Validating cognitive impairments found in the BACHD rat model of Huntington disease through the use of control tests that account for the animals' reduced motivation

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Dokumentart: PhDThesis
Date: 2017
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Rieß, Olaf (Prof. Dr.)
Day of Oral Examination: 2017-11-13
DDC Classifikation: 000 - Computer science, information and general works
150 - Psychology
500 - Natural sciences and mathematics
570 - Life sciences; biology
590 - Animals (Zoology)
610 - Medicine and health
630 - Agriculture and related technologies
Keywords: Ratte , Nervendegeneration , Tiermodell , Kognition , Konditionierung , Motivation , Fettsucht
Other Keywords: Skinner Box
Huntington Erkrankung
Huntington disease
Neurodegenerative disorder
Animal model
Skinner box
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Huntington disease is an autosomal-dominantly inherited, neurodegenerative disease that is caused by a specific mutation in the gene encoding the huntingtin protein. Expression of the mutated protein results in extensive neuronal loss throughout the brain, although certain brain regions are more heavily affected. The resulting clinical symptoms include a range of motoric, psychiatric, cognitive, and metabolic changes that progress until the patients are unable to care for themselves, and ultimately result in an early death. There is currently no disease-modifying treatment available. Thus, continued efforts in both clinical and preclinical research are of importance. Several animal models of Huntington disease have been established following the discovery of the huntingtin gene and the disease-causing mutation. Each model has strengths and weaknesses, and their combined use is of importance for preclinical research concerning disease mechanisms and potential therapeutics. Thorough characterization of a given animal model is important in order to understand to what extent it models the actual disease and how to work with it in an appropriate way. The current thesis includes a series of studies focusing on the characterization of a recently established rat model for Huntington disease, called the BACHD rats. These rats carry a transgenic construct, which expresses the full-length mutated protein that causes Huntington disease. The project included the assessment of body size and body composition as well as investigations of motivational and cognitive phenotypes. Results indicated that male BACHD rats were obese, while simultaneously showing discreet developmental deficits. These phenotypes might be caused by neuropathology of the hypothalamus, which has also been noted among Huntington disease patients. Assessment of the BACHD rats’ performance on a test of motivation suggested that the rats’ altered body composition might affect their interest in working for food rewards. Strategies to circumvent this influence were evaluated, as motivational differences might confound investigations of other behavioral aspects. Through the use of control tests, robust phenotypes of cognitive impairments among the BACHD rats were characterized. Similar phenotypes have been found among rats with fronto-striatal lesions, suggesting that disease-related neuropathology might be causing the BACHD rat’s phenotypes. Ultimately, the work presented in the current thesis served to further the research on how to work with Huntington disease models in general, and the BACHD rats in particular. In addition, the noted phenotypes would likely be suitable in future preclinical testing of potential therapeutic agents, although specific investigations to determine the underlying neuropathology are still of importance.

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