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Automated behavioural testing and drug treatment in mouse models of Huntington's disease

University of British Columbia

Rodent genetic models are a critical tool for understanding the pathogenesis of neurological disorders, and for evaluating the efficacy and safety of novel therapeutics. Unfortunately, behavioural studies of rodents can be vulnerable to false positives or negatives, as many behaviours have substantial inter-animal variability and are sensitive to environmental stressors (which in turn vary between facilities and experimenters). Developing tools to decrease the impact of these stressors and increase the throughput of pre-clinical research is an important area of focus to help deal with this problem. To this end, my thesis project is focused on the development and testing of two automated, self-directed behavioural testing systems that are accessible to mice from their home-cage and can be accessed at will, 24 hours per day. Animals are individually identified through radio-frequency identification (RFID) tagging, allowing for mice to be group-housed and tested alongside their littermates. This design eliminates the need for the animal to be exposed to novel environments, and minimizes experimenter interaction, significantly reducing two of the largest stressors associated with animal behaviour. These two systems can be used, respectively, to assess motor phenotypes via a forelimb lever-positioning task (PiPaw), and to treat animals with drug through their drinking water (PiDose). I applied these home-cage tools to two mouse models of Huntington’s disease (HD), a genetic neurodegenerative disorder that causes debilitating motor dysfunction, in addition to cognitive and psychiatric symptoms. Using the PiPaw system, I found that young HD mice had impairments on a task that required them to hold a lever within a rewarded position range, but not when they had to make a short-duration pull to a defined target. Deficits in older HD mice were dependent on the specific genetic model, with the transgenic YAC128 model showing little to no impairment on the task but knock-in Q175-FDN mice showing substantial motor deficits. We also observed altered patterns of task engagement and changes in the circadian activity patterns of both HD mouse models. These two home-cage systems are open-source, low-cost and built with easily obtainable parts, and should prove useful for experimenters performing basic and translational rodent research.

Text

2021-01-06

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76973

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/