This work was supported in part by the National Institutes of Health under award numbers R01NS120882, RF1NS119165, and R01NS103785 and the Department of Defense award number AZ190017. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health or the Department of Defense.

The experiments performed were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Kentucky, and both the ARRIVE and the Guide for the Care and Use of Laboratory Animals guidelines were followed during the study.
1. Surgical setup
NOTE: Mice are housed in groups of 4-5/cage, humidity in the housing room is maintained at 43%-47%, and the temperature is maintained at 22-23 &#730;C. Mice are given ad libitum access to food and water and exposed to a 12 h/12 h light/dark cycle (7 a.m./7 p.m.).
<ol>
	<li>Use a designated surgical area, such as a hood or dedicated surgical procedure room, to perform the animal surgery.</li>
	<li>Ensure that the surgical area includes a heating pad, a stereotaxic frame equipped with an electromagnetic impactor, and an anesthesia mask designed to administer isoflurane gas (see Figure 1A).</li>
	<li>Ensure that the surgeon or personnel involved in the surgery wear a clean lab coat, a face mask, gloves, and a surgical cap.</li>
	<li>Use sterile surgical tools, sterile cotton-tipped applicators, and gauze pads. Use a hot bead sterilizer to sterilize the instruments between mice during the day of surgery.</li>
	<li>Use an anesthesia induction chamber to prepare the mouse for surgery in a pre-op area.</li>
	<li>Use heating pads to maintain the animal&#39;s temperature, clean post-op mouse holding cages, and timers to record the righting reflex of the mouse after surgery.</li>
</ol>
2. Pre-surgery procedure
<ol>
	<li>Prepare the head support apparatus (see Figure 1B).
	<ol>
		<li>Remove the rolled end ridge from a 1 mL latex pipette bulb (inflatable end) (see Figure 1C).</li>
		<li>Attach the bulb to the tubing using parafilm (see Figure 1C).</li>
		<li>Connect the tubing to a 10 mL syringe using a stopcock. Fill the syringe with water (see Figure 1C). 
		NOTE: The 1 mL latex pipette bulb will be placed under the mouse&#39;s head to displace the impact force away from the ears. Try to remove as much air as possible from the bulb before use so that the bulb is filled with mostly water and not air.</li>
	</ol>
	</li>
	<li>Impactor setup.
	<ol>
		<li>Select the 5 mm probe tip, screw it to the piston at the bottom center of the actuator (inside the larger cylinder), and gently tighten the probe without applying excessive force. Re-tighten the tip between impacts (see Figure 1B).</li>
		<li>Before turning on the impactor, ensure that the Extend/Retract switch is positioned in the center Off position. Then, connect the cable on the actuator to the jack on the front panel of the impactor control box and the sensor cable to the jack on the front panel. Then, turn on the power switch on the back panel (see Figure 1D). 
		NOTE: The Extend/Retract toggle switch needs to remain in the center Off position when not in use.</li>
		<li>Set up the impact velocity by rotating the large knob on the left side of the control box until an impact velocity of 5.0 &#177; 0.2 m/s appears on the display (see Figure 1D).</li>
		<li>Set the dwell counter&#160;to 100 ms by turning the dials until the dwell reads 0.01 (see Figure 1D). 
		NOTE: The dwell is the time of contact before automatic retraction occurs.</li>
		<li>Place the impactor actuator on an ice pack to prevent the plastic cylinder from expanding, which locks the cylinder in place, preventing the movement of the cylinder and the delivery of future impacts (see Figure 1E).</li>
	</ol>
	</li>
	<li>Prepare the mouse for surgery.
	<ol>
		<li>Visually inspect the mouse before surgery and eliminate the mouse from the study if one of the following conditions is observed: poor coat condition, lethargy, or poor weight (&#60;20 g) for a 4-month-old mouse.</li>
		<li>Anesthetize the mouse with 4%-5% isoflurane in 100% oxygen using an induction chamber placed on a heating pad for 1-2 min.</li>
		<li>Shave the fur from the operative site using an electric hair clipper.</li>
		<li>Clean the head with sterile alcohol prep pads and apply a topical anesthetic to the shaved scalp at least 15 min before the start of the surgery.</li>
		<li>Return the mouse to a clean holding cage before the surgery. Start the surgery after at least 15 min of topical anesthetic application (induction time). 
		NOTE: The time for anesthesia could vary depending on the anesthetic used in the procedure.</li>
	</ol>
	</li>
	<li>Check one more time that the stereotaxic frame, impactor, and digital stereotaxic display (see Figure 1F) are ready to be used.</li>
	<li>Return the mouse to the isoflurane induction chamber with 4%-5% isoflurane in 100% oxygen for approximately 3 min.</li>
	<li>Fix the mouse in the head stage.</li>
</ol>
3. Surgical procedure
<ol>
	<li>Secure the mouse into the stereotaxic frame using lightweight acetal resin tapered point ear bars, a bite bar, and a mouse anesthesia mask (see Figure 1G,H). The isoflurane gas is delivered at 2%-3% in room air at 100-200 mL/min. Carefully monitor the mouse&#39;s respiration to ensure the depth of anesthesia and adjust the level of gas as needed.</li>
	<li>Apply sterile eye lubricant to the eyes to prevent corneal drying.</li>
	<li>Sterilize the scalp with povidone-iodine swabs and sterile alcohol pads three times.</li>
	<li>Ensure the mouse is deeply anesthetized by verifying the lack of a toe-pinch response.</li>
	<li>Make an approximately 1 cm midline scalp incision between the eyes and neck using a scalpel, exposing the skull (see Figure 1I).</li>
	<li>Allow the skull to dry for 1-2 min.</li>
	<li>Identify bregma (the intersection point of the coronal and sagittal sutures) and lambda (the intersection of the sagittal and lambdoid sutures) (see Figure 1J). 
	NOTE: A mouse brain atlas could be used for reference.</li>
	<li>Place the head support apparatus under the head and inflate the bulb with water until it is pressing against the bottom of the mouse&#39;s head but not lifting the head away from the bite bar. 
	NOTE: This step is essential to reduce possible ear issues from the CHI. Any animal with damage to the ear from the ear bars, resulting in rolling or bleeding, should be eliminated from the study and euthanized.</li>
	<li>Move the impactor into place over the animal&#39;s head.</li>
	<li>Extend the impactor by placing the Extend/Retract toggle switch (on the impactor control box) on Extend. 
	NOTE: Be sure to check that the tip is fully extended by pulling down on the tip.</li>
	<li>Line up the impactor until it is centered over the bregma (see Figure 1K).</li>
	<li>Reset the digital stereotaxic x and y coordinates in the stereotaxic reader to 0 (on the touch screen control)</li>
	<li>Align the probe over the impact location by moving the probe from the bregma over to the target coordinates: medial-lateral = 0.0 mm, anterior-posterior = &#8722;1.6 mm.</li>
	<li>Clip the contact sensor to the animal&#39;s ear.
	<ol>
		<li>Slowly lower the probe tip with the extended probe until first contact with the surface is made. Stop at the beep.</li>
		<li>Reset the digital stereotaxic z coordinates in the stereotaxic reader to 0.</li>
	</ol>
	</li>
	<li>Carefully inspect if the tip is flush with the skull (medial-lateral and anterior-posterior planes). 
	NOTE: Positioning the probe tip is the most crucial step of this process to prevent skull fractures and ear damage.</li>
	<li>Retract the impactor by placing the toggle switch on the control box in the Retract position. The tip withdraws and has no more contact with the animal&#39;s head until the time of impact.</li>
	<li>Set the impact depth by adjusting the dorsal-ventral depth to &#8722;1.2 mm. 
	NOTE: The depth of the impact affects the severity of the injury. The depth should be titered for different ages, weights, and strains of mice to the desired injury severity. The depth may need to be adjusted/re-titered over time to maintain a consistent injury severity. The severity can be assessed neuropathologically: microglia and astrocytes (IHC), and behaviorally: the radial arm water maze and the active avoidance test.</li>
	<li>Carefully monitor the mouse&#39;s respiration to ensure the anesthesia depth and adjust the gas level as needed. 
	NOTE: Often, the percentage of isoflurane gas should be lowered or shut off for 10-20 s prior to impact. Watch closely for the respiration to accelerate slightly. If respiration is too slow at the time of impact, the animal may die within the first 60 s after the impact from apnea. This can be prevented by adjusting the depth of anesthesia in the seconds before the impact.</li>
	<li>Induce the impact by pressing the right toggle switch to impact. The probe tip goes down at the displayed velocity, and then stays down for the set dwell time and retracts. 
	NOTE: Sham mice receive identical handling to the CHI mice, but the impact is not delivered.</li>
	<li>Start the timer immediately after the CHI impact is delivered to record the righting times (time to return from the side position to the prone position) or start the timer when the mouse is removed from the stereotaxic frame for the sham mice. The average righting reflex time is 5-15 min. 
	NOTE: The righting reflex times may vary based on mouse strain and age.</li>
	<li>Evaluate the mice for visible skull fractures, hemorrhages, and apnea. Exclude the mice with a depressed skull fracture or visible hemorrhage from the study. 
	NOTE: There are graded levels of skull fractures. Animals with decompressed skull fractures, where the bone is observably pressing into the brain tissue, are euthanized (CO2 first, and decapitation used as a secondary method). If the impactor tip is set correctly, these types of skull fractures are exceedingly rare. If a skull fracture does occur, the more common presentation is a small drop of blood on the skull and a slight tactile roughing of the skull, often along the suture connecting the posterior tip of the nasal bone. These mice are noted as possible skull fracture in the records but are not normally excluded from the study.</li>
	<li>Remove the animal from the stereotaxic frame.</li>
	<li>Close the scalp by stapling the skin together. 
	NOTE: Absorbable or non-absorbable sutures could be used to close the scalp as an alternative to staples.</li>
	<li>Apply triple antibiotic ointment with a sterile cotton-tipped applicator to the closed incision.</li>
	<li>Return the mouse to a clean holding cage for recovery. Half of the recovery cage is on a heating pad (low setting), providing the ability to move away from the heat when awake and maintaining the animal&#39;s temperature while unconscious (see Figure 1L). 
	NOTE: The mouse is placed on its side in the recovery cage. To prevent suffocation, place the animal in a recovery cage without bedding or on a tissue if bedding is in the cage.</li>
	<li>Return the Extend/Retract toggle switch to the Center/Off position. 
	NOTE: The current will continue running if the switch is left in either the extend or retract position, causing the piston to swell. The impactor will then not be functional until the piston cools down.</li>
	<li>Remove the impactor from its holder and gently place it on the ice pack. 
	NOTE: Keeping the impactor on an ice pack helps reduce the potential swelling of the impactor.</li>
	<li>Monitor the animal until the righting reflex occurs and document the time until righting (see Figure 1M). 
	NOTE: The righting reflex is defined as the moment the mouse returns to a prone position. The cage needs to be left undisturbed; the mouse could right if the cage is touched, moved, or exposed to some noises.</li>
	<li>Return the mice to their home cage when they are awake and alert. Usually, within 1 h after injury, animals are fully conscious and ambulating. Also, add some moist food at the bottom of the cage.</li>
</ol>
4. Post-surgery care
<ol>
	<li>Monitor the animals for 5 days post-surgery.</li>
	<li>Record their weight and any physical/ behavioral changes like breathing rate (qualitative respiratory function), gait, body and hair coat condition, eating, drinking, defecation, and urination.</li>
	<li>Observe the mouse for any sign of discomfort and the surgical wound for swelling, exudates or red edges, ordehiscence. Contact a veterinarian if the animal shows signs of pain and discomfort (vocalizations, not moving, hypothermia, does not drink or eat).</li>
	<li>Remove the staples 7-10 days post-surgery under anesthesia and on a heating pad. 
	&#8203;NOTE: If non-absorbable sutures are used, they must be removed 7-10 days post-surgery under anesthesia.</li>
</ol>
5. Cleaning
<ol>
	<li>Clean and sterilize the surgical area and tools.</li>
	<li>Clean the probe tip after each use and at the end of the day with alcohol prep pads. 
	NOTE: The impactor is calibrated at the factory and is reported to be stable over time and use. No routine calibration is needed. However, the impactor and stereotaxic frame should be routinely inspected. Also, the model endpoint perimeters such as righting reflex time, mortality, and neuropathology should be monitored to evaluate possible experimental drift.</li>
</ol>
6. Exclusion criteria
<ol>
	<li>Exclude animals prior to surgery with a poor health condition, like poor weight &#60;20 g for a 4-month-old mouse, lethargy, and poor coat condition.</li>
	<li>Exclude animals with complications during surgery like a depressed skull fracture, a visible hemorrhage related to surgery, or ear bleeding.</li>
	<li>Exclude animals from the study with the following post-surgery symptoms: failure to eat and/or to move normally, unusual vocalizations, weight loss, or failure of the wound to heal normally after surgery. 
	NOTE: This model could be used as a repetitive model of mild TBI. If the mice receive the second surgery 24 h apart from the first one, the staples or suture could be removed, and the same incision could be used to expose the skull. A new incision needs to be made if a longer time elapses between the surgeries.</li>
</ol>

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The authors have nothing to disclose.

Several steps are involved in recreating a consistent injury model using the described model. First, it is critical to correctly secure the animal into the stereotaxic frame. The animal's head should not be able to move laterally, and the skull should be completely flat with bregma and lambda reading the same coordinates. Correctly placing the ear bars is the most difficult aspect of this surgery, and this can only be learned with practice. If the skull is not level, the head should be adjusted before inducing CHI. Failu...

Traumatic brain injury (TBI) is caused by an external force on the brain, often associated with falls, sports injuries, physical violence, or road accidents. In 2014, the Centers for Disease Control and Prevention determined that 2.53 million Americans visited the emergency department to seek medical help for TBI-related accidents1. Since mild TBI (mTBI) represents the majority of TBI cases, over the past several decades, multiple models of mTBI have been adopted, which include weight drop, piston-driven closed head injury and controlled cortical impact, rotational injury, mild fluid percussion injury, and blast injury models2,3. The heterogeneity of the mTBI models is useful to address the different features associated with mTBI seen in people and to help evaluate the cellular and molecular mechanisms associated with brain injury.
Of the commonly used models of closed head injury, one of the first and most widely used models is the weight drop method, where an object is dropped from a specific height onto the animal&#39;s head (anesthetized or awake)2,4. In the weight drop method, the injury&#39;s severity depends on several parameters, including craniotomy performed or not, head fixed or free, and the distance and weight of the falling object2,4. One disadvantage of this model is the high variability in the severity of the injury and the high mortality rate associated with respiratory depression5,6. A common alternative is to deliver the impact using a pneumatic or electromagnetic device, which can be done directly on the exposed dura (controlled cortical impact: CCI) or closed skull (closed head injury: CHI). One of the strengths of the piston-driven injury is its high reproducibility and low mortality. However, CCI requires craniotomy7,8, and a craniotomy itself induces inflammation9. Instead, in the CHI model, there is no need for craniotomy. As already stated, each model has limitations. One of the limitations of the CHI model described in this paper is that the surgery is performed using a stereotaxic frame, and the head of the animal is immobilized. While the full head immobilization assures reproducibility, it does not account for movement after the impact that could contribute to the injury associated with a mTBI.
This protocol describes a basic method to perform a CHI impact with a commercially available electromagnetic impactor device10 in a mouse. This protocol details the exact parameters involved to achieve a highly reproducible injury. In particular, the investigator has precise control over the parameters (depth of injury, dwell time, and velocity of impact) to precisely define the injury severity. As described, this CHI model produces an injury that results in bilateral pathology, both diffuse and microscopic (i.e., chronic activation of glia, axonal and vascular damage), and behavioral phenotypes11,12,13,14,15. In addition, the described model is considered mild as it does not induce structural brain lesions based on MRI or gross lesions on pathology even 1 year after the injury16,17.

<table><tbody><tr><td>9 mm Autoclip Applier</td><td>Braintree scientific</td><td>ACS- APL</td><td>Surgery</td></tr><tr><td>9 mm Autoclip Remover</td><td>Braintree scientific</td><td>ACS- RMV</td><td>Surgery</td></tr><tr><td>9 mm Autoclip, Case of 1,000 clips</td><td>Braintree scientific</td><td>ACS- CS</td><td>Surgery (Staples)</td></tr><tr><td>Aperio ImageScope software&amp;nbsp;</td><td>Leica BioSystems</td><td>NA&amp;nbsp;</td><td>IHC</td></tr><tr><td>BladeFLASK Blade Remover</td><td>Fisher Scientific</td><td>22-444-275</td><td>Surgery</td></tr><tr><td>Cotton tip applicator</td><td>VWR</td><td>89031-270</td><td>Surgery</td></tr><tr><td>Digitial mouse stereotaxic frame</td><td>Stoelting</td><td>51730D</td><td>Surgery</td></tr><tr><td>Dumont #7 Forceps</td><td>Roboz</td><td>RS-5047</td><td>Surgery</td></tr><tr><td>Ear bars</td><td>Stoelting</td><td>51649</td><td>Surgery</td></tr><tr><td>EthoVision XT 11.0&amp;nbsp;</td><td>Noldus Information Technology</td><td>NA</td><td>RAWM&amp;nbsp;</td></tr><tr><td>Fiber-Lite</td><td>Dolan-Jeffer Industries</td><td>UN16103-DG</td><td>Surgery</td></tr><tr><td>Fisherbrand Bulb for Small Pipets</td><td>Fisher Scientific</td><td>03-448-21</td><td>Head support apparatus</td></tr><tr><td>Gemini Avoidance System</td><td>San Diego Instruments</td><td>NA</td><td>Active avoidance</td></tr><tr><td>Heating Pad</td><td>Sunbeam&amp;nbsp;</td><td>732500000U</td><td>Surgery prep</td></tr><tr><td>HRP conjugated goat anti-rabbit IgG&amp;nbsp;</td><td>Jackson Immuno Research laboratories</td><td>111-065-144&amp;nbsp;</td><td>IHC</td></tr><tr><td>Induction chamber</td><td>Kent Scientific</td><td>VetFlo-0530XS</td><td>Surgery prep</td></tr><tr><td>Isoflurane, USP</td><td>Covetrus</td><td>NDC: 11695-6777-2</td><td>Surgery</td></tr><tr><td>Mouse gas anesthesia head holder</td><td>Stoelting</td><td>51609M</td><td>Surgery</td></tr><tr><td>Neuropactor Stereotaxic Impactor</td><td>Neuroscience Tools</td><td>n/a</td><td>Surgery: Formally distributed by Lecia as impact one</td></tr><tr><td>NexGen Mouse 500</td><td>Allentown&amp;nbsp;</td><td>n/a</td><td>Post-surgery, holding cage</td></tr><tr><td>Parafilm</td><td>Bemis</td><td>PM992</td><td>Head support apparatus</td></tr><tr><td>Peanut - Professional Hair Clipper</td><td>Whal</td><td>8655-200&amp;nbsp;</td><td>Surgery prep</td></tr><tr><td>Povidone-Iodine Solution USP, 10% (w/v), 1% (w/v) available Iodine, for laboratory</td><td>Ricca</td><td>3955-16</td><td>Surgery</td></tr><tr><td>Puralube Vet Oinment,petrolatum ophthalmic ointment, Sterile ocular lubricant</td><td>Dechra</td><td>17033-211-38</td><td>Surgery</td></tr><tr><td>Rabbit anti-GFAP&amp;nbsp;</td><td>Dako</td><td>Z0334</td><td>IHC</td></tr><tr><td>Rabbit anti-IBA1&amp;nbsp;</td><td>Wako</td><td>019-19741</td><td>IHC</td></tr><tr><td>8-arm Radial Arm Water Maze</td><td>MazeEngineers</td><td>n/a</td><td>RAWM&amp;nbsp;</td></tr><tr><td>Scale</td><td>OHAUS CS series</td><td>BAL-101</td><td>Surgery prep</td></tr><tr><td>Scalpel Handle #7 Solid 6.25&quot;&amp;nbsp;</td><td>Roboz</td><td>RS-9847</td><td>Surgery</td></tr><tr><td>Sterile Alcohol Prep Pads (isopropyl alcohol 70% v/v)</td><td>Fisher Brand</td><td>22-363-750</td><td>Surgery prep</td></tr><tr><td>SumnoSuite low-flow anesthesia system</td><td>Kent Scientific</td><td>SS-01</td><td>Surgery</td></tr><tr><td>10 mL syringe Luer-Lok Tip</td><td>BD Bard-Parker</td><td>302995</td><td>Head support apparatus</td></tr><tr><td>Timers</td><td>Fisher Scientific</td><td>6KED8</td><td>Surgery</td></tr><tr><td>Topical anesthetic cream</td><td>L.M.X 4</td><td>NDC 0496-0882-15</td><td>Surgery prep</td></tr><tr><td>Triple antibiotic ointment</td><td>Major</td><td>NDC 0904-0734-31</td><td>Post-surgery</td></tr><tr><td>Tubing</td><td>MasterFlex</td><td>96410-16</td><td>Head support apparatus</td></tr><tr><td>Vaporizer Single Channel Anesthesia System</td><td>Kent Scientific</td><td>VetFlo-1210S</td><td>Surgery prep</td></tr></tbody></table>

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.

This stereotaxic electromagnetic impactor device is versatile. It is used for both an open skull controlled cortical impact (CCI) or a closed head injury (CHI) surgery. Furthermore, the injury severity can be modulated by changing the injury parameters such as impact velocity, dwell time, impact depth, impactor tip, and injury target. Herein is described a CHI surgery using a 5.0 mm steel tip impactor. This injury is considered mild because there are no structural brain lesions. The mortality rate in adult mice is less t...

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

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 ...

electromagnetic-controlled-closed-head-model-mild-traumatic-brain

Research

JoVE Journal

Neuroscience

2.1K Views.  University of Kentucky. Het protocol beschrijft licht traumatisch hersenletsel in een muismodel. In het bijzonder wordt een stapsgewijs protocol om een milde middellijn gesloten hoofdletsel en de karakterisering van het diermodel te induceren volledig uitgelegd.

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

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 ...

Murine Model of Controlled Cortical Impact for the Induction of Traumatic Brain Injury

The Centers for Disease Control and Injury Prevention estimate that almost 2 million people sustain a traumatic brain injury (TBI) every year in the United States. In fact, TBI is a contributing factor to over a third of all injury-related mortality. Nonetheless, the cellular and molecular mechanisms underlying the pathophysiology of TBI are poorly understood. Thus, preclinical models of TBI capable of replicating the injury mechanisms pertinent to TBI in human patients are a critical research need. The controlled cortical impact (CCI) model of TBI utilizes a mechanical device to directly impact the exposed cortex. While no model can full recapitulate the disparate injury patterns and heterogeneous nature of TBI in human patients, CCI is capable of inducing a wide range of clinically applicable TBI. Furthermore, CCI is easily standardized allowing investigators to compare results across experiments as well as across investigative groups. The following protocol is a detailed description of applying a severe CCI with a commercially available impacting device in a murine model of TBI.

Here we describe a protocol for the induction of murine traumatic brain injury via an open-head controlled cortical impact.

The Centers for Disease Control and Injury Prevention estimate that almost 2 million people sustain a traumatic brain injury (TBI) every year in the ...

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 ...

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

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.

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 ...

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 ...

JoVE Encyclopedia of Experiments

Neuropathology

Trauma

Generating a Closed-Head Mild Traumatic Brain Injury in a Murine Model

<a href='https://app.jove.com/v/61244/low-intensity-blast-wave-model-for-preclinical-assessment-closed-head'>Source: Logsdon, A. F., et al. Low-intensity Blast Wave Model for Preclinical Assessment of Closed-head Mild Traumatic Brain Injury in Rodents. J. Vis. Exp.&#160;(2020)</a>This video demonstrates the induction of closed-head mild traumatic brain injury in a mouse model using a pressurized gas shock tube setup. The generated pressure wave ruptures the polyester membrane, delivering a shockwave to the mouse&#8217;s head that results in rapid brain movement within the skull, causing a mild traumatic brain injury.

Source: Logsdon, A. F., et al. Low-intensity Blast Wave Model for Preclinical Assessment of Closed-head Mild Traumatic Brain Injury in Rodents. J. Vis. ...

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

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