Behavioral and Neurological Phenotyping in the Mouse

Tucci, Valter; Blanco, Gonzalo; Nolan, Patrick M.

doi:10.1002/9783527611942.ch6

Cited by 3 publications

(3 citation statements)

References 159 publications

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“…Because many human disease models have been and continue to be developed in the mouse, mice are vital for determining gene function in disease and in the development of future therapies. Assays for grip strength, placing response, rope grip test, open field locomotor activity, SHIRPA assessment, swim speed, swim quality, gait measurement and rotarod assessment are all widely used to assess motor function in the mouse (for an overview, see Tucci et al, 2006 ). Moreover, a number of these assays have been used to track disease progression in mouse mutants ( Carter et al, 1999 ; Fernagut et al, 2002 ; Wooley et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

Early motor deficits in mouse disease models are reliably uncovered using an automated home cage wheel-running system: a cross-laboratory validation

Mandillo

Heise

Garbugino

et al. 2014

Disease Models &Amp; Mechanisms

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Deficits in motor function are debilitating features in disorders affecting neurological, neuromuscular and musculoskeletal systems. Although these disorders can vary greatly with respect to age of onset, symptomatic presentation, rate of progression and severity, the study of these disease models in mice is confined to the use of a small number of tests, most commonly the rotarod test. To expand the repertoire of meaningful motor function tests in mice, we tested, optimised and validated an automated home-cage-based running-wheel system, incorporating a conventional wheel with evenly spaced rungs and a complex wheel with particular rungs absent. The system enables automated assessment of motor function without handler interference, which is desirable in longitudinal studies involving continuous monitoring of motor performance. In baseline studies at two test centres, consistently significant differences in performance on both wheels were detectable among four commonly used inbred strains. As further validation, we studied performance in mutant models of progressive neurodegenerative diseases – Huntington’s disease [TgN(HD82Gln)81Dbo; referred to as HD mice] and amyotrophic lateral sclerosis [Tg(SOD1G93A)dl1/GurJ; referred to as SOD1 mice] – and in a mutant strain with subtle gait abnormalities, C-Snap25Bdr/H (Blind-drunk, Bdr). In both models of progressive disease, as with the third mutant, we could reliably and consistently detect specific motor function deficits at ages far earlier than any previously recorded symptoms in vivo: 7–8 weeks for the HD mice and 12 weeks for the SOD1 mice. We also conducted longitudinal analysis of rotarod and grip strength performance, for which deficits were still not detectable at 12 weeks and 23 weeks, respectively. Several new parameters of motor behaviour were uncovered using principal component analysis, indicating that the wheel-running assay could record features of motor function that are independent of rotarod performance. This represents a powerful new method to detect motor deficits at pre-symptomatic stages in mouse disease models and should be considered as a valid tool to investigate the efficacy of therapeutic agents.

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Section: Introductionmentioning

confidence: 99%

Early motor deficits in mouse disease models are reliably uncovered using an automated home cage wheel-running system: a cross-laboratory validation

Mandillo

Heise

Garbugino

et al. 2014

Disease Models &Amp; Mechanisms

Self Cite

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show abstract

“…Weight is an indicator of health in mouse models of human neurodegenerative disease and decreases with disease progression. Taken together, the motor tasks test strength, endurance, balance and fine motor, grasping capability, reflecting the neuromuscular function, coordination and gait requiring the corticostriatal and nigrostriatal pathways [19,55,61,65].…”

Section: Discussionmentioning

confidence: 99%

“…Forelimb grip strength is indicative of fine motor skills which require neuromuscular function and muscle strength [61]. It is measured as the force required to break the mouse's grip from a bar [45].…”

Section: Forelimb Grip Strengthmentioning

confidence: 99%

Temporal Phenotypic Changes in Huntington’s Disease Models for Preclinical Studies

St-Cyr

Smith

Davidson

2022

JHD

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Background: Mouse models bearing genetic disease mutations are instrumental in the development of therapies for genetic disorders. Huntington’s disease (HD) is a late-onset lethal dominant genetic disorder due to a CAG repeat within exon 1 of the Huntingtin (Htt) gene. Several mice were developed to model HD through the expression of a transgenic fragment (exon 1 of the human HTT), the knock-in mutation of the CAG repeat in the context of the mouse Htt gene, or the full-length HTT human gene. The different mouse models present distinct onset, symptoms, and progression of the disease. Objective: The objective of this study is to advise on the best behavioral tests to assess disease progression in three HD mouse models. Methods: We tested N171-82Q transgenic mice, zQ175 knock-in mice, and BACHD full-length mice in a comprehensive behavior test battery in early, mid-, and late disease stages. Results: We contrast and compare the models and the emerging phenotypes with the available literature. These results suggest the most effective behavioral tests and appropriate sample sizes to detect treatment efficacy in each model at the different ages. We provide options for early detection of motor deficits while minimizing testing time and training. Conclusion: This information will inform researchers in the HD field as to which mouse model, tests and sample sizes can accurately and sensitively detect treatment efficacy in preclinical HD research.

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Reliability, robustness, and reproducibility in mouse behavioral phenotyping: a cross-laboratory study

Mandillo

Tucci

Hölter³

et al. 2008

Physiological Genomics

239

182

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Establishing standard operating procedures (SOPs) as tools for the analysis of behavioral phenotypes is fundamental to mouse functional genomics. It is essential that the tests designed provide reliable measures of the process under investigation but most importantly that these are reproducible across both time and laboratories. For this reason, we devised and tested a set of SOPs to investigate mouse behavior. Five research centers were involved across France, Germany, Italy, and the UK in this study, as part of the EUMORPHIA program. All the procedures underwent a cross-validation experimental study to investigate the robustness of the designed protocols. Four inbred reference strains (C57BL/6J, C3HeB/FeJ, BALB/cByJ, 129S2/SvPas), reflecting their use as common background strains in mutagenesis programs, were analyzed to validate these tests. We demonstrate that the operating procedures employed, which includes open field, SHIRPA, grip-strength, rotarod, Y-maze, prepulse inhibition of acoustic startle response, and tail flick tests, generated reproducible results between laboratories for a number of the test output parameters. However, we also identified several uncontrolled variables that constitute confounding factors in behavioral phenotyping. The EUMORPHIA SOPs described here are an important start-point for the ongoing development of increasingly robust phenotyping platforms and their application in large-scale, multicentre mouse phenotyping programs.

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Behavioral and Neurological Phenotyping in the Mouse

Cited by 3 publications

References 159 publications

Early motor deficits in mouse disease models are reliably uncovered using an automated home cage wheel-running system: a cross-laboratory validation

Early motor deficits in mouse disease models are reliably uncovered using an automated home cage wheel-running system: a cross-laboratory validation

Temporal Phenotypic Changes in Huntington’s Disease Models for Preclinical Studies

Reliability, robustness, and reproducibility in mouse behavioral phenotyping: a cross-laboratory study

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