Mandillo Silvia, Heise Ines, Garbugino Luciana, Tocchini-Valentini Glauco P, Giuliani Alessandro, Wells Sara, Nolan Patrick M
CNR - Institute of Cell Biology and Neurobiology - EMMA, 00015 Monterotondo Scalo, Italy.
Dis Model Mech. 2014 Mar;7(3):397-407. doi: 10.1242/dmm.013946. Epub 2014 Jan 13.
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)(dl)1/GurJ; referred to as SOD1 mice]--and in a mutant strain with subtle gait abnormalities, C-Snap25(Bdr)/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.
运动功能缺陷是影响神经、神经肌肉和肌肉骨骼系统的疾病中的致残特征。尽管这些疾病在发病年龄、症状表现、进展速度和严重程度方面差异很大，但对小鼠这些疾病模型的研究仅限于少数几种测试，最常用的是转棒试验。为了扩展小鼠中有意义的运动功能测试项目，我们测试、优化并验证了一种基于自动饲养笼的跑步轮系统，该系统包括一个带有均匀间隔梯级的传统轮子和一个缺少特定梯级的复杂轮子。该系统能够在无操作人员干扰的情况下自动评估运动功能，这在涉及运动性能连续监测的纵向研究中是很有必要的。在两个测试中心的基线研究中，在四种常用的近交系小鼠中，两个轮子上的性能始终存在显著差异。作为进一步的验证，我们研究了进行性神经退行性疾病的突变模型——亨廷顿舞蹈病[TgN(HD82Gln)81Dbo；称为HD小鼠]和肌萎缩侧索硬化症[Tg(SOD1G93A)(dl)1/GurJ；称为SOD1小鼠]——以及一种具有轻微步态异常的突变品系C-Snap25(Bdr)/H（盲醉，Bdr）的运动性能。在这两种进行性疾病模型中，与第三种突变品系一样，我们能够在比体内任何先前记录的症状早得多的年龄可靠且一致地检测到特定的运动功能缺陷：HD小鼠为7-8周，SOD1小鼠为12周。我们还对转棒试验和握力性能进行了纵向分析，在12周和23周时分别仍未检测到缺陷。使用主成分分析发现了几个新的运动行为参数，表明跑步轮试验可以记录与转棒试验性能无关的运动功能特征。这代表了一种在小鼠疾病模型的症状前阶段检测运动缺陷的强大新方法，应被视为研究治疗药物疗效的有效工具。
