On the Neurobiology of Physical Activity in Mice and Human : In search of Eating Disorders Determinants

High levels of physical activity (PA) have a strong and manifold influence on the course of anorexia nervosa (AN). However, this symptom is often not assessed in the clinical and scientific practice. Consequently, questions regarding the etiology of high levels of PA in AN patients remain unanswered. It is hoped that increased understanding of the factors which influence the voluntary PA levels could lead to more accurate treatments and prevention programs. Genetic factors have strong contribution to the levels of PA. It may be possible to investigate the biological pathways involved in the regulation of PA by unraveling the genetic architecture of this heritable phenotype. These efforts are, however, complicated by the fact that numerous additional factors (such as psychological, cultural and environmental factors) have an influence on the levels of PA. Taking under consideration the complex basis of PA, as well as the potential relevance of PA for AN pathology, we aimed in the current thesis: 1) to elucidate some of the biological basis of PA; and 2) to understand the role of PA in the course of ED pathology. As far as the first aim is concerned, we applied various methodologies to assess novel candidate genes and genetic regions for PA. In case of human studies, we conducted genetic association analysis for high levels of PA and genetic variants present in candidate genetic regions. In case of mouse studies, we applied multiple approaches in order to examine genetic basis of running wheel activity – a behavior considered to be a model of PA in humans. We conducted a genome wide scan of novel candidate genetic regions using a panel of chromosome substitution strains. Furthermore, we validated two possible candidate genes for running wheel activity, namely Nfatc2 and Ptpn1. In order to do so we used a Nfatc2 deficient mice and an shRNA mediated knockdown for the Ptpn1 gene. Finally, we made an effort to integrate the findings originating from the two species. As far as the second aim is concerned, we conducted research using two different populations: 1) general population from TwinsUK database, in which the levels of PA were recorder by means of self-reported questionnaires; and, 2) clinical sample of adolescent anorexia nervosa patients with the levels of PA measured by means of accelerometers. Our results suggest that high levels of PA can be considered a risk factor for AN and diminish during physical and psychological recovery. Furthermore, we discovered novel murine candidate regions, on chromosomes 2 and 19, for voluntary running wheel activity. Syntenic human region on chromosome 20 was shown to be associated with high levels of PA in two independent populations. Two interesting candidate genes for running wheel activity were further characterized (Nfatc2 and Ptpn1). In case of Ptpn1 we could show its functional relevance for food anticipatory activity measured with the use of running wheels. Finally, we critically evaluated the translational approach to research regarding complex phenotypes. We recommend caution when attempting translational research of this complex phenotype