Name: assessing functional performance in the mdx mouse model
Uploaded: 2014-03-27T21:45:00
Description: Watch this Scientific Journal Video about Assessing Functional Performance in the Mdx Mouse Model at JoVE.com

We would like to thank Margriet Hulsker for her photographic assistance and help in obtaining images of mice and the reviewers for their very constructive comments. This work was supported by ZonMw, TREAT-NMD (contract number LSHM-CT-2006-036825) and the Duchenne Parent Project.

The experiments described here were approved by the Animal Ethics Committee (DEC) of the Leiden University Medical Center (LUMC). Mice were bred by the animal facility of the LUMC and kept in individually ventilated cages with 12 hr light dark cycles. They had ad libitum access to water and standard chow.
When performing any of the functional tests described below, experimental conditions have to be strictly controlled to reduce variation. Preferably, age and gender matched mice shoul...

<ol>
	<li>Blake, D. J., Weir, A., Newey, S. E., Davies, K. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Function+and+genetics+of+dystrophin+and+dystrophin-related+proteins+in+muscle.">Function and genetics of dystrophin and dystrophin-related proteins in muscle.</a> Physiol. Rev. 82, 291-329 (2002).</li><li>Hoffman, E. P., Brown, R. H., Kunkel, L. 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Disord. 17, 38-46 (2007).</li><li>van Putten, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+3+months+mild+functional+test+regime+does+not+affect+disease+parameters+in+young+mdx+mice.">A 3 months mild functional test regime does not affect disease parameters in young mdx mice.</a> Neuromuscul. Disord. 20, 273-280 (2010).</li><li>De Luca, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gentamicin+treatment+in+exercised+mdx+mice:+Identification+of+dystrophin-sensitive+pathways+and+evaluation+of+efficacy+in+work-loaded+dystrophic+muscle.">Gentamicin treatment in exercised mdx mice: Identification of dystrophin-sensitive pathways and evaluation of efficacy in work-loaded dystrophic muscle.</a> Neurobiol. Dis. 32, 243-253 (2008).</li><li>Radley-Crabb, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+single+30min+treadmill+exercise+session+is+suitable+for+'proof-of+concept+studies'+in+adult+mdx+mice:+A+comparison+of+the+early+consequences+of+two+different+treadmill+protocols.">A single 30min treadmill exercise session is suitable for 'proof-of concept studies' in adult mdx mice: A comparison of the early consequences of two different treadmill protocols.</a> Neuromuscul. 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The&#160;functional tests presented here are reproducible, easy to perform and applicable to wild type and dystrophic mice independent of their age. The tests provide useful tools to pre clinically assess muscle function, strength, condition, and coordination. When testing the effects of a compound on the natural history of the disease, the noninvasive tests described here (forelimb grip strength, both hanging tests and the rotarod test) can be nicely combined in a functional test regime where these tests are performed o...

Duchenne muscular dystrophy (DMD) is the most common neuromuscular disorder affecting 1:5,000 newborn boys. This severe and progressive muscle wasting disease is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the synthesis of functional dystrophin protein. Muscle fibers lacking dystrophin are vulnerable to exercise induced damage. Upon exhaustion of the muscle&#39;s regenerative capacity, and due to chronic inflammation of damaged muscle, fibers are replaced by connective tissue and fat, subsequently leading to a loss of function. Generally, DMD patients lose ambulation of the lower limbs early in the second decade. Later, also the muscles of the arms and shoulder girdle are affected and patients often develop thoracolumbar scoliosis due to asymmetric weakening of the muscles supporting the spinal cord. Assisted ventilation is generally required in the late teens or early twenties. Respiratory and heart failure lead to death in the third or fourth decade1.
Although the causative gene has been discovered over 25 years ago2, there is no cure available for DMD. However, improved health care and the use of corticosteroids have increased life expectancy in the Western world3. With the use of animal models like the mdx mouse, major steps forward into the discovery of potential therapeutic strategies have been made. The mdx mouse is the most commonly used DMD mouse model. It has a point mutation in exon 23 of the murine Dmd gene and consequently lacks dystrophin4. Over the last couple of years, many proposed strategies have progressed into clinical trials5-9. In these trials, improvement of muscle function is the primary endpoint, underlying the importance of testing the benefit of compounds on muscle function in mice during the pre clinical stage of testing.
Like DMD patients, also the dystrophin negative muscle fibers of mdx mice are vulnerable to exercise induced damage and their muscle function is impaired compared to C57BL/10ScSnJ wild type mice. This impairment can be assessed with a variety of functional tests. Some of these tests are noninvasive and do not interfere with muscle pathology (e.g. forelimb grip strength, hanging tests and rotarod running). Therefore they can be used to monitor the natural history of the disease or determine the effects of compounds on disease progression. To get an in depth picture of the influence of compounds on muscle function in mdx mice, a functional test regime that does not interfere with disease progression consisting of all of these tests can be used10.
Alternatively, forced treadmill running can be used to intentionally exacerbate disease progression and test the protective capacities of compounds11. The treadmill can also be used as outcome measure in which running time till exhaustion is measured12, or as a tool to fatigue mdx mice so that they perform less well in a subsequent functional test ensuring larger differences in performance between treatment groups13. When choosing functional tests, their effect on disease progression should be kept in mind especially when testing dystrophic mice like the mdx mouse14.
We here describe in detail how to perform the most commonly used functional tests in a reliable and reproducible manner based on available standard operating procedures from the TREAT-NMD network. <a href="http://www.treat-nmd.eu/resources/research-resources/dmd-sops/" target="_blank">Click here to visit TREAT-NMD</a>.

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			<td height="21" style="height:21px;width:216px;">Mouse grip strength meter</td>
			<td style="width:331px;">Chatillon DFE (re-sold by Columbus Instruments)</td>
			<td style="width:119px;"># 80529</td>
			<td style="width:167px;"></td>
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			<td height="21" style="height:21px;width:216px;">Hanging wire 2 limbs device</td>
			<td style="width:331px;">Cloth hanger or custom made device</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Hanging wire 4 limbs device</td>
			<td style="width:331px;">Lid of rat cage or custom made device</td>
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			<td height="21" style="height:21px;width:216px;">Rotarod</td>
			<td style="width:331px;">Ugo Basil</td>
			<td style="width:119px;"># 47600</td>
			<td></td>
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			<td height="21" style="height:21px;width:216px;">Treadmill for mice Exer 3/6</td>
			<td style="width:331px;">Columbus Instruments</td>
			<td style="width:119px;"># 1055SRM</td>
			<td></td>
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assessing functional performance in the mdx mouse model

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder for which no cure is available. Nevertheless, several potential pharmaceutical compounds and gene therapy approaches have progressed into clinical trials. With improvement in muscle function being the most important end point in these trials, a lot of emphasis has been placed on setting up reliable, reproducible, and easy to perform functional tests to pre clinically assess muscle function, strength, condition, and coordination in the mdx mouse model for DMD. Both invasive and noninvasive tests are available. Tests that do not exacerbate the disease can be used to determine the natural history of the disease and the effects of therapeutic interventions (e.g. forelimb grip strength test, two different hanging tests using either a wire or a grid and rotarod running). Alternatively, forced treadmill running can be used to enhance disease progression and/or assess protective effects of therapeutic interventions on disease pathology. We here describe how to perform these most commonly used functional tests in a reliable and reproducible manner. Using these protocols based on standard operating procedures enables comparison of data between different laboratories.

The forelimb grip strength of wild type and mdx mice increases between the age of 4-12 weeks and reduces again in older mice. Impairments in force can already be observed in young&#160;mdx mice. Representative data of 9 week old female mice are shown in Figures 1A and 1B. Although fatigue does not differ between the strains yet at this age, mdx mice are weaker than wild type mice. We do not have data yet on fatigability in older mdx and wild type mice....

Watch this Scientific Journal Video about Assessing Functional Performance in the Mdx Mouse Model at JoVE.com

Assessing Functional Performance in the Mdx Mouse Model

The primary outcome measure in clinical trials for neuromuscular disorders is generally improved muscle function. Therefore, assessing the effect of potential therapeutic compounds on muscle performance pre clinically in mouse models is of great importance. We here describe several functional tests to address this.

Assessing Functional Performance in the Mdx Mouse Model

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder for which no cure is available. Nevertheless, several potential ...

assessing-functional-performance-in-the-mdx-mouse-model

Research

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Behavior

A Method for Investigating Age-related Differences in the Functional Connectivity of Cognitive Control Networks Associated with Dimensional Change Card Sort Performance

The ability to adjust behavior to sudden changes in the environment develops gradually in childhood and adolescence. For example, in the Dimensional Change Card Sort task, participants switch from sorting cards one way, such as shape, to sorting them a different way, such as color. Adjusting behavior in this way exacts a small performance cost, or switch cost, such that responses are typically slower and more error-prone on switch trials in which the sorting rule changes as compared to repeat trials in which the sorting rule remains the same. The ability to flexibly adjust behavior is often said to develop gradually, in part because behavioral costs such as switch costs typically decrease with increasing age. Why aspects of higher-order cognition, such as behavioral flexibility, develop so gradually remains an open question. One hypothesis is that these changes occur in association with functional changes in broad-scale cognitive control networks. On this view, complex mental operations, such as switching, involve rapid interactions between several distributed brain regions, including those that update and maintain task rules, re-orient attention, and select behaviors. With development, functional connections between these regions strengthen, leading to faster and more efficient switching operations. The current video describes a method of testing this hypothesis through the collection and multivariate analysis of fMRI data from participants of different ages.

This video presents a method of examining age-related changes in functional connectivity of cognitive control networks engaged by targeted tasks/processes. The technique is based on multi-variate analysis of fMRI data.

The ability to adjust behavior to sudden changes in the environment develops gradually in childhood and adolescence. For example, in the Dimensional ...

The Emotional Stroop Task: Assessing Cognitive Performance under Exposure to Emotional Content

The emotional Stroop effect (ESE) is the result of longer naming latencies to ink colors of emotion words than to ink colors of neutral words. The difference shows that people are affected by the emotional content conveyed by the carrier words even though they are irrelevant to the color-naming task at hand. The ESE has been widely deployed with patient populations, as well as with non-selected populations, because the emotion words can be selected to match the tested pathology. The ESE is a powerful tool, yet it is vulnerable to various threats to its validity. This report refers to potential sources of confounding and includes a modal experiment that provides the means to control for them. The most prevalent threat to the validity of existing ESE studies is sustained effects and habituation wrought about by repeated exposure to emotion stimuli. Consequently, the order of exposure to emotion and neutral stimuli is of utmost importance. We show that in the standard design, only one specific order produces the ESE.

The emotional Stroop effect (ESE) is the result of longer naming latencies to ink colors of emotion words than those of neutral words. This report refers to potential sources of confounding and includes a modal experiment that provides the means to control for them.

The emotional Stroop effect (ESE) is the result of longer naming latencies to ink colors of emotion words than to ink colors of neutral words. The ...

The Rodent Psychomotor Vigilance Test (rPVT): A Method for Assessing Neurobehavioral Performance in Rats and Mice

The human Psychomotor Vigilance Test (PVT) is a widely used procedure for measuring changes in fatigue and sustained attention. The present article describes a rodent version of the PVT&#8212;termed the &#34;rPVT&#34;&#8212;that measures similar aspects of attention (i.e., performance accuracy, motor speed, premature responding, and lapses in attention). Data are presented that demonstrate both the short- and long-term usefulness of the rPVT when employed with laboratory rats. Rats easily learn the rPVT, and learning to perform the basic procedure takes less than two weeks of training. Once acquired, rat performances in the rPVT show a high degree of similarity to these same performance measures in the human PVT, including similarities in, lapses in attention, reaction times, vigilance decrements across session time (i.e., the human &#34;time-on-task&#34; effects), and the response-stimulus interval (RSI) effect described for humans. Thus the rPVT can be an extremely valuable tool for assessing the effects of a wide range of variables on sustained attention quite similar to human PVT performances, and thus can be useful for developing novel treatments for neurobehavioral dysfunctions.

The Rodent Psychomotor Vigilance Test rPVT: A Method for Assessing Neurobehavioral Performance in Rats and Mice

A rat version of the human Psychomotor Vigilance Test (PVT) is described that measures aspects of attention similar to those measured with the human PVT, including aspects of human vigilance such as performance accuracy, motor speed, premature responding, and lapses in attention.

The human Psychomotor Vigilance Test (PVT) is a widely used procedure for measuring changes in fatigue and sustained attention. The present article ...

Assessing Spatial Memory Impairment in a Mouse Model of Traumatic Brain Injury Using a Radial Water Tread Maze

Despite the recent increase in use of mouse models in scientific research, researchers continue to use cognitive tasks that were originally designed and validated for rat use. The Radial Water Tread (RWT) maze test of spatial memory (designed specifically for mice and requiring no swimming) has been shown previously to successfully distinguish between controlled cortical impact-induced TBI mice and sham controls. Here, a detailed protocol for this task is presented. The RWT maze capitalizes on the natural tendency of mice to avoid open areas in favor of hugging the sides of an apparatus (thigmotaxis). The walls of the maze are lined with nine escape holes placed above the floor of the apparatus, and mice are trained to use visual cues to locate the escape hole that leads out of the maze. The maze is filled with an inch of cold water, sufficient to motivate escape but not deep enough to require that the mouse swim. The acquisition period takes only four training days, with a test of memory retention on day five and a long-term memory test on day 12. The results reported here suggest that the RWT maze is a feasible alternative to rat-validated, swimming-based cognitive tests in the assessment of spatial memory deficits in mouse models of TBI.

Here we present a protocol for a mouse-specific test of cognition that does not require swimming. This test can be used to successfully distinguish controlled cortical impact-induced traumatic brain injury mice from sham controls.

Despite the recent increase in use of mouse models in scientific research, researchers continue to use cognitive tasks that were originally designed and ...

Measuring Active and Passive Tameness Separately in Mice

Domesticated animals such as dogs and laboratory mice show a high level of tameness, which is important for humans to handle them easily. Tameness has two behavioral components: a reluctance to avoid humans (passive tameness) and a motivation to approach humans (active tameness). To quantify these components in mice, we previously developed behavioral tests for active tameness, passive tameness, and the willingness to stay on a human hand, each designed to be completed within 3 min. The data obtained were used for selective breeding, with a large number of mice analyzed per generation. The active tameness test measures the movement of the mouse toward a human hand and the contact it engages in. The passive tameness test measures the duration of time that a mouse tolerates human touch. In the stay-on-hand test, a mouse is placed on a human hand and touched slowly using the thumb of that hand; the duration of time that the animal remains on the hand is measured. Here, we describe the test set-up and apparatus, explain the procedures, and discuss the appropriate data analysis. Finally, we explain how to interpret the results.

Tameness in animals includes a reduction of avoidance responses to humans (passive tameness) and an increase in active approaches to humans (active tameness). Here, we describe detailed protocols for three behavioral tests (active tameness, passive tameness, and stay-on-hand tests) to separately measure the active and passive tameness of mice.

Domesticated animals such as dogs and laboratory mice show a high level of tameness, which is important for humans to handle them easily. Tameness has two ...

Assessing the Coherence of Parents' Short Narratives Regarding their Child Using the Five-Minute Speech Sample Procedure

Valid and efficient measures for assessing the quality of parent-child relationships are needed to facilitate research and evidence-based practice with parents. This paper focuses on such a method, namely Five-Minute Speech Sample-Coherence (FMSS-Coherence). In this method, a parent is asked to speak for five uninterrupted minutes about her/his child and their relationship. The resulted narrative is coded for coherence, namely the extent to which the parent provides&#160;in the narrative&#160;a clear, consistent, multidimensional and well-supported portrayal of the child. FMSS-Coherence is based on attachment research that shows that the coherence of parents&#8217; narratives is indicative of the quality of the parent-child relationship and child adjustment. It overcomes the limitations of attachment narrative measures which are typically labor intensive. FMSS-Coherence is less nuanced than extant attachment narrative measures. Yet, studies of families from different cultural backgrounds, across different child ages and in the context of typically developing children as well as children with special needs suggest that coherence can be reliably evaluated using the FMSS procedure. Furthermore, parents&#8217; FMSS-Coherence is associated with parenting quality and children&#8217;s socio-emotional adjustment. Thus, it holds promise for researchers and practitioners who seek a relatively time- and cost-effective method for assessing the coherence of parents&#8217; narratives regarding their child.

This paper introduces a method for assessing the coherence of parents' short narratives regarding their child and their relationship using the five-minute speech sample procedure.

Valid and efficient measures for assessing the quality of parent-child relationships are needed to facilitate research and evidence-based practice with ...

A Task for Assessing the Impact of a Partner on the Speed and Accuracy of Motor Performance in Rats

To our knowledge, no study has examined the effect of mere presence on accuracy of performance in animals. Therefore, we developed an experimental task to measure rats&#8217; motor performance (speed and accuracy) in a social condition. Rats were trained to run on a runway and pull down a lever at the end of the runway. In testing, rats performed the task solitarily (single) or in the presence of a confederate rat beyond the lever (pair or a social condition). As indices of the performance speed, we measured the time needed to start running, run through the runway, and pull down the lever. As the index of performance accuracy, we counted the number of trials in which rats could pull down the lever during their first attempt. One-way and two-way repeated-measure analyses of variance were used to analyze the data. This run-and-pull task enabled us to examine the effect of the presence of another conspecific on both speed and accuracy of motor performance in one experiment. The results showed that rats performed the task faster but less accurately in pair sessions than in single sessions. This protocol would be a valid animal model to examine the effect of mere presence on speed and accuracy of motor performance in rats.

A procedure to measure the speed and accuracy of rats&rsquo; motor performance in a social condition is described. The protocol enables us to investigate the effect of the mere presence of others on speed and accuracy of motor performance in one experiment.

To our knowledge, no study has examined the effect of mere presence on accuracy of performance in animals. Therefore, we developed an experimental task to ...

Training Dogs for Awake, Unrestrained Functional Magnetic Resonance Imaging

We present a canine functional Magnetic Resonance Imaging (fMRI) training protocol that can be done in a cost-effective manner, with high-energy dogs, for acquisition of functional and structural data. This method of training dogs for awake, unrestrained fMRI employs a generalization procedure of stationing in several dissimilar locations to facilitate transfer of the stationing behavior to the real MRI scan environment; it does so without the need for extensive training time in the MRI scan environment, which can be expensive. Further, this method splits the training of a stationing (i.e., chin rest) behavior from desensitization to the MRI environment (i.e., 100+ decibel scan audio), the latter accomplished during dedicated Auditory Exposure conditioning sessions. The complete training and testing protocol required 14 hours and resulted in immediate transfer to novel locations. We also present examples of canine fMRI data that have been acquired from visual face processing and olfactory discrimination paradigms.

Magnetic resonance imaging (MRI) on unrestrained awake dogs is a new method with several advantages over imaging with physical or chemical restraint. This protocol introduces a cost-effective training method that minimizes training in the MRI environment, which can be expensive, and maximizes the subject pool available for canine functional MRI.

We present a canine functional Magnetic Resonance Imaging (fMRI) training protocol that can be done in a cost-effective manner, with high-energy dogs, for ...

Human Circadian Phenotyping and Diurnal Performance Testing in the Real World

In our continuously developing &#39;around the clock&#39; society, there is a need to increase our understanding of how changes in biology, physiology and psychology influence our health and performance. Embedded within this challenge, is the increasing need to account for individual differences in sleep and circadian rhythms, as well as to explore the impact of time of day on performance in the real world. There are a number of ways to measure sleep and circadian rhythms from subjective questionnaire-based methods to objective sleep/wake monitoring, actigraphy and analysis of biological samples. This paper proposes a protocol that combines multiple techniques to categorize individuals into Early, Intermediate or Late circadian phenotype groups (ECPs/ICPs/LCPs) and recommends how to conduct diurnal performance testing in the field. Representative results show large differences in rest-activity patterns derived from actigraphy, circadian phase (dim light melatonin onset and peak time of cortisol awakening response) between circadian phenotypes. In addition, significant differences in diurnal performance rhythms between ECPs and LCPs emphasizes the need to account for circadian phenotype. In summary, despite the difficulties in controlling influencing factors, this protocol allows a real-world assessment of the impact of circadian phenotype on performance. This paper presents a simple method to assess circadian phenotype in the field and supports the need to consider time of day when designing performance studies.

Here, we present a method to investigate diurnal rhythms in performance following accurate categorization of participants into circadian phenotype groups based on the Munich ChronoType Questionnaire, gold standard circadian phase biomarkers and actigraphic measures.

In our continuously developing &#39;around the clock&#39; society, there is a need to increase our understanding of how changes in biology, physiology and ...

Evaluation of the Cognitive Performance of Hypertensive Patients with Silent Cerebrovascular Lesions

Evidence accumulated from the last decade has proven that silent cerebrovascular lesions (SCLs) and their underlying pathogenic processes contribute to cognitive decline in the elderly. However, the distinct effects of each type of the lesions on cognitive performance remain unclear. Moreover, research data from Chinese elderly with SCLs is scarce. In this study, 398 otherwise healthy hypertensive elderly subjects (median age 72 years) were included and assessed. All participates were required to complete a battery of structured neuropsychological assessment, including forward and backward digit span tests, symbol digit modalities test, Stroop test, verbal fluency test and Montreal Cognitive Assessment. These tests were used to assess attention, executive function, information processing speed, language, memory and visuospatial function. A multi-sequence 3T MRI scanning was arranged within one month of the neuropsychological assessment to evaluate the burden of SCLs. SCLs were rated visually. Cerebral microbleeds (CMBs) and silent lacunes (SLs) were identified as strictly lobar CMBs and SLs or deep CMBs and SLs according to their locations, respectively. Similarly, white matter hyperintensities (WMHs) were separated into periventricular WMHs (PVHs) and deep WMHs (DWMHs). A series of linear regression models were used to assess the correlation between each type of SCLs and individual cognitive function domain. The results showed that CMBs tend to impair language-related cognition. Deep SLs affect executive function, but this association disappeared after controlling for other types of SCLs. PVHs, rather than DWMHs, are associated with cognitive decline, especially in executive function and processing speed. It is concluded that different aspects of SCLs have differential impact on cognitive performance in hypertensive elderly Chinese.

Here, we present a protocol to assess whether various types of silent cerebrovascular lesions are differentially associated with deficits in certain cognitive domains in a cohort of 398 hypertensive elderly Chinese, using a combination of neuropsychological tests and multi-sequence 3T MRI scanning.

Evidence accumulated from the last decade has proven that silent cerebrovascular lesions (SCLs) and their underlying pathogenic processes contribute to ...