &amp;Eacute;tats-Unis</td><td>900-C</td><td></td></tr><tr><td>Stereotaxic frame - electrode manipulator</td><td>KOPF instruments 7324 Elmo St, Tujunga, CA 91042, &amp;Eacute;tats-Unis</td><td>960</td><td></td></tr><tr><td>Stereotaxic frame - u-frame</td><td>KOPF instruments 7324 Elmo St, Tujunga, CA 91042, &amp;Eacute;tats-Unis</td><td>900-U</td><td></td></tr><tr><td>Triton x-100</td><td>Sigma Aldrich Chimie S.a.r.l&lt;br/&gt; 80 Rue de Luzais&lt;br/&gt; L&#039;lsle-d&#039;Abeau Chesnes - BP701&lt;br/&gt; 38297 Saint-Quentin-Fallavier Cedex&lt;br/&gt; France</td><td>X100</td><td></td></tr><tr><td>Vectashield</td><td>Vector laboratories</td><td>H-1000-10</td><td>Mounting medium</td></tr><tr><td>Vibratome</td><td>Leica Biosystems, Richmond, IL USA</td><td>VTS1000</td><td></td></tr><tr><td></td><td>Jackson laboratory The Jackson Laboratory 600 Main Street Bar Harbor, ME USA 04609</td><td></td><td>UCR</td></tr></tbody></table>

a pediatric concussion model in mice: closed head injury with long-term disorders (child)

Concussions and mild traumatic brain injuries (mTBI) during childhood represent a significant health endangerment, with many patients later in life exhibiting debilitating physiological, neurological, and psychosocial outcomes. The cellular and molecular pathophysiological mechanisms are relatively unknown, and this significant gap effectively precludes investigations into specific therapeutic strategies to mitigate chronic sequelae. No single animal concussion model recapitulates all the features reported in human subjects, and current models are designed to answer specific research questions. We set out to develop a juvenile concussion that recapitulates clinical early, and long-term symptomology encountered, termed Closed Head Injury with Long-term Disorder (CHILD). In this model, a concussive force via an electromagnetic impactor is delivered to the head of a lightly anesthetized unrestrained post-natal day 17 (P17) mouse, allowing free rotation of the head. Mice are placed on a tightly stretched tin foil across a stereotactic device, and the impactor is carefully aligned with the targeted cortical region. The electromagnetic impactor facilitates the selection of impact depth, dwell, and duration to determine injury severity. A strength of this model is that it allows head rotation, an important clinical feature. After impact, mice are immediately monitored for righting time and time to explore their environment, followed by their return to their dam. Increasing the severity of concussion results in intracranial bleeds in a subset of mice. Mice can be routinely monitored for behavior and neuroimaging over their lifespan, as desired. Various injury severities mimic the heterogeneous nature of juvenile concussions. The current standard CHILD model exhibits no skull fracture, no observable conventional neuroimaging change (similar to clinical), but leads to progressive and persistent neuronal death, altered diffusion MRI, modified neuronal activity and plasticity, increased gliosis, and progressive behavioral perturbations with age. In summary, this CHILD model mimics the early and long-term features observed in many clinical concussion patients.

The CHILD model is a relatively rapid and reproducible model of mTBI in pediatric mice, also allowing for variations in severity and location. The CHILD mice, as expected, exhibited significantly longer recovery times from closed head injury (Figure 3). When cohorts (n = 36 female sham, n = 140 male sham, n = 30 female G1, n = 55 male G1, n = 32 female G2, n = 141 male G2) were aggregated, a delay in righting time was observed (Figure 3A, 3-way ANOVA p ...

A Pediatric Concussion Model in Mice: Closed Head Injury with Long-Term Disorders (CHILD)

Pediatric concussions can result in long-term sequelae with physiological and psychological perturbations. This pediatric concussion mouse model results in long-term neuroinflammation, white matter alterations, and neuronal modifications with behavioral dysfunction. The model can be adapted to differential impact locations or repeated concussions to assess lifetime changes.

Concussions and mild traumatic brain injuries (mTBI) during childhood represent a significant health endangerment, with many patients later in life ...

a-pediatric-concussion-model-mice-closed-head-injury-with-long-term

Research

JoVE Journal

Neuroscience

330 Views.  UMR 7372 CNRS/Université de La Rochelle. Pediatric concussions can result in long-term sequelae with physiological and psychological perturbations. This pediatric concussion mouse model results in long-term neuroinflammation, white matter alterations, and neuronal modifications with behavioral dysfunction. The model can be adapted to differential impact locations or repeated concussions to assess lifetime changes.

Video: A Pediatric Concussion Model in Mice: Closed Head Injury with Long-Term Disorders (CHILD)

A Repetitive Concussive Head Injury Model in Mice

Despite the concussion/ mild traumatic brain injury (mTBI) being the most frequent occurrence of traumatic brain injury, there is still a lack of knowledge on the injury and its effects. To develop a better understanding of concussions, animals are often used because they provide a controlled, rigorous, and efficient model. Studies have adapted traditional animal models to perform mTBI to stimulate mild injury severity by changing the injury parameters. These models have been used because they can produce morphologically similar brain injuries to the clinical condition and provide a spectrum of injury severities. However, they are limited in their ability to present the identical features of injuries in patients. Using a traditional impact system, a repetitive concussive injury (rCHI) model can induce mild to moderate human-like concussion. The injury degree can be determined by measuring the period of loss of consciousness (LOC) with a sign of a transient termination of breathing. The rCHI model is beneficial to use for its accuracy and simplicity in determining mTBI effects and potential treatments.

Concussion presents the most common type of traumatic brain injury. Therefore, a repetitive concussive animal model, which replicates the important features of an injury in patients, may provide a means to study concussion in a rigorous, controlled, and efficient manner.

Despite the concussion/ mild traumatic brain injury (mTBI) being the most frequent occurrence of traumatic brain injury, there is still a lack of ...

Medicine

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.

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 ...

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.

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

Low-intensity Blast Wave Model for Preclinical Assessment of Closed-head Mild Traumatic Brain Injury in Rodents

Traumatic brain injury (TBI) is a large-scale public health problem. Mild TBI is the most prevalent form of neurotrauma and accounts for a large number of medical visits in the United States. There are currently no FDA-approved treatments available for TBI. The increased incidence of military-related, blast-induced TBI further accentuates the urgent need for effective TBI treatments. Therefore, new preclinical TBI animal models that recapitulate aspects of human blast-related TBI will greatly advance the research efforts into the neurobiological and pathophysiological processes underlying mild to moderate TBI as well as the development of novel therapeutic strategies for TBI.
Here we present a reliable, reproducible model for the investigation of the molecular, cellular, and behavioral effects of mild to moderate blast-induced TBI. We describe a step-by-step protocol for closed-head, blast-induced mild TBI in rodents using a bench-top setup consisting of a gas-driven shock tube equipped with piezoelectric pressure sensors to ensure consistent test conditions. The benefits of the setup that we have established are its relative low-cost, ease of installation, ease of use and high-throughput capacity. Further advantages of this non-invasive TBI model include the scalability of the blast peak overpressure and the generation of controlled reproducible outcomes. The reproducibility and relevance of this TBI model has been evaluated in a number of downstream applications, including neurobiological, neuropathological, neurophysiological and behavioral analyses, supporting the use of this model for the characterization of processes underlying the etiology of mild to moderate TBI.

We present here a protocol of a blast wave model for rodents to investigate neurobiological and pathophysiological effects of mild to moderate traumatic brain injury. We established a gas-driven, bench-top setup equipped with pressure sensors allowing for reliable and reproducible generation of blast-induced mild to moderate traumatic brain injury.

Traumatic brain injury (TBI) is a large-scale public health problem. Mild TBI is the most prevalent form of neurotrauma and accounts for a large number of ...

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.

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.

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

Validating Injury Response and Behavioral Assessments in an mTBI Rat Model

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.

Author Spotlight: Advancing Traumatic Brain Injury Research - A Closed-Head Model for Accurate Replication and Rapid Assessment 

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.

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

rmTBI Induction in Mice via a Closed-Head Injury Method

Modified Mouse Model of Repetitive Mild Traumatic Brain Injury Incorporating Thinned-Skull Window and Fluid Percussion

Mild traumatic brain injury is a clinically highly heterogeneous neurological disorder. Highly reproducible traumatic brain injury (TBI) animal models with well-defined pathologies are urgently needed for studying the mechanisms of neuropathology after mild TBI and testing therapeutics. Replicating the entire sequelae of TBI in animal models has proven to be a challenge. Therefore, the availability of multiple animal models of TBI is necessary to account for the diverse aspects and severities seen in TBI patients. CHI is one of the most common methods for fabricating rodent models of rmTBI. However, this method is susceptible to many factors, including the impact method used, the thickness and shape of the skull bone, animal apnea, and the type of head support and immobilization utilized. The aim of this protocol is to demonstrate a combination of the thinned-skull window and fluid percussion injury (FPI) methods to produce a precise mouse model of CHI-associated rmTBI. The primary objective of this protocol is to minimize factors that could impact the accuracy and consistency of CHI and FPI modeling, including skull bone thickness, shape, and head support. By utilizing a thinned-skull window method, potential inflammation due to craniotomy and FPI is minimized, resulting in an improved mouse model that replicates the clinical features observed in patients with mild TBI. Results from behavior and histological analysis using hematoxylin and eosin (HE) staining suggest that rmTBI can lead to a cumulative injury that produces changes in both behavior and gross morphology of the brain. Overall, the modified CHI-associated rmTBI presents a useful tool for researchers to explore the underlying mechanisms that contribute to focal and diffuse pathophysiological changes in rmTBI.

Author Spotlight: Optimizing Rodent Models for Investigating the Mechanisms and Rehabilitation in Repeated Mild Traumatic Brain Injury

This protocol presents a modified mouse model of repetitive mild traumatic brain injury (rmTBI) induced via a closed-head injury (CHI) method. The approach features a thinned-skull window and fluid percussion to reduce the inflammation commonly caused by meninges exposure, along with improved reproducibility and accuracy in modeling rmTBI in rodents.

Mild traumatic brain injury is a clinically highly heterogeneous neurological disorder. Highly reproducible traumatic brain injury (TBI) animal models ...

Development of an Uncomplicated Mild Traumatic Brain Injury Model Modified by Weight-Drop Method and Evidenced by Magnetic Resonance Imaging

Mild traumatic brain injury (mTBI), known as concussion, accounts for more than 85% of brain injuries globally. Specifically, uncomplicated mTBI showing negative findings in routine clinical imaging in the acute phase hinders early and appropriate care in these patients. It has been acknowledged that different impact parameters may affect and even accelerate the progress of subsequent neuropsychological symptoms following mTBI. However, the association of impact parameters during concussion to the outcome has not been extensively examined. In the current study, an animal model with closed-head injury (CHI) modified from the weight-drop injury paradigm was described and demonstrated in detail. Adult male Sprague-Dawley rats (n = 20) were randomly assigned to CHI groups with different impact parameters (n = 4 per group). Longitudinal MR imaging studies, including T2-weighted imaging and diffusion tensor imaging, and sequential behavioral assessments, such as modified neurological severity score (mNSS) and the beam walk test, were conducted over a 50-day study period. Immunohistochemical staining for astrogliosis was performed on day 50 post-injury. Worse behavioral performance was observed in animals following repetitive CHI compared to the single injury and sham group. By using longitudinal magnetic resonance imaging (MRI), no significant brain contusion was observed at 24 h post-injury. Nevertheless, cortical atrophy and alteration of cortical fractional anisotropy (FA) were demonstrated on day 50 post-injury, suggesting the successful replication of clinical uncomplicated mTBI. Most importantly, changes in neurobehavioral outcomes and image features observed after mTBI were dependent on impact number, inter-injury intervals, and the selected impact site in the animals. This in vivo mTBI model combined with preclinical MRI provides a means to explore brain injury on a whole-brain scale. It also allows the investigation of imaging biomarkers sensitive to mTBI across varying impact parameters and severity levels.

Here, we present a protocol to establish a closed-head injury animal model replicating the neuroimage outcome of uncomplicated mild traumatic brain injury with the preserved brain structure in the acute phase and long-term brain atrophy. Longitudinal magnetic resonance imaging is the primary method used for evidence.

Mild traumatic brain injury (mTBI), known as concussion, accounts for more than 85% of brain injuries globally. Specifically, uncomplicated mTBI showing ...

Modeling Repetitive Concussive Head Injuries in a Mouse Model

<a href='https://app.jove.com/v/54530/a-repetitive-concussive-head-injury-model-in-mice'>Source: Yang, Z., et.al.&#160;A Repetitive Concussive Head Injury Model in Mice. J. Vis. Exp. (2016).</a>This video demonstrates the induction of repetitive concussive head injuries in a mouse using an electromagnetic impact device. The procedure involves positioning the impact tip between the interfrontal and lambdoid sutures on the skull of an anesthetized mouse and using a probe tip to precisely set the impact depth. The impact is delivered at a controlled velocity and depth to simulate mild traumatic brain injuries, followed by a recovery period, with the injuries repeated at specified intervals.

Source: Yang, Z., et.al.&#160;A Repetitive Concussive Head Injury Model in Mice. J. Vis. Exp. (2016).This video demonstrates the induction of repetitive ...