Name: assessment of sensorimotor function in mouse models of parkinson's disease
Uploaded: 2013-06-17T13:00:00
Duration: 10 min 32 s
Description: Watch this Scientific Journal Video about Assessment of Sensorimotor Function in Mouse Models of Parkinson's Disease at JoVE.com

This work is funded by NIH/NINDS NS07722-01 and the Gardner Family Center for Parkinson's Disease and Movement Disorders.

Optimally mice should be tested during their active (dark) cycle. The mice in our laboratory are maintained on a reverse light/dark cycle that enables us to conveniently test the mice during their active period (and ours). Testing is not started until at least one hour into the dark cycle. However, it is not always possible for an investigator to maintain a separate mouse room with a reverse light cycle. In that case, all three tests can be performed during the light cycle but keep in mind that time to traverse on the beam, number of steps and rears in the cylinder, and contact and removal times may be longer when tested during this time.
All three tests described below can be performed by one experimenter, but for those who are not as experienced handling and working with mice or have little to no experience measuring behavior in mice then an additional experimenter may be needed. In this case the second experimenter can assist with the challenging beam test by placing mice on the beam while the other experimenter records the trial or in the adhesive removal test the second experimenter can run the timer while the other places the sticker on the snout and places the mouse in the cage.
1. Challenging Beam Traversal Procedure
<ol>
	<li>Invert 3 clean mouse cages on a tabletop or in a mouse cage-changing station. Line the cages up evenly so that they can support the length of the beam (1 meter).</li>
	<li>Assemble the four sections of the beam from the widest to narrowest section and place on top of the inverted mouse cages.</li>
	<li>Place the homecage of the mice that you plan to test on its side and at the end of the beam so that the narrowest end of the beam leads right into the homecage.</li>
	<li>Pick up the first mouse by the base of its tail and support its hindlimbs with the palm of your hand. Place the mouse at the wide end of the beam and let go of its tail and remove your hand.</li>
	<li>Let the mouse sniff and move around in order to become better oriented to the apparatus- if the mouse turns around gently redirect it to the desired direction.</li>
	<li>Lift up the homecage (even if it has cagemates in it) keeping it in the same position on its side and bring it close to the test mouse. As the test mouse begins to try and enter the homecage move it back so that the mouse does not enter but makes a step forward. Continue to do this all the way down the beam. At the end allow the mouse to enter the homecage. Do the same procedure for each mouse in the cage. This is the first "assisted" trial.</li>
	<li>The beam should be thoroughly cleaned between cages with a disinfectant provided by the animal care or veterinary staff. Within a cage it is important to clean off any urine or fecal pellets off the beam before the next mouse is run because this will distract the next mouse.</li>
	<li>Once all of the mice in the cage have gone through one assisted trial then pick up the first mouse again and place it at the wide end of the beam. If needed, with your hand gently orient the mouse in the desired direction and lightly touch its backside to encourage it to move along the length of the beam into its homecage. If the mouse stops to sniff or walk off the beam correct the mouse with your hand or pick it up and place it on the same section where it walked off. Have your hand nearby to guide the mouse to the end of the beam. You want to try and minimize the mouse stopping and exploring while on the beam. The more this is done during training the less the mouse tends to do it during testing.</li>
	<li>The trial ends when the mouse places one of its forelimbs into the homecage. The next mouse can then receive its 2nd trial. Mice receive a total of 5 trials on the first training day, alternating between mice so that each mouse has an intertrial interval of ~30 sec or more. Typically by the last few trials mice will traverse the length of the beam, on their own, without need for correcting.</li>
	<li>24 hr later day 2 of training can begin. On day 2 the mice receive 5 more trials on the same beam set-up as in day 1. The mice should not need any assistance but may need to be corrected or touched on the backside to prevent stopping or exploring.</li>
	<li>24 hr later the actual test day can begin. For the test day, the beam is set up in a similar manner to the previous 2 training days. However, now a mesh grid that corresponds to each beam width is placed on top of each beam section. A videocamera is used to record all beam traversal trials and can be performed by one or multiple experimenters.</li>
	<li>Label a card with the essential experiment information (date, mouse #, trial #, etc.). Place this card in front of the camera and record for 2-3 sec so that it is clear which mouse is being tested and what trial it is on.</li>
	<li>The mouse is placed on top of the grid surface on the widest section of the beam and recorded as it moves along the beam. The recording should be close enough so that the entire length of the mouse's body is visible on the camera. If it is too far then slips are difficult to see and if it is too close then limb movements can be missed. The camera should be positioned so that the grid is in the middle of the viewer.</li>
	<li>On the Test day all mice receive 5 trials on the grid-surfaced beam.</li>
</ol>
2. Analysis of Beam Video
<ol>
	<li>Videos can be viewed directly from the camera or connected to a television or computer for a larger screen view. Videotapes should be scored by an experimenter blind to genotype and treatment condition within the experiment.</li>
	<li>Errors for each trial are scored as the video is played in slow motion. Slips or errors are counted when the mouse is facing and moving forward. A slip through or outside of the grid is considered an error when the limb slips beyond 0.5 cm below the grid surface (halfway down). Any slips made after a mouse stops or orients its head to the side are not considered errors. If the mouse is not moving forward and a limb or limbs repeatedly slips through the grid it is NOT considered an error. On the narrow section of the beam the base of the hindlimbs can be on top of the grid and the toes hanging off the side, this is not considered an error.</li>
	<li>Steps are also counted in slow motion. The hindlimb facing the camera is used to track the number of steps. Counting begins when the mouse makes its first step forward and ends when the mouse places its forelimb into the homecage.</li>
	<li>Time to traverse is scored using a stopwatch and is done in real time. The timer is started when the mouse begins to move forward and ends when the first forepaw is placed in the homecage.</li>
</ol>
3. Spontaneous Activity in the Cylinder Procedure
<ol>
	<li>Invert 3 clean mouse cages on a tabletop or in a mouse cage-changing station. Arrange two cages next to each other ~18 cm apart so that the front of the cages are facing the experimenter. The remaining cage is placed behind the other two cages and will serve to support the mirror.</li>
	<li>Place the piece of glass on top of the 2 cages and position it so the glass is being supported by the outer edge of the first 2 cages.</li>
	<li>Place the cylinder on top of the glass and the mirror at an angle beneath the glass, leaning on the 3rd cage in back. The angle can range anywhere from 30&deg;- 45&deg; but more importantly the view from the mirror has to include the full diameter of the cylinder.</li>
	<li>Set the videocamera up in front of the mirror and adjust both the mirror and videocamera until you can view the entire diameter of the bottom of the cylinder.</li>
	<li>Set the timer for 3 min and label a card with the important experiment details (date, mouse#, etc.). Videorecord the label for 2-3 sec.</li>
	<li>Place the mouse in the cylinder and press record and the timer. Record the mouse for three minutes. It is important that the testing area is quiet as loud noises and conversation can distract the mouse and potentially cause freezing behavior.</li>
	<li>During the 3 min use a hand counter to count the number of rears the mouse makes while in the cylinder. A rear is defined as a vertical movement with both forelimbs off the floor so that the mouse is standing only on its hindlimbs. At the end of 3 min remove the mouse and place it back into its homecage.</li>
	<li>Clean the cylinder and glass with a disinfectant provided by the animal care or veterinary staff. Allow the cleaning solution to dry before placing the next mouse in the cylinder.</li>
</ol>
4. Analysis of Spontaneous Activity
<ol>
	<li>Videos can be viewed directly from the camera or connected to a television or computer for a larger screen view. The videotapes should be scored by an experimenter blind to genotype and treatment condition within the experiment.</li>
	<li>Forelimb steps are counted as the video is played back in slow motion. A forelimb step is counted when an animal moves both forelimbs sequentially across the floor of the cylinder in one consecutive movement. A forelimb movement is not counted if the time between the movement of one forelimb and the other forelimb is longer than 5 sec. Hindlimb steps are counted in the same manner as forelimb steps.</li>
	<li>Time spent grooming is measured using a stopwatch and playing back the video in real time. Grooming bouts on the snout, vibrissae, and body are measured.</li>
</ol>
5. Adhesive Removal
<ol>
	<li>Place mouse in its homecage in the testing room or in a mouse cage-changing station.</li>
	<li>Remove the feeder bin from the cage and replace the cage lid. Allow the mice/mouse to habituate to the testing room and the cage without the feeder for 1 hr.</li>
	<li>For testing use a clean cage to place cagemates so the test mouse is the only one in the homecage. Remove ~3/4 of the bedding and place it in the clean cage with the cagemates.</li>
	<li>In the homecage scruff the test mouse in order to restrain it and using a pair of small forceps place one adhesive label onto the snout of the mouse. Gently press the label on the snout with the forcep and release the mouse. Place the lid on the cage and start a stopwatch. When the mouse makes an attempt to remove the label with its forepaws record the time. If the mouse makes contact but does not remove the label then keep the timer going until it does remove it and record that time as well (contact and removal time).</li>
	<li>If the mouse does not contact or remove the sticker within 60 sec then the trial is ended and the sticker is removed manually by the experimenter.</li>
	<li>Place the test mouse in the clean cage and remove the next mouse and place it in the homecage and begin testing. All mice receive 3 trials. It is important to alternate between mice rather than doing all three trials in a mouse at one time. Trials where the label falls off or is not secure on the snout are not counted.</li>
</ol>

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We have no conflicts of interest.

In the present study we show how to perform and analyze three useful tests of sensorimotor function in mice. These include the challenging beam, spontaneous activity in the cylinder, and response to sensory stimuli (adhesive removal). These tests were chosen for the following reasons 1) we and others have found them to be highly sensitive to varying degrees of nigrostriatal dopaminergic dysfunction in genetic mouse models14,16-18, 2) only a short amount of training is required for the beam and handling for the response to sensory stimuli tests and once trained the assays can be performed in one test session, and 3) the price of the equipment needed to perform the tests is quite low compared to purchasing more automated equipment such as the rotarod and open field chambers.
The challenging beam test is not only useful at detecting motor performance and coordination deficits in genetic mouse models of PD but is also useful in uncovering impairments in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated and 6-hydroxydopamine-treated mice and norepinephrine deficient mice19, 23-25. In addition, we find the challenging beam to be less influenced by body weight compared to other tests of motor performance and coordination (rotarod and pole test). This is particularly beneficial when working with aged male mice that can weigh up to 50+ grams. Similar to the beam, alterations in spontaneous activity are reliably observed in parkin knockout, PQ311X, Thy1-aSyn, Pitx3-aphakia, and LRRK2 mice14, 16-18, 26. The adhesive removal test is also sensitive to genetic manipulation including parkin knockout, parkin Q311X, Thy1-aSyn, and DJ-1 knockout mutations in mice14,16, 17, 22. In the unilateral 6-hydroxydopamine-treated mouse the adhesive removal test is performed in a manner similar to how it is typically done with rats1,2. The adhesive label is placed on each forepaw using a forcep and the time to remove the label is recorded. We found that 6-hyrdoxydopamine-treated mice will remove the label from the unaffected limb prior to removing the label on the affected limb 19.
This test battery is easy to implement in aging studies using chronic treatments but it is also easy to use in pharmacological studies. Once animals are trained and ready for testing a test station for each assay can be set up. The animals are then run in the same order on each test. The drug of interest can be administered and once the desired drug peak concentration is reached each mouse can be tested on the beam and then moved to the cylinder for three minutes and then to the adhesive removal test. We found this strategy to work well when testing different dopamine agonists in mice18, 21. Both the beam and adhesive removal tests are amenable to repeated testing, however spontaneous activity in the cylinder is affected by repeated testing resulting in reduced activity over time16. Depending on how robust the deficit is in the mouse you may still be able to detect differences with repeated testing in the cylinder16. In general, habituation and reduced activity is observed as soon as the 2nd exposure to the cylinder however, we find that we can get sufficient activity levels when we run the spontaneous activity test immediately following beam traversal in pharmacological studies18,21. The number of spontaneous activity testing sessions to include in a study will be dependent on mouse strain (some are definitely more active than others) and treatment duration. In our pharmacological studies in mice on a mixed C57BL/6 X DBA background we measured activity between 2-4 times and the testing sessions were separated by one week21.
The beam and cylinder tests do require post-testing analysis of videorecorded behaviors. For this aspect of the analysis it is particularly important to have raters that are blind to the experimental conditions. When we train new raters in the laboratory we have the person score behavior on videotapes previously analyzed by an expert rater from the lab. The criteria are explained and shown to the new rater and then the person begins to score the previously analyzed tapes on their own. The scores are then compared to the expert' ratings. The person is not allowed to rate new data until they are within 95-98% accuracy of the expert. All data is then randomly spot-checked for accuracy by an expert rater.
The battery of tests described in this study is designed to assess sensorimotor function in mice. However, whenever characterizing a novel mouse model of disease it is always important to do a basic examination of the animal as well. Body weight and temperature should be monitored throughout testing and any abnormal behaviors should be noted, like the removal of vibrissae or clasping of the hindlimbs when picked up by the tail. Basic neurological assessments are described elsewhere in detail27-29.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder primarily characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the development of Lewy body inclusions in central and peripheral systems. Patients suffer from sensorimotor impairments, including bradykinesia, tremor, rigidity, and postural instability that worsen over time. Although rare, familial forms of the disease discovered over the last 15 years have led to the identification of important novel targets for potential disease-modifying therapeutics. Mutations in genes encoding alpha-synuclein, parkin, DJ-1, LRRK2, and ATP13A2 among others mark the development of a new "generation" of animal models of PD, genetic mouse models.
	Excellent non-drug-induced behavioral measures exist for the extensively studied unilateral 6-hydroxydopamine (6-OHDA) rat model of PD. These include tests for limb-use asymmetry, movement initiation, somatosensory neglect, reaching abilities, and more recently ultrasonic vocalizations1-6. These tests are sensitive to varying degrees of nigrostriatal dopamine neuron loss and have been used extensively to evaluate the efficacy of various types of potential therapeutics7-11. However, with the genetic mouse models there is not a clear consensus on the best sensorimotor tests to use or how many to use. This is problematic when characterizing a novel genetic mouse model, in preclinical studies, and when trying to make comparisons between models. Over the past decade we have worked to put together a battery of sensorimotor tests for mice similar to what has been used successfully in rats. The tests described in this article have been used to help characterize numerous genetic mouse models of PD and are currently used in preclinical studies testing novel potential therapeutics12.
	The most common tests used to assess motor function in mice are activity in the open field and the rotarod test of coordination13. Although both of these tests are automated, relatively easy to use and provide information on sensorimotor function, they often lack the sensitivity needed to detect subtle alterations in the nigrostriatal dopamine system. For example, parkin deficient mice with subtle alterations in dopamine function do not display impairments on the rotarod but do display motor impairments on a challenging beam test14. In addition, mice treated with moderate doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) do not show impairments on the rotarod but do have significant alterations in gait and impairments on an inverted grid test15. Therefore, studies that use only the rotarod for phenotypic assessment may miss more subtle impairments. An optimal approach, in our opinion, to behavioral characterization is one that includes a battery of tests that are sensitive to different aspects of sensory and motor function, and subtle changes in basal ganglia function13-15. Here we describe how to measure and analyze sensorimotor function in mice using a challenging beam traversal test, a test of spontaneous activity in the cylinder, and a response to sensory stimuli test.

<table border="1">
 <tbody>
 <tr>
 <td>Material Name</td>
 <td>Company</td>
 <td>Dimensions</td>
 <td>Comments</td>
 </tr>
 <tr>
 <td>Challenging beam apparatus</td>
 <td>Starks Plastics</td>
 <td>Segment 1= 3.5 cm 
 Segment 2= 2.5 cm 
 Segment 3= 1.5 cm 
 Segment 4= 0.5 cm</td>
 <td>Contact information: 
 11276 Sebring Dr. 
 Forest Park ,OH 45240 USA 
Ph +1 (513) 541-4591 
 Fax +1 (513) 541-6773</td>
 </tr>
 <tr>
 <td>Cylinder</td>
 <td>Starks Plastics</td>
 <td>15.5 cm diameter 
 12.7 cm height</td>
 <td>Contact information: 
 11276 Sebring Dr. 
 Forest Park ,OH 45240 USA 
Ph +1 (513) 541-4591 
 Fax +1 (513) 541-6773</td>
 </tr>
 <tr>
 <td>Mesh Grid Wiring</td>
 <td>Ace Hardware</td>
 <td>1 cm2</td>
 <td></td>
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 <tr>
 <td>Mouse Cages</td>
 <td>Ancare</td>
 <td>19 x 29 x 12.7 cm</td>
 <td></td>
 </tr>
 <tr>
 <td>Glass</td>
 <td>Ace Hardware</td>
 <td>19 cm2</td>
 <td></td>
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 <td>Mirror</td>
 <td>Ace Hardware</td>
 <td>18 x 13 cm</td>
 <td></td>
 </tr>
 <tr>
 <td>Camcorder</td>
 <td>Sony HDR-HC9</td>
 <td></td>
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 </tr>
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 <td>MiniDV Tapes</td>
 <td>Sony DVC premium</td>
 <td>90 min long play</td>
 <td></td>
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 <td>Labels</td>
 <td>AveryColor Coding Labels </td>
 <td>6.35 mm diameter (1/4" Round) </td>
 <td></td>
 </tr>
 </tbody>
 </table>

assessment of sensorimotor function in mouse models of parkinson's disease

Sensitive and reliable behavioral outcome measures are essential to the evaluation of potential therapeutic treatments in preclinical trials for many neurodegenerative diseases. In Parkinson's disease, sensorimotor tests sensitive to varying degrees of nigrostriatal dysfunction are fundamental for testing the efficacy of potential therapeutics. Reliable and quite elegant sensorimotor measures exist for rats, however many of these tests measure sensorimotor asymmetry within the rat and are not entirely suitable for the newer genetic mouse models of PD. We have put together a battery of sensorimotor tests inspired by the sensitive tests in rats and adapted for mice. The test battery highlighted in this study is chosen for a) its sensitivity in a wide variety of mouse models of PD, b) its ease in implementing into a study, and c) its low expense. These tests have proven useful in characterizing novel genetic mouse models of PD as well as in testing potential disease-modifying therapies.

The challenging beam, spontaneous activity in the cylinder, and adhesive removal tests are all highly useful assays of sensorimotor function in mice. We have found alterations in sensorimotor function using these tests in multiple genetic and toxin mouse models of Parkinson's disease including parkin knockout, parkin Q311X, Pitx3-aphakia, alpha-synuclein overexpressing, and unilateral 6-hydroxydopamine mice14, 16-19. Here we show data collected from mice overexpressing human wildtype alpha-synuclein under the Thy1 promoter (Thy1-aSyn) and Pitx3-aphakia mice 18,20. On the challenging beam we reliably detect increased errors per step in Thy1-aSyn compared to wildtype mice (Figure 1). In the same line of mice we also repeatedly detect a robust decrease in hindlimb stepping in the cylinder (Figure 2)12, 16, 21. In the adhesive removal test Pitx3-aphakia mice with a profound decrease in nigrostriatal dopamine neurons show significantly increased time to contact compared to wildtype controls (Figure 3).
 <img src="/files/ftp_upload/50303/50303fig1.jpg" alt="Figure 1"/> 
 Figure 1. Errors on the challenging in Wildtype (n=13) and Thy1-aSyn (n=4) at 4 months of age. A) Errors per step, mean of five trials. B) Mean errors at each beam width. ** represents p&lt;0.01 respectively compared to Wildtype mice. Student's t-test.
 <img src="/files/ftp_upload/50303/50303fig2.jpg" alt="Figure 2"/> 
 Figure 2. Hindlimb stepping in the cylinder in Wildtype (n=13) and Thy1-aSyn (n=4) mice at 4 months of age. * represents p&lt;0.05 compared to Wildtype. Student's t-test.
 <img src="/files/ftp_upload/50303/50303fig3.jpg" alt="Figure 3"/> 
 Figure 3. Contact time in Wildtype (n=10) and Pitx3-aphakia (n=12) mice at 4 weeks of age. ** represents p&lt;0.01 compared to Wildtype. Mann-Whitney U.
 <table border="1">
<tbody>
 <tr>
 <td>Test</td>
 <td>Parameters</td>
 <td>Analysis Options</td>
 </tr>
 <tr>
 <td rowspan="3">Challenging Beam</td>
 <td>Errors</td>
 <td rowspan="3">Beam Widths (Errors only) Mean of 5 Trials Individual Trials</td>
 </tr>
 <tr>
 <td>Time</td>
 </tr>
 <tr>
 <td>Steps</td>
 </tr>
 <tr>
 <td rowspan="4">Spontaneous Activity</td>
 <td>Forelimb Steps</td>
 <td rowspan="2">Mean Forelimb/Hindlimb Ratio</td>
 </tr>
 <tr>
 <td>Hindlimb Steps</td>
 </tr>
 <tr>
 <td>Rears</td>
 <td>Mean</td>
 </tr>
 <tr>
 <td>Grooming Time</td>
 <td>Mean</td>
 </tr>
 <tr>
 <td rowspan="2">Adhesive Removal</td>
 <td>Contact time</td>
 <td rowspan="2">Mean Median Best/Worst Score Removal time Contact time score</td>
 </tr>
 <tr>
 <td>Removal time</td>
 </tr>
</tbody>
 </table>
 Table 1. Sensorimotor function Test Battery: Analysis Options.

Watch this Scientific Journal Video about Assessment of Sensorimotor Function in Mouse Models of Parkinson's Disease at JoVE.com

Assessment of Sensorimotor Function in Mouse Models of Parkinson&#039;s Disease

In Parkinson's disease and movement disorders in general, sensitive and reliable behavioral assays are essential for testing novel potential therapeutics. Here, we describe a manageable battery of sensorimotor tests for mice that are sensitive to varying degrees of injury to the nigrostriatal system and useful for preclinical studies.

Assessment of Sensorimotor Function in Mouse Models of Parkinson's Disease

Sensitive and  reliable behavioral outcome measures are essential to the evaluation of  potential therapeutic treatments in preclinical trials for many  ...

assessment-sensorimotor-function-mouse-models-parkinson-s

Research

JoVE Journal

Behavior

Nest Building as an Indicator of Health and Welfare in Laboratory Mice

The minimization and alleviation of suffering has moral and scientific implications. In order to mitigate this negative experience one must be able to identify when an animal is actually in distress. Pain, illness, or distress cannot be managed if unrecognized. Evaluation of pain or illness typically involves the measurement of physiologic and behavioral indicators which are either invasive or not suitable for large scale assessment. The observation of nesting behavior shows promise as the basis of a species appropriate cage-side assessment tool for recognizing distress in mice. Here we demonstrate the utility of nest building behavior in laboratory mice as an ethologically relevant indicator of welfare. The methods presented can be successfully used to identify thermal stressors, aggressive cages, sickness, and pain. Observation of nest building behavior in mouse colonies provides a refinement to health and well-being assessment on a day to day basis.

We demonstrate the utility of nest building behavior in laboratory mice as an indicator of welfare. Nest scoring is a sensitive technique that is altered by temperature, illness, and aggression. The time to integrate into nest test (TINT) is a simple cage-side assessment that can detect postoperative pain.

The minimization and alleviation of  suffering has moral and scientific implications. In order to mitigate this  negative experience one must be able to ...

Behavioral Phenotyping of Murine Disease Models with the Integrated Behavioral Station (INBEST)

Due to rapid advances in genetic engineering, small rodents have become the preferred subjects in many disciplines of biomedical research. In studies of chronic CNS disorders, there is an increasing demand for murine models with high validity at the behavioral level. However, multiple pathogenic mechanisms and complex functional deficits often impose challenges to reliably measure and interpret behavior of chronically sick mice. Therefore, the assessment of peripheral pathology and a behavioral profile at several time points using a battery of tests are required. Video-tracking, behavioral spectroscopy, and remote acquisition of physiological measures are emerging technologies that allow for comprehensive, accurate, and unbiased behavioral analysis in a home-base-like setting. This report describes a refined phenotyping protocol, which includes a custom-made monitoring apparatus (Integrated Behavioral Station, INBEST) that focuses on prolonged measurements of basic functional outputs, such as spontaneous activity, food/water intake and motivated behavior in a relatively stress-free environment. Technical and conceptual improvements in INBEST design may further promote reproducibility and standardization of behavioral studies.

Behavioral Phenotyping of Murine Disease Models with the Integrated Behavioral Station INBEST

Prolonged and comprehensive monitoring of mice in a home-cage environment provides a deeper understanding of aberrant behavior in murine models of brain diseases. This paper describes the Integrated Behavioral Station (INBEST) as the key component of contemporary behavioral analysis.

Due to rapid advances in genetic engineering, small rodents have become the preferred subjects in many disciplines of biomedical research. In studies of ...

Compensatory Limb Use and Behavioral Assessment of Motor Skill Learning Following Sensorimotor Cortex Injury in a Mouse Model of Ischemic Stroke

Mouse models have become increasingly popular in the field of behavioral neuroscience, and specifically in studies of experimental stroke. As models advance, it is important to develop sensitive behavioral measures specific to the mouse. The present protocol describes a skilled motor task for use in mouse models of stroke. The Pasta Matrix Reaching Task functions as a versatile and sensitive behavioral assay that permits experimenters to collect accurate outcome data and manipulate limb use to mimic human clinical phenomena including compensatory strategies (i.e., learned non-use) and focused rehabilitative training. When combined with neuroanatomical tools, this task also permits researchers to explore the mechanisms that support behavioral recovery of function (or lack thereof) following stroke. The task is both simple and affordable to set up and conduct, offering a variety of training and testing options for numerous research questions concerning functional outcome following injury. Though the task has been applied to mouse models of stroke, it may also be beneficial in studies of functional outcome in other upper extremity injury models.

Mouse models have become increasingly popular in studies of behavioral neuroscience. As models advance, it is important to develop sensitive behavioral measures specific to the mouse. This protocol describes the Pasta Matrix Reaching Task, which is a skilled motor task for use in mouse models of stroke.

Mouse models have become increasingly popular in the field of behavioral neuroscience, and specifically in studies of experimental stroke. As models ...

Behavioral Assessment of the Aging Mouse Vestibular System

Age related decline in balance performance is associated with deteriorating muscle strength, motor coordination and vestibular function. While a number of studies show changes in balance phenotype with age in rodents, very few isolate the vestibular contribution to balance under either normal conditions or during senescence. We use two standard behavioral tests to characterize the balance performance of mice at defined age points over the lifespan: the rotarod test and the inclined balance beam test. Importantly though, a custom built rotator is also used to stimulate the vestibular system of mice (without inducing overt signs of motion sickness). These two tests have been used to show that changes in vestibular mediated-balance performance are present over the murine lifespan. Preliminary results show that both the rotarod test and the modified balance beam test can be used to identify changes in balance performance during aging as an alternative to more difficult and invasive techniques such as vestibulo-ocular (VOR) measurements.

Motor control and balance performance are known to deteriorate with age. This paper presents a number of standard noninvasive behavioral tests with the addition of a simple rotary stimulus to challenge the vestibular system and show changes in balance performance in a murine model of aging.

Age related decline in balance performance is associated with deteriorating muscle strength, motor coordination and vestibular function. While a number of ...

Community-based Adapted Tango Dancing for Individuals with Parkinson's Disease and Older Adults

Adapted tango dancing improves mobility and balance in older adults and additional populations with balance impairments. It is composed of very simple step elements. Adapted tango involves movement initiation and cessation, multi-directional perturbations, varied speeds and rhythms. Focus on foot placement, whole body coordination, and attention to partner, path of movement, and aesthetics likely underlie adapted tango&#8217;s demonstrated efficacy for improving mobility and balance. In this paper, we describe the methodology to disseminate the adapted tango teaching methods to dance instructor trainees and to implement the adapted tango by the trainees in the community for older adults and individuals with Parkinson&#8217;s Disease (PD). Efficacy in improving mobility (measured with the Timed Up and Go, Tandem stance, Berg Balance Scale, Gait Speed and 30 sec chair stand), safety and fidelity of the program is maximized through targeted instructor and volunteer training and a structured detailed syllabus outlining class practices and progression.

Community-based Adapted Tango Dancing for Individuals with Parkinson&#039;s Disease and Older Adults

Adapted tango has demonstrated efficacy for improving mobility and balance. We describe the dissemination of adapted tango teaching methods to dance instructor trainees and the implementation of adapted tango by the trainees in the community for improving mobility and balance in older adults and individuals with Parkinson&#8217;s disease.

Adapted tango dancing improves mobility and balance in older adults and additional populations with balance impairments. It is composed of very simple ...

Automated, Long-term Behavioral Assay for Cognitive Functions in Multiple Genetic Models of Alzheimer's Disease, Using IntelliCage

Multiple factors&#8212;such as aging and genes&#8212;are frequently associated with cognitive decline. Genetically modified mouse models of cognitive decline, such as Alzheimer&#39;s disease (AD), have become a promising tool to elucidate the underlying mechanisms and promote the therapeutic advances. An important step is the validation and characterization of expected behavioral abnormality in the models, in the case of AD, cognitive decline. The long-term behavioral investigations of laboratory animals to study the effect of aging demand substantial efforts from researchers. The IntelliCage system is a high-throughput and cost-effective test battery for mice that eliminates the need for daily human handling. Here, we describe how the system is utilized in the long-term phenotyping of a genetic Alzheimer&#39;s disease model, specifically focusing on the cognitive functions. The experiment employs repeated battery of tests that assess spatial learning and executive functions. This cost-effective age-dependent phenotyping allows us to identify the transient and/or permanent effects of genes on various cognitive aspects.

Automated, Long-term Behavioral Assay for Cognitive Functions in Multiple Genetic Models of Alzheimer&#039;s Disease, Using IntelliCage

This paper describes a protocol for cognitive assessments for genetic models of the Alzheimer&#39;s disease using the IntelliCage system, which is a high throughput automated behavioral monitoring system with operant conditioning.

Multiple factors&#8212;such as aging and genes&#8212;are frequently associated with cognitive decline. Genetically modified mouse models of cognitive ...

Behavioral Assessments of Spontaneous Locomotion in a Murine MPTP-induced Parkinson's Disease Model

Parkinson&#8217;s disease (PD) is a common neurodegenerative disorder disease, causing the phenomenon of shaking, rigidity, slowness of movement and dementia. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can lead to some Parkinson&#8217;s-like symptoms by destroying dopaminergic neurons in the substantia nigra of the brain. It has been thus used to establish PD models in various animal studies. Here, mice receive MPTP injections (20 mg/kg/day) for seven days and the behavioral tests are performed on the eighth day. This model is adapted efficiently in the study of PD. The behavioral tests here include the cylinder test and the open field test. The cylinder experiment is used to detect the animals&#8217; ability to lift their front paws when put into a different environment. As the PD model mice show arching&#8212;the mouse arches its back&#8212;the number of paw liftings decrease. This test is easy to execute. The open field test is used to detect the amount of time the mice spend on running, walking, and remaining immobile. We analyze animals&#8217; movements in open field using software and obtain data. Lastly, we use L-DOPA, one of the most commonly used PD drugs, as one example to show how to apply this model to the study of PD drugs. Our results indicate that MPTP neurotoxicity induces motor deficit which can be mitigated by L-DOPA.

Behavioral Assessments of Spontaneous Locomotion in a Murine MPTP-induced Parkinson&#039;s Disease Model

We describe establishment of a murine model for Parkinson's disease using MPTP, and behavioral assessments using cylinder and open field tests to measure motor function. We then use L-DOPA as one example to show how to apply this model in the study of PD drugs.

Parkinson&#8217;s disease (PD) is a common neurodegenerative disorder disease, causing the phenomenon of shaking, rigidity, slowness of movement and ...

Supramaximal Intensity Hypoxic Exercise and Vascular Function Assessment in Mice

Exercise training is an important strategy for maintaining health and preventing many chronic diseases. It is the first line of treatment recommended by international guidelines for patients suffering from cardiovascular diseases, more specifically, lower extremity artery diseases, where the patients' walking capacity is considerably altered, affecting their quality of life. 
Traditionally, both low continuous exercise and interval training have been used. Recently, supramaximal training has also been shown to improve athletes' performances via vascular adaptations, amongst other mechanisms. The combination of this type of training with hypoxia could bring an additional and/or synergic effect, which could be of interest for certain pathologies. Here, we describe how to perform supramaximal intensity training sessions in hypoxia on healthy mice at 150% of their maximal speed, using a motorized treadmill and a hypoxic box. We also show how to dissect the mouse in order to retrieve organs of interest, particularly the pulmonary artery, the abdominal aorta, and the iliac artery. Finally, we show how to perform ex vivo vascular function assessment on the retrieved vessels, using isometric tension studies.

High-intensity training in hypoxia is a protocol that has been proven to induce vascular adaptations potentially beneficial in some patients and to improve athletes&#39; repeated sprint ability. Here, we test the feasibility of training mice using that protocol and identify those vascular adaptations using ex vivo vascular function assessment.

Exercise training is an important strategy for maintaining health and preventing many chronic diseases. It is the first line of treatment recommended by ...

Dynamic Digital Biomarkers of Motor and Cognitive Function in Parkinson's Disease

As Parkinson&#8217;s disease (PD) is a heterogeneous disorder, personalized medicine is truly required to optimize care. In their current form, standard scores from paper and pencil symptom- measures traditionally used to track disease progression are too coarse (discrete) to capture the granularity of the clinical phenomena under consideration, in the face of tremendous symptom diversity. For this reason, sensors, wearables, and mobile devices are increasingly incorporated into PD research and routine care. These digital measures, while more precise, yield data that are less standardized and interpretable than traditional measures, and consequently, the two types of data remain largely siloed. Both of these issues present barriers to the broad clinical application of the field&#8217;s most precise assessment tools. This protocol addresses both problems. Using traditional tasks to measure cognition and motor control, we test the participant, while co-registering biophysical signals unobtrusively using wearables. We then integrate the scores from traditional paper-and-pencil methods with the digital data that we continuously register. We offer a new standardized data type and unifying statistical platform that enables the dynamic tracking of change in the person&#8217;s stochastic signatures under different conditions that probe different functional levels of neuromotor control, ranging from voluntary to autonomic. The protocol and standardized statistical framework offer dynamic digital biomarkers of physical and cognitive function in PD that correspond to validated clinical scales, while significantly improving their precision.&#160;

Dynamic Digital Biomarkers of Motor and Cognitive Function in Parkinson&#039;s Disease

This protocol offers a digitization of portions of traditional clinical tasks commonly used to measure cognition and motor control in Parkinson&#8217;s disease. Clinical tasks are digitized while biophysical rhythms are co-registered from different functional levels of the nervous systems, ranging from voluntary, spontaneous, automatic to autonomic.

As Parkinson&#8217;s disease (PD) is a heterogeneous disorder, personalized medicine is truly required to optimize care. In their current form, standard ...

Low-Cost Gait Analysis for Behavioral Phenotyping of Mouse Models of Neuromuscular Disease

Measurement of animal locomotion is a common behavioral tool used to describe the phenotype of a given disease, injury, or drug model. The low-cost method of gait analysis demonstrated here is a simple but effective measure of gait abnormalities in murine models. Footprints are analyzed by painting a mouse&#8217;s feet with non-toxic washable paint and allowing the subject to walk through a tunnel on a sheet of paper. The design of the testing tunnel takes advantage of natural mouse behavior and their affinity for small dark places. The stride length, stride width, and toe spread of each mouse is easily measured using a ruler and a pencil. This is a well-established and reliable method, and it generates several metrics that are analogous to digital systems. This approach is sensitive enough to detect changes in stride early in phenotype presentation, and due to its non-invasive approach, it allows for testing of groups across life-span or phenotypic presentation.

Footprint analysis is a low-cost alternative to digitized gait analysis programs for researchers quantifying movement abnormalities in mice. Because of its speed, simplicity, and longitudinal potential, it is ideal for behavioral phenotyping of mouse models.

Measurement of animal locomotion is a common behavioral tool used to describe the phenotype of a given disease, injury, or drug model. The low-cost method ...