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I. MORGANSTERN, B. FERETIC, K. HOMA, S. MALEKIANI, M. NILGES, N. PATERSON, N. ROBERTS, E. SABATH, G. SARDARYAN, L. THIEDE, T. HANANIA

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Transgenic mice over-expressing human SOD1-G93A are commonly employed as an animal model of familial ALS. The present study was aimed at identifying behavioral tests that are most sensitive to the emergence of behavioral/neurological deficits in male and female SOD1 G93A mice (SOD-1) compared to wild-type (WT) controls. Specifically, the test battery consisted of commonly used metrics such as fore- and hind-limb grip strength, rotarod, open field and more complex proprietary algorithm-based behavioral platforms such as NeuroCube® and SmartCube® Systems.

The results of the present study indicated that both fore- and hind-limb grip strength as well as rotarod performance declined with age and disease progression. The open field test revealed time-dependent changes in locomotor and rearing performances in SOD-1 mice of both genders, with relatively stable performance in WT controls. In addition to these routine tests of neurological and motor function, sophisticated algorithm-based systems were employed and determined a strong phenotype effect in the SOD-1 mice at a much earlier age. Specifically, by using the NeuroCube® system to measure gait deficits, we found that SOD-1 mice showed a reduction in step and stride length and an increase in stride, stand and swing duration compared to WT mice, which was evident as early as 8 weeks and progressed with age. Similarly, by using our SmartCube® technology that measures whole animal behavior, we identified behavioral changes as early as 6-7 weeks of age in the SOD-1 mice. Interestingly, at young ages the mutant mice showed a unique hyperactive phenotype consisting of increased mobility, exploratory behavior, grooming and sniffing compared to WT mice which declined with disease progression.

In summary, the platform of behavioral tests employed here demonstrate that while routine behavioral paradigms are able to detect neurological and motor function deficits in SOD-1 versus WT mice as early as 13-15 weeks of age, more advanced computer vision systems are able to identify distinctive behavioral patterns and discriminate the phenotype as early as 6-8 weeks of age. This earlier period of disease identification presents a valuable model in which to explore and improve future assessment of potential therapeutic approaches for ALS.