Name: Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS) (Video) | JoVE Journal
Uploaded: 2012-03-17T14:00:00.000+00:00
Duration: 12 min 35 s
Description: Learn clinical testing and spinal cord removal in the SOD1 G93A mouse model for ALS research. This method demonstrates rotor and hanging wire tests to assess motor function and prepare tissue for immunohistological analysis.

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5 minutes

LT has received grant support from the Forschungsf&ouml;rderungsprogramm of the University Medicine G&ouml;ttingen. PL and MB were supported by the DFG Research Center for Molecular Physiology of the Brain (CMPB), G&ouml;ttingen. The authors thank Dr. Lars Tatenhorst for assistance with videography and Birgit Liebau for help with audio and video editing.

Animals were purchased from Jackson Laboratory (# 002726) 1. They are clinically scored and subjected to a test of motor function (rotarod test) and of muscular strength (hanging wire test). All these tests and the later killing of the animals in order to prepare the spinal cord have been performed in very close accordance to the local guidelines for proper conduct of animal experiments. 
1. Clinical Score 
Apart from assessment for body weight mice are examined for signs of motor deficit with the following 4 point scoring system 2: 
4 points: normal (no sign of motor dysfunction)
3 points: hind limb tremors are evident when suspended by the tail
2 points: gait abnormalities are present
1 point: dragging of at least one hind limb
0 point: symmetrical paralysis, inability to right itself or loss of 20% of maximum body weight; in this case the animals are immediately euthanized and the experiment is terminated
2. Tests of Motor Function and Muscular Strength 
Hanging wire 
This test is used to assess muscular strength 3, 4. All animals perform this test at least one or two days after the rotarod test. Each mouse is placed on a custom-made wire lid with intervals of 0.8 cm and cautiously turned upside down, 60 cm above a straw covered bottom. After training for three consecutive times of at least 180 s the latency to fall is measured. Each mouse is given up to three attempts to hold on to the inverted lid for a maximum of 180 s and the longest period is recorded.
Rotarod Test
The rotarod apparatus (Ugo Basile, Comerio, Italy) was used to measure motor coordination, balance and motor learning ability 3, 4. A good performance requires a high degree of sensorimotor coordination. The machine should be placed in a calm and non-disturbing environment to avoid distractive stimuli for the tested animal. It consists of a computer-controlled motor-driven rotating spindle and five lanes for five mice. Falls of the mice are detected automatically by pressure on a plastic plate at the bottom. After training for three consecutive times of at least 180 s at a constant speed of 15 r.p.m. the time for which an animal can remain on the rotating rod is measured. Each animal undergoes three trials and the longest latency without falling is recorded. The time of 180 s is chosen as cut-off time because the majority of significant differences in motor coordination are detected in this time frame.
3. Spinal Cord Preparation
<ol class="lalpha">
 <li> Animals are killed by CO2 insufflation in accordance with the local guidelines and are immediately perfused transcardially with PBS solution followed by a 4% paraformaldehyde solution. </li>
 <li> In order to prepare the spinal cord of the sacrificed mouse, the animal is placed onto an operation table and the four limbs are fixed on the side in order to expose the back side of the mouse. </li>
 <li> A short wash with a 70% ethanol solution cleans the site of dissection and flattens the hair coat. </li>
 <li> Then the skin is incised with a sharp scalpel in the median line. In order to facilitate cutting the skin is stretched to both sides. If leg muscles shall be prepared, their skin has also to be incised. </li>
 <li> After the skin incision is completed, it is pulled aside with a pair of tweezers to expose the underlying superficial fascia of the body. </li>
 <li> The musculature of the neck and the nuchal ligament have to be removed and are carefully prepared. Be careful not to incise to deeply and lesion the spinal cord. The shoulder muscles can also be removed in order to better expose the spinal column. </li>
 <li> Then the paravertebral muscles are removed from the entire spinal column. </li>
 <li> In order to open the spinal column several laminectomies have to be performed. One should start from the upper cranial part at the site of the atlanto-occipital joint. </li>
 <li> It is easiest to remove the fixation of the upper two limbs and overstretch the neck to be better able to perform the laminectomy of the first vertebrae. These are pulled away without touching the exposed cervical spinal cord. </li>
 <li> More vertebrae are removed by first transecting the vertebral arches at both sides with angled scissors and then pulling on the dorsal processes. Remaining lateral parts of the vertebrae should be removed to facilitate later complete removal of the spinal cord. </li>
 <li> An anatomical landmark of the lumbar spinal cord is the intumescence that is also present in the cervical spinal cord. </li>
 <li> Having finished the laminectomy of the entire spinal cord, make sure that you also transect all ventral roots and release the spinal cord from the dura mater of the meninges. </li>
 <li> Then the cervical spinal cord is cut cranially and you start to remove the spinal cord. </li>
 <li> Finally the spinal cord is also cut at the distal cauda-equina to be completely released. </li>
 <li> Ultimately, the spinal cord is placed into a postfixating solution (e.g. 4% paraformaldehyde) overnight and can be further processed. We usually cryosection the spinal cord to prepare it for immunohistological analysis. 
   </li>
</ol>
4. Representative Results 
The technique of spinal cord preparation represents the focus of this video article. It is an essential prerequisite for later tissue sectioning and ultimately for immunohistological analysis of spinal cord sections. As an example of a final result, an immunohistochemical workup of the anterior horn region of the mouse lumbar spinal cord of a wildtype (wt) and of a SOD G93A transgene (tg) mouse is demonstrated. Motor neurons can be identified with a primary anti-ChAT antibody and subsequent fluorescent labeling with a secondary Cy3 antibody. In addition, a nuclear counter-stain with DAPI (4,6-diamidino-2-phenylindole) has been performed (Figure 1).
<img src="/files/ftp_upload/3936/3936fig1.jpg" alt="Fluorescence microscopy of anterior horn tissues showing ChAT and DAPI staining comparison." data-altupdatedat="1787630408000" data-alt="Figure 1"> 
Figure 1. Fluorescent photomicrographs visualizing the immunodetection of motoneurons with anti-ChAT antibody (red) and cellular nuclei counter-stain by DAPI (blue) in the mouse lumbar spinal cord anterior horn of a wildtype (wt) (on the left) and of a SOD G93A transgenic (tg)(on the right) mouse at the age of 130 days. Scale bar: 40 μm.
As the immunohistochemical analysis of the SOD G93A mice is not the primary scope of this article please consult the original publication in which these transgenic mice have been characterized and more recent ones which study therapeutic approaches for further reference 1, 5, 6. If therapeutic effects shall be differentiated on the immunohistological level clearly defined quantitative evaluation algorithms should be applied supported by a stereological software (for example see 7).

<ol><li>Gurney, M. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Motor+neuron+degeneration+in+mice+that+express+a+human+Cu%2C+Zn+superoxide+dismutase+mutation%5BTitle%5D)+AND+%22Science%22%5BJournal%5D)">Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation.</a> Science. 264 (5166), 1772-1775 (1994).</li>
<li>Weydt, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Assessing+disease+onset+and+progression+in+the+SOD1+mouse+model+of+ALS%5BTitle%5D)+AND+%22Neuroreport%22%5BJournal%5D)">Assessing disease onset and progression in the SOD1 mouse model of ALS.</a> Neuroreport. 14 (7), 1051-1054 (2003).</li>
<li>Crawley, J. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Behavioral+phenotyping+strategies+for+mutant+mice%5BTitle%5D)+AND+%22Neuron%22%5BJournal%5D)">Behavioral phenotyping strategies for mutant mice.</a> Neuron. 57 (6), 809-818 (2008).</li>
<li>Miana-Mena, F. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Optimal+methods+to+characterize+the+G93A+mouse+model+of+ALS%5BTitle%5D)+AND+%22Amyotroph.+Lateral+Scler.+Other+Motor+Neuron+Disord%22%5BJournal%5D)">Optimal methods to characterize the G93A mouse model of ALS.</a> Amyotroph. Lateral Scler. Other Motor Neuron Disord. 6 (1), 55-62 (2005).</li>
<li>Zhong, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Activated+protein+C+therapy+slows+ALS-like+disease+in+mice+by+transcriptionally+inhibiting+SOD1+in+motor+neurons+and+microglia+cells%5BTitle%5D)+AND+%22J.+Clin.+Invest%22%5BJournal%5D)">Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells.</a> J. Clin. Invest. 119 (11), 3437-3449 (2009).</li>
<li>Pitzer, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Granulocyte-colony+stimulating+factor+improves+outcome+in+a+mouse+model+of+amyotrophic+lateral+sclerosis%5BTitle%5D)+AND+%22Brain%22%5BJournal%5D)">Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis.</a> Brain. 131 (Pt. 12), 3335-3347 (2008).</li>
<li>Gowing, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Ablation+of+proliferating+microglia+does+not+affect+motor+neuron+degeneration+in+amyotrophic+lateral+sclerosis+caused+by+mutant+superoxide+dismutase%5BTitle%5D)+AND+%22J.+Neurosci%22%5BJournal%5D)">Ablation of proliferating microglia does not affect motor neuron degeneration in amyotrophic lateral sclerosis caused by mutant superoxide dismutase.</a> J. Neurosci. 28 (41), 10234-10244 (2008).</li>
<li>Scott, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((interpretation+of+studies+in+the+standard+murine+model+of+ALS%5BTitle%5D)+AND+%22Amyotroph+Lateral+Scler%22%5BJournal%5D)">interpretation of studies in the standard murine model of ALS.</a> Amyotroph Lateral Scler. 9 (1), 4-15 (2008).</li>
<li>Turner, B. J., Talbot, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Transgenics%2C+toxicity+and+therapeutics+in+rodent+models+of+mutant+SOD1-mediated+familial+ALS%5BTitle%5D)+AND+%22Prog+Neurobiol%22%5BJournal%5D)">Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS.</a> Prog Neurobiol. 85 (1), 94-134 (2008).</li>
<li>Corse, A. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Preclinical+testing+of+neuroprotective+neurotrophic+factors+in+a+model+of+chronic+motor+neuron+degeneration%5BTitle%5D)+AND+%22Neurobiol+Dis%22%5BJournal%5D)">Preclinical testing of neuroprotective neurotrophic factors in a model of chronic motor neuron degeneration.</a> Neurobiol Dis. 6 (5), 335-346 (1999).</li>
<li>Knippenberg, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Significance+of+behavioural+tests+in+a+transgenic+mouse+model+of+amyotrophic+lateral+sclerosis+%28ALS%29%5BTitle%5D)+AND+%22Behav+Brain+Res%22%5BJournal%5D)">Significance of behavioural tests in a transgenic mouse model of amyotrophic lateral sclerosis (ALS).</a> Behav Brain Res. 213 (1), 82-87 (2010).</li>
<li>Burgess, R. W., Cox, G. A., Seburn, K. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Neuromuscular+disease+models+and+analysis%5BTitle%5D)+AND+%22Methods+Mol.+Biol%22%5BJournal%5D)">Neuromuscular disease models and analysis.</a> Methods Mol. Biol. 602, 347-393 (2010).</li>
<li>Hayworth, C. R., Gonzalez-Lima, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Pre-symptomatic+detection+of+chronic+motor+deficits+and+genotype+prediction+in+congenic+B6.SOD1%28G93A%29+ALS+mouse+model%5BTitle%5D)+AND+%22Neuroscience%22%5BJournal%5D)">Pre-symptomatic detection of chronic motor deficits and genotype prediction in congenic B6.SOD1(G93A) ALS mouse model.</a> Neuroscience. 164 (3), 975-985 (2009).</li>
<li>Ludolph, A. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Guidelines+for+preclinical+animal+research+in+ALS%2FMND%3A+A+consensus+meeting%5BTitle%5D)+AND+%22Amyotroph+Lateral+Scler%22%5BJournal%5D)">Guidelines for preclinical animal research in ALS/MND: A consensus meeting.</a> Amyotroph Lateral Scler. 11 (1-2), 38-45 (2010).</li>
<li>Boillee, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Onset+and+progression+in+inherited+ALS+determined+by+motor+neurons+and+microglia%5BTitle%5D)+AND+%22Science%22%5BJournal%5D)">Onset and progression in inherited ALS determined by motor neurons and microglia.</a> Science. 5778 (3), 1389-1392 (2006).</li>
</ol>

No conflicts of interest declared.

The SOD1 (G93A) genetic mouse model is a valuable animal model to study the disease course of progressive motoneuron loss comparable to human amyotrophic lateral sclerosis 8. A variety of different treatment paradigms have been evaluated in this model and represent a basis for later testing in human clinical studies 8-10. In order to be able to detect significant differences in an experimental treatment study in these mice, it is of eminent importance to include at least 24 litter-matched gender-bal...

<table><tbody><tr><td>Rota-Rod for Mice</td><td>Ugo Basile</td><td># 47600</td><td></td></tr><tr><td>Hanging wire device</td><td>Custom Made</td><td></td><td></td></tr><tr><td>Operation Table Operation lamp Protective gloves</td><td></td><td></td><td></td></tr><tr><td>&amp;#8220;Iris&amp;#8221; Scissors, angled to side</td><td>Fine Science Tools</td><td>14063-09</td><td></td></tr><tr><td>Cohan-Vannas Spring Scissors, straight</td><td>Fine Science Tools</td><td>15000-10</td><td></td></tr><tr><td>Micro forceps</td><td>Hammacher, Solingen, Germany</td><td>HWC 111-10</td><td></td></tr><tr><td>Scalpel &amp;#8220;pr&amp;#228;zisa plus&amp;#8221;</td><td>Dahlhausen, K&amp;#246;ln, Germany</td><td>11.000.00.510, FIG 10</td><td></td></tr></tbody></table>

clinical testing and spinal cord removal in a mouse model for amyotrophic lateral sclerosis (als)

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 years for the sporadic disease and around 50 years for the familial disease. Due to its progressive course, 50% of the patients die within 30 months of symptom onset. In order to evaluate novel treatment options for this disease, genetic mouse models of ALS have been generated based on human familial mutations in the SOD gene, such as the SOD1 (G93A) mutation. Most important aspects that have to be evaluated in the model are overall survival, clinical course and motor function. Here, we demonstrate the clinical evaluation, show the conduction of two behavioural motor tests and provide quantitative scoring systems for all parameters. Because an in depth analysis of the ALS mouse model usually requires an immunohistochemical examination of the spinal cord, we demonstrate its preparation in detail applying the dorsal laminectomy method. Exemplary histological findings are demonstrated. The comprehensive application of the depicted examination methods in studies on the mouse model of ALS will enable the researcher to reliably test future therapeutic options which can provide a basis for later human clinical trials.

A mouse model for amyotrophic lateral sclerosis (ALS) is examined clinically and behaviorally. As a prerequisite for an accompanying immunohistological analysis the preparation of the spinal cord is depicted in detail.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 ...

Hello, my name is Lar Turner. I'm a postdoc in the Department of Neurology at the University of Ingham, Germany. Hi, my name is Lin Gunda.I'm a medical student and I'm doing my thesis work in this lab. Today we are going to show you the clinical testing of the SODG 93, A Moss model of atrophic lateral sclerosis. Furthermore, we'll demonstrate the motor function test with a so-called rotor test and additionally, another motor function test with the hanging Wire grip in order to perform an immuno logic analysis.After functional testing of the a s mice, a necessary procedure consists in the removal of the spinal cord, the STIC nerve, and the gastroc muscle. We want to show these surgical procedure in detail and one present some exemplary immuno logic findings at the end. Okay, but Now let's first start with the clinical testing.This is a free moving wild type MOE that does not show any clinical symptoms like muscle tremor or Parsis in our clinical classification system. That would be score four. This is a transgenic A LS moe.In an early disease stage, it exhibits a severe tremor of the right hin limb that classifies it as SCORE three E.The severe gait abnormalities Classify this animal as score two. Dragging of at least one hind limb are classified as clinical score one in the Hanging wire test, crude muscular rib strength is evaluated. Each mouse is placed on a CustomMade wire and cautiously turned upside down above the straw covered button.After Training for three consecutive times of at least 180 seconds, the latency to falls measured. Each mouse is given up to three attempts to hold onto the inverted lid for a maximum of 180 seconds, and the longest period is recorded In comparison To the white wire type mouse on the right side. The plaque transgenic mouse on the left is very weak and falls off the lid before reaching the Maximum.The Rotor rod apparatus is used to measure motor coordination, balance and motor learning ability. A good performance requires a high decree of sensory motor coordination. It consists of a computer controlled, motor driven rotating spindle, and five lanes for five m.Faults of the mice are detected automatically by pressure on the bottom plastic plate. After training for three consecutive times of at least 180 seconds at a constant speed of 15 rounds per minute, the time for which an animal can remain on the rotating rot is measured. Each animal undergoes three trials and the longest latency without falling is recorded.The healthy wild type mos on the left hand side is running without difficulty on the rotor rod. In contrast, the transgenic a s mo on the right side has severe problems to even remain on the rotor rod and slips off after a while observed from behind. You see the severe running difficulties of the left retre mouse.In comparison with the healthy wire tap mouse, it is not able to keep up with the rotor rod speed and cannot push upwards with the HIN limbs. In order to perform an immunochemical analysis of the spinal cord, the animals have to be sacrificed. It is very important to always strictly follow the local guidelines for proper conduct of animal experiments.In this context, In this Very simplified overview of the vertebral column and its surrounding tissues, the main anatomical structures are depicted. We will place the animal on its ventral side and start to prepare the muscles from the dorsal bag. After the muscular tissue is removed, we will access the vertebral column that encloses the spinal cord.After the animal has been sacrificed and perfused with a paraform height containing solution, the spinal cord can be removed. The animal is placed onto an operation table and the full limbs are fixed on the sides and order to expose the backside of the mouse. The animal is wetted to flatten the hair coat and facilitate the following skin incision.For this, a sharp scalpel is used. Be careful to stretch the skin to both sides. To facilitate cutting the leg muscle shall be prepared.Their skin has also to be incised. After the skin incision is completed, it is gently pulled aside. With a pair of tweezers having Removed the leg muscles and the sciatic nerve, we continue to approach the spinal cord and placed the animal on a new operation table.Now it is easy to identify the cranium neck, muscles, and spinal column. Having identified all these structures, it is easy to proceed to the next step. The muscles of the neck and the nu ligament have to be removed.Be careful not to incise too deeply and lead the vertebral column. In the next Step, the paravertebral muscles are removed entirely to expose the vertebral column. In order To access the spinal column, several ectomies have to be done.We start from the cervical part of the vertebral column, including the Atlantic occipital joint. To perform the laminectomy, we have to cut the vertebral arch to be able to remove all the vertebral processes from the vertebral Body. As explained before the laminectomy start with the cutting of the vertebral arches.Then the laina can be pulled away. Again, take care not to lesion the spinal cord as many more ral have to be removed. It is quite helpful to use angled scissors and inci several vertebral arches of both sides at a time.Then pull on the dorsal processes to entirely remove the vertebral lamine and the closeup. You see that the pair of scissors have to be carefully inserted most laterally at the side of the spinal canal. Remaining Lateral parts of the vertebral column have to be removed to facilitate the later complete removal of the spinal cord.An Anatomical landmark of the spinal cord are the so-called cervical and lumbar esencia. Having finished the ectomies of the entire spinal cord, make sure that you also transect all ventral roots of the spinal cord and release it from the dur matter of the meninges. Next, The cervical spinal cord is cut.Cranially and its removal is started again. Touch the spinal cord very cautiously in order not to harm this tissue, because this could cause severe limitations for later immuno immunochemical Analysis. The removal Of the spinal cord is further continued at the thoracic level and proceeded to the lumbar part.It is Finally cut again this time at the side of the cord equina. Now we are able to completely release it. Here You see the spinal cord placed right next to its original location in the RAL column.Ultimately, it is placed into a Paraform Hyde post fixating Solution. As a classical example for spinal cord immunohistochemical analysis, you can apply an antibody that recognizes choline, acetyl transferase to identify motor neurons in the spinal cord anterior horn. Here you see a large number of motor neurons in a healthy wild type Animal.In Contrast, the transgenic a LS animal at end stage does exhibit a much smaller number of motor neurons in the Anterior horn. Watching This video article, you should have learned the basic clinical examination of the SODG 93. A mouse model of atrophic lateral sclerosis.Two motor behavioral tests have been demonstrated the rotor test and the hanging wire test. They provide a good possibility to evaluate basic motor function. They are easy to perform, sensitive in detection of motor deficit and time efficient.The main part of this video consists in a demonstration of the preparation technique of the spinal cord. This can of course be applied to any other mouse disease model and is an essential step for the later immunochemical analysis of disease pathology in the spinal cord. Thank you for watching.We hope that this video article will be helpful for your future experiments.

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Learn clinical testing and spinal cord removal in the SOD1 G93A mouse model for ALS research. This method demonstrates rotor and hanging wire tests to assess motor function and prepare tissue for immunohistological analysis.

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

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