PHENORAT · EID on the advanced science and technology of rat models for neurodegenerative diseases

EID on the advanced science and technology of rat models for neurodegenerative diseases

EID on the advanced science and technology of rat models for neurodegenerative diseases (PhenoRat) PROJECT OBJECTIVES: Neurodegenerative brain diseases constitute a major health problem in Europe, and their impact on public health and society is increasing with the aging of the populations. One of the most important bottlenecks for finding more effective drugs for brain disorders is the lack of valid animal models. To address this bottleneck, PhenoRat has focused on the characterisation and validation of transgenic rat models for two neurodegenerative diseases with the aim to define read-outs for preclinical treatment studies: Huntington disease (HD) and spinocerebellar ataxia type 17 (SCA17). Behavioural phenotyping is hindered by the lack of reliable tracking of rodents in a social setting for an extended period of time, which is needed to assess social behaviour. To overcome this, PhenoRat aimed to develop novel methods and techniques for the automated assessment of the behaviour of socially housed rats, to develop statistical methods, algorithms and software tools that facilitate the automated detection of animal behaviour and to apply these novel methods in HD and SCA17 rats. WORK PERFORMED SINCE THE BEGINNING OF THE PROJECT: PhenoRat partners have established a lively network and profited from the exchange of both knowledge and research capabilities and resources. A joint paper, planned to be written by PhenoRat fellows and PIs together shows the sustainability of the network. All fellows were integrated in the training program of PhenoRat – both local and network-wide training measures. They organised a symposium as part of the Measuring Behaviour Conference 2016 to present the results of their work to a wider scientific audience. In addition, they engaged in several outreach activities for a non-scientific audience. The PhenoRat website (www.phenorat.eu) was established to raise the public awareness of the project. It also contains internal pages that are used as a teaching and reference tool for the fellows. MAIN RESULTS: Generation, detailed phenotyping and validation of HD and SCA17 rat models: We performed a high throughput phenotypic characterisation and molecular assessment of a transgenic rat model for SCA17. Special attention was given in the disease progression and development of behavioural and molecular signs throughout the lifespan of the transgenic rats. In this project we provided evidence that the transgenic SCA17 rats show an anxiety phenotype at the age of 3 months. In addition, social interaction is disrupted in the last stages of the disease in line with SCA patients, providing evidence for the value of this animal model. No cognitive impairments were discovered in the SCA17 rats and regarding the motor control, an impairment of the fine motor control seems to appear already early in life, before the manifestation of the rest of the symptoms, whereas the gross motor control problems are revealed later in the animals' disease development. Aggregate levels have been shown to increase over time in the cerebellum in contrast with the endogenous soluble levels of the TBP that are steadily but significantly decreased compared to the wildtype controls. Low aggregation levels were quantified in the cortex and striatum. Finally, dopaminergic and serotonergic system of these animals was intact. A thorough phenotyping of a transgenic rat BAC model for HD was performed with a focus on prodomal symptoms and their stability over disease course relevant to define features presented by HD patients. PhenoRat provided first evidence that transgenic BACHD rats display impulsivity early in life, as do early symptomatic HD patients, thus adding to the face validity of the model. Development of new technology, statistical algorithms and software tools to analyse rat behaviour: To advance the automated analysis of rodent social behaviour, PhenoRat collected 2D and 3D datasets of rodent social interactions and developed first algorithms for the analysis of the 3D-datasets. In addition, social behaviour recognition from tracking information obtained from videos was substantially brought forward. Including: (i) Improvement of tracking and knowledge on how feature quality affects the recognition; (ii) Modelling the temporal information to improve recognition; (iii) Development of a recognition system that is robust to altered experimental settings. FINAL RESULTS AND THEIR POTENTIAL IMPACT AND USE: PhenoRat produced a group of well-trained young scientists for the future of this important field, with a strong focus on intersectoral and international collaboration that is also reflected by the plan to award double PhD degrees from both the Dutch and the German academic partners. The strong focus on inter-sector working experience with both academic and industrial partners, plus a broad-ranging scientific training enabling “thinking outside the box” and complementary skill training, enables the fellows to meet the demands of the European employment market. Regarding the scientific results, PhenoRat contributed to the development of model systems that translate to the human pathology of HD and SCA17 by a thorough phenotyping of rodent models for HD and SCA 17 with a focus on prodomal symptoms. Novel automated behavioural paradigms for rats and new analysis methods, algorithms and online tools for behavioural phenotyping were developed and validated. SOCIO-ECONOMIC IMPACT AND THE WIDER SOCIETAL IMPLICATIONS OF THE PROJECT: In addition to educating fellows for the European employment market, the PhenoRat outreach program should also be mentioned as a measure that achieved impact on society. Thorough characterisation of the animal models for HD and SCA 17 has indicated new targets for pre-clinical trials. In addition, the development of automated systems for the analysis of social behaviour in rodents was significantly pushed forward, potentially reducing the burden of behavioural experiments. This may reduce time and therefore costs for analysis of pre-clinical trials in the future. In the long-term these results will clearly impact patients, care takers and patients families significantly, but likely need another 10 years or so to reach patients in terms of new treatment paradigms. CONTACT DETAILS: University of Tuebingen Institute of Medical Genetics and Applied Genomics, Research Management Calwerstrasse 7 72076 Tuebingen Germany Phone +49 7071 29 72191 Fax +49 7071 29 25061 Email Carola.Reinhard@med.uni-tuebingen.de

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