We have funded the creation of a system that enables continuous monitoring of group-housed rats or mice in their home cage with automated analysis of their behaviour and activity.
Challenge Contractor: Professor Douglas Armstrong
Organisation: Actual Analytics
Start date: 2012 / 2013
Duration: 3 years + 3 years
Amount: £0.5M + £0.5M
Sponsors: Rodent Big Brother – AstraZeneca / Rodent Little Brother – MRC Harwell
Measurement of the activity and behaviour of individual rats provides critical information in studies from basic research through to drug development. For example, rats are used in safety pharmacology studies to assess potential drug toxicities on the central nervous system (CNS). Locomotor activity is measured in rats placed singly in an unfamiliar test arena, whereas behaviour is assessed manually in the home cage environment or in a testing arena (e.g. the open field test) to detect signs such as lethargy, seizures and sleep disturbances which may be relevant to the clinic. Single housing and unfamiliar environments can affect animal welfare. Observing behaviour is labour intensive and often conducted during the daytime when rats are naturally less active. For some studies body temperature is measured manually or by using surgically implanted telemetry transducers. Depending on the company and the drug being tested, up to 100 rats may be used per drug in such studies.
Addressing the welfare concerns associated with monitoring individual animals, AstraZeneca posed the Rodent Big Brother Challenge to develop an automated non-surgical system, to measure individual activity, behaviour and body temperature of group-housed rats over a minimum of a 24-hour period in their home cage.
The Rodent Big Brother Challenge was awarded to Professor Douglas Armstrong from the Edinburgh-based SME Actual Analytics. Working with AstraZeneca, the team created the Actual Home Cage Analyser (HCA) system, which provides unobtrusive, continuous monitoring of group-housed rats for the full study duration, avoiding the need for single housing and allowing testing in the familiar home cage environment. The HCA system can be incorporated into standard vivarium racks with the position, activity and temperature of individual rats measured by tagging the animals with subcutaneous RFID chips that are tracked using a baseplate containing a series of RFID antennae.
Behavioural data is obtained using high grade video recording and infrared LED lighting placed above the cage. The video analysis software has been trained to automatically detect specific behaviours associated with neuro-behavioural or CNS issues monitored during safety pharmacology studies, including rearing and sleep disturbance. The technology evaluation and verification work were published in PLoS ONE in 2017.
3Rs and scientific benefits
Actual Analytics and AstraZeneca validated the HCA system using sedative and stimulatory drugs in dosing protocols designed to compare data between light and dark phases. AstraZeneca demonstrated that the HCA system can detect changes in ambulatory and vertical activity, and subcutaneous temperature, in group-housed rats, consistent with published data. Importantly, the system detected drug effects missed by traditional methods which could have an impact in the clinic. This study was published in the Journal of Pharmacological and Toxicological Methods in 2018.
To build further confidence in the HCA system for safety pharmacology studies, the NC3Rs has convened an industry consortium which involves the contract research organisation, Charles River, contributing their time and resources to test three compounds provided by three major pharmaceutical companies.
The Actual HCA system was adapted for use with mice to address the Rodent Little Brother Challenge posed by MRC Harwell in 2012. Validation of the system was performed by MRC Harwell with three commonly used mouse strains. This revealed novel insights into mouse social interactions and behaviour which have major implications for the choice of strain used and the interpretation of scientific findings. For example, in studies on circadian biology, bouts of activity were identified consistently in mice during the light phase, whereas traditional approaches, which monitor activity using running wheels, show negligible activity during this phase. There were also strain specific alterations in the levels of activity over a 24-hour period that had not been previously detected. MRC Harwell now routinely use the HCA system for the identification of early deficits in mouse models of neurodegenerative diseases helping to better characterise the models and identify humane endpoints to limit animal suffering. To help annotate the extensive behavioural data sets obtained from the HCA system, working with Zooniverse, the NC3Rs and MRC Harwell have launched a citizen science project – a first for the 3Rs.
Through the Rodent Big and Little Brother Challenges, Actual Analytics has developed a global client base of academics and companies. They have gone on to secure CRACK IT Solutions seed funding with collaborators at Queen Mary University London to apply the HCA system to monitor the welfare of rats used in research on spinal cord and traumatic brain injury.
Sponsor in-kind contributions
AstraZeneca provided a range of in-kind contributions. This included in-house testing of prototype systems in real-world experimental settings and scientific validation studies to build confidence in the system. MRC Harwell provided space and caging equivalent to 100 cage-spaces a week (approximately £1k per week in caging revenue).
AstraZeneca and MRC Harwell also provided 0.5 and 0.35 of a full-time equivalent (scientific staff) respectively per year over the project period.
This case study was published in our 2019 CRACK IT Review.