Standardization and statistical approaches to therapeutic trials in the R6/2 mouse

The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington's and prion diseases

“…Standard methods for detecting the HD transgenic (Tg) phenotype are weight loss, clasping, and declining performance in rotarod and grip-strength tests (8,15). In other laboratories and in our own, these metrics did not reliably detect disease onset until 9-11 weeks (10,15). Recently earlier detection has been achieved by examining running-wheel activities (16).…”

Mouse models of Huntington's disease

“…We hope that the recommendations provided below will improve the comparisons of results between laboratories, and aid in uncovering therapies that may be more translatable into successful trials (Table 4). These recommendations are in alignment with the NINDS and CHDI Foundation visions, and with the continuing efforts of the HD research community to execute meaningful preclinical trials (Bates and Hockly, 2003;Hockly et al, 2003;Landis et al, 2012).…”

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…Since BDNF has been shown to increase neurogenesis (Benraiss et al, 2001;Pencea et al, 2001), an appealing hypothesis is that the restoration of hippocampal BDNF levels by enriched environment may lead to an increase hippocampal neurogenesis, which can in turn contribute to the observed behavioral improvements. Based on these studies, many groups are now using an enriched environment as the standard housing for these mice, and any given therapy would need to exert additional effects to be proven effective (Hockly et al, 2003b). The described findings also suggest that promoting environmental stimulation could have an effect on disease progression by improving the quality of life of patients afflicted with this disorder.…”

“…Furthermore, both genetic (e.g., number of CAG repeats) and environmental factors (e.g., number of pups in a litter, maternal nutrition status, age at weaning, cage size, degree of environmental enrichment, diet, number of animals per cage, etc.) can contribute to the overall wellbeing and survival of the mice, and consequently to the observed results (Hockly et al, 2003b). Thus, these factors should be taken into consideration when comparing the effects of different therapeutic strategies.…”

“…Moreover, the search for therapies is also dependent on a careful standardization of experimental protocols (namely on the use of appropriate behavioral tests) and a sophisticated statistical approach to analyze the outcome parameters. In this respect, a careful study by Hockly et al (2003b) has shown that rotarod performance, grip strength and weight loss produce quantitative, reliable and reproducible data that can be easily analyzed by standard statistical methods and reveal the progressive nature of the disease. In a subsequent study (Hickey et al, 2005), R6/2 mice were shown to present behavioral deficits in tests of motor function, namely the running wheel activity and climbing behavior, as early as 4.5 weeks of age, a time when rotarod performance and grip strength were still normal.…”