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Large-scale, high-throughput automated systems for phenotyping mouse models of human disease

Final Report Summary - PHENOSCALE (Large-scale, high-throughput automated systems for phenotyping mouse models of human disease)

In order to improve the standardisation and throughput of mouse phenotyping, the PHENOSCALE project developed a new high throughput automated phenotyping platform in the form of three home cages called PSS 009. These formed a highly flexible modular solution for state of the art automated metabolic and behavioural monitoring of small laboratory animals. Mice could be housed in these cages for the entire duration over which data was recorded. This allowed for measurements of behavioural and metabolic parameters in the home cage, as opposed to transferring mice into a separate test cage. Eliminating the need for transfer between cages reduced animal stress and associated variation in data, as well as time needed for acclimation and increasing throughput. The modules developed in the PHENOSCALE project were metabolism, motor skills and cognition and welfare. These modules could be combined in a unique single system to allow monitoring within a home cage.

In addition, the Phenomaster software was developed to allow easy experimental design, recording and analysing data. The measured data could be easily exported in various formats and used further in statistic programmes or databases. The Phenomaster system could be operated with an unlimited amount of simultaneously measured home cages of different standard configurations run by the same software.

The three modules developed and tested in PHENOSCALE were the following:

1. PSS 009 ME metabolic: Metabolic performance was measured via indirect calorimetry oxygen (O2) consumption and carbon dioxide (CO2) production, respiratory exchange rate (RER) and energy expenditure (EE). Drinking and feeding behaviour was monitored with high precision sensors, amounts and time patterns. Up to 6 sensors per cage controlled food or liquid access per time or amount. Spontaneous home cage activity was monitored via sensor frames, including total activity, ambulatory and fine movements, rearing.
2. PSS 009 MO, motor skill: Regarding the running wheel (RW) activity measurement of voluntary wheel running took place on a standard wheel and a complex wheel lacking some bars with optional personal computer (PC) controlled 'enabled and disabled' function and workload control.
3. PSS 009 COWE, cognition and welfare: Two operant behavioural insert modules were included, namely nose poke (NP), where the mouse poked its nose into a hole in order to gain a food reward and a RW enabled for running as a reward.

A key part of the PHENOSCALE project was the close collaboration between the small and medium enterprise (SME) leader, TSE Systems and experienced academic research groups, namely MRC Harwell, United Kingdom, HMGU Helmholtz Zentrum München, Germany, and CNR National Research Council and IIT Italian Institute of Technology, Italy. This enabled TSE to improve the design of their modules and the academic groups to develop standard operating procedures (SOPs) to suit their requirements for high throughput phenotyping.

The TSE Phenomaster system was developed to allow for automated modular high throughput phenotyping of small laboratory animals for the assessment of behavioural and physiological phenotypes. As already mentioned, TSE developed three modules which could be put in home cages: PSS 009 ME, MO and COWE.

The PHENOSCALE project has the following objectives:

1. high-throughput phenotyping, consisting in primary, secondary and tertiary phenotyping
2. development of new Empress SOPs using PSS 009 and validation of this approach with selected mouse models at different sites, i.e. European mouse clinics
3. optimisation of the high-throughput technology systems by advanced interfacing and extended software capabilities
4. promotion of the new high-throughput systems and novel established SOPs to other phenotyping centres.



Each module was tested at two or three mouse clinics, in MRC Harwell, HMGU Helmholtz Zentrum München, CNR and IIT. The mouse clinics feedback results to TSE who made refinements to the equipment and software then returned the upgrade to the clinics for further testing. SOPs were developed by the clinics and comparative testing was performed on selected background strains of mice and mutant lines with phenotypes relevant to the equipment being tested.

The results of this project suggested that the use of automated behavioural tests in the mouse home cage environment was a promising approach. Indeed, this strategy resulted in a reduction of the duration of the experiments and a considerable increase in the amount of data recorded. By using the developed protocol, combined with the COWE system, we were able to extract information about the overall behavioural performance of each animal, the circadian modulation of behaviour and the fine timing performance at each trial. Furthermore, compared to existing standard protocols, all our data were recorded as timestamps of events occurring in the cage.

The monitoring, in real time, of the animal performance allowed the experimenter to continuously monitor the welfare of the animal. Most current research in mice was conducted by daily handling of the animals and all procedures were performed at the daytime, when the animal was under its subjective night. We showed that we could reduce the handling of the animal and, at the same time, test the animals according to their physiological sleep and wake rhythms. The test was very much reproducible across laboratories.

During the project TSE Systems made a number of changes to improve the different components. The most critical developments for motor skills were the following:

1. modification of the wheel drums for motor skill by exchanging the fixed bars with screw able bars producing complex drums
2. the running wheel mechanism was developed so that motor skill testing could be done in IVC greenline cages.

With respect to metabolism the modifications were the following:

1. a high speed oxygen and carbon dioxide (O2/CO2) sensor was added to enable the high speed testing time needed for high through put systems. High speed sampling was developed with the air being actively drawn out.
2. complete new design of universal drinking and feeding bottles was proposed, ensuring they were autoclavable, with improved height adjustment and spillage protection
3. cage lids for the IVC greenline series were constructed
4. hardware components for the controlling of the system were transferred into 19 draws which could be built into a server cabinet which greatly improved the appearance of the system and any technical service to the system.

Regarding cognition and welfare the modifications were the following:

1. standardisation of operant walls to fit into all possible cage types
2. running wheels from the motor skill system could be added to the COWE systems for reward research
3. the most important improvement was in the software, a completely new software, compatible with Windows7 to provide the user with a user friendly graphical interface. From now on the user would have the possibility to put together graphically their individual programme. This enabled more than 100 % flexibility. The combination of this new software, together with the updated Phenomaster software, achieved an ultimate control and data recording system which was not viable and technically possible by the time of the project elaboration.

To conclude, TSE Systems had the whole package for automated phenotyping in a wide range of characteristics by the end of the project lifetime.

TSE Systems created or updated a series of marketing materials which were used to introduce the concept to our sales' partners. The sales force made a total of 15 trips in the period between November 2010 and May 2011 to directly discuss the PHENOSCALE project with daughter companies or distributors. In addition, between November 2010 and May 2011, TSE representatives made a total of 224 trips to selected academic institutions and events. During these discussions, an estimated total of 1 100 scientists were alerted to PHENOSCALE. In the period between November 2010 and May 2011 TSE Systems also participated in 33 scientific conferences with a trade exhibition and presented the project to approximately 1 200 scientists in direct communication. Moreover, product demonstrations commenced at selected trade exhibitions and for individual prospects, where the appropriate equipment was showcased. The MGU was mentioned as the reference centre in these cases. A special lecture highlighting this part of the project was intended to be held at the distributor meeting. Highlighting the influence of MGU in the project would be facilitated by demonstrating published results, which were made available in poster format.

The PHENOSCALE public website could be accessed at http://www.phenoscale.com/.