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Phenotyping behavioral and cognitive processes is a critical practice in mouse research and reliable phenotypic assessment is an essential component of building well-defined links between genes and behavioral/cognitive functions. The success of behavioral screens in neurobehavioral mouse genetics depends on the identification of reliable, reproducible, and high-throughput behavioral/cognitive measures from individual animals irrespective of the differences in opinions regarding how to tackle phenotyping in different behavioral domains. Furthermore, reliable behavioral assays must be resistant to inevitable environmental differences across laboratories since protocols can be replicated but not all the environmental conditions. Here we present a cross-laboratory study of interval timing behaviors in mice. Two classically used mouse inbred substrains, C57BL/6J and C57BL/6N, were studied over several days in home-cages containing automated testing apparatus. Remarkably, all timing measures in mouse performance showed a robust reproducibility across centers and even small differences between the two substrains were comparable across laboratories. Moreover, we have observed a consistent increase in error rate during the light phase of the light–dark cycle, which suggests that mouse performance during this phase is compromised by a possible sleep inertia-like effect. Overall, our study demonstrates that analysis of mouse timing behavior can lead to robust and reliable endophenotypes in mouse behavioral genetic studies.

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.

Environmental enrichment has been proven to have positive effects on both behavioral and physiological phenotypes in rodent models of mental and neurodevelopmental disorders. In this study, we used mice lacking the µ-opioid receptor gene (Oprm1 −/−), which has been shown to have deficits in social competence and communication, to assess the hypothesis that early enrichment can ameliorate sociability during development and adulthood. Due to the immaturity of sensory-motor capabilities of young pups, we chose as environmental stimulation a second lactating female, who provided extra maternal care and stimulation from birth. The results show that double mothering normalized the abnormal response to maternal separation in Oprm1 −/− pups and increased social motivation in juveniles and adult knockout mice. Additionally, we observed that Oprm1 −/− mice act as less attractive social partners than wild types, which suggests that social motivation can be modulated by the stimulus employed. This experiment supports previous findings suggesting that early social environmental stimulation has profound and long-term beneficial effects, encouraging the use of nonpharmacological interventions for the treatment of social defects in neurodevelopmental diseases.

Amyotrophic Lateral Sclerosis (ALS) is a disease in which physical activity plays a controversial role. Epidemiological studies indicate an association between intense exercise and risk of developing ALS. To study the impact of physical activity on ALS, mouse models rely mostly on forced exercise. In this study we hypothesized that voluntary wheel running could represent a better model of the influence of exercise in the pathogenesis of ALS. We used an automated home-cage running-wheel system that enables individual monitoring of performance. To verify the effect of voluntary running on disease progression, prognosis and survival as well as motor functions, we challenged SOD1G93A low-copy male and female mice on one (1 RW, at age 24 weeks) or multiple (3 RW) running sessions at age 13, 18, and 24 weeks. In parallel we measured performance on Rotarod and Grip strength tests at different ages. Several parameters were analyzed through Principal Component Analysis in order to detect what indices correlate and may be useful for deeper understanding of the relation between exercise and disease development. We found mutant male mice more negatively affected than females by prolonged and repeated exercise. SOD1G93A low-copy male mice showed shorter survival, increased body weight loss and poorer disease prognosis when exposed to multiple running sessions. These findings could encourage the investigation of the pathogenetic mechanisms underlying the supposedly increased risk to develop ALS in humans engaged in specific and intense exercise activities.

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