Translational neuroscience of anorexia nervosa: A genetic and environmental interplay underlying behavioural hyperactivity in mice

Anorexia Nervosa is a severe mental illness, affecting young females more than males. Anorexia nervosa runs a chronic, relapsing course and is associated with high disability and mortality rates. The hallmark of the disease is keeping a low body weight, less than 85% of what is expected. The etiology of anorexia nervosa is complex (unknown), with risks involving environmental, temperamental, developmental and genetic factors. Though not specified in the diagnosis criteria, excessive physical activity has also been described as a prominent feature of the disorder. It plays a significant role in the development, maintenance and recovery rate of the disorder. This thesis aims at unraveling genetic and environmental factors affecting the hyperactivity behavior and the susceptibility to the activity based anorexia (ABA) model, which models this feature in rodents. Rodent studies take place under controlled genetic and environmental conditions, where the dissection of complex phenotypes is facilitated. In the thesis we report on the following novel findings. Physical activity levels prior to the restriction phase were found to highly predict the susceptibility levels across a set of eleven inbred mouse strains exposed to the ABA model. Mapping of hyperactivity behavior, by screening of the chromosome substitution (CS) panel, generated from C7BL/6J and A/J mice, in the ABA model, has shown potential quantitative trait loci (QTL) on mouse chromosomes 4, 12 and 13. Further analysis revealed a locus in the proximal region of chromosome 12, however, additional research is needed to search for candidate genes within the QTL interval that contribute to the observed phenotype. Early life events (inter- and intra- strain cross-fostering experiments in mice) were able to modulate genetic background in the highly ABA susceptible CS mouse strain 4. Change in maternal environment, of CS strain 4, was associated with significant differences in DNA methylation when compared to the mice raised by their own biological mothers. Several genes implicated in different psychiatric disorders, such as Cntnap2, showed hypermethylated regions and were related to reduced ABA susceptibility following cross-fostering. Thus, early life events may modulate genetic background susceptibility for adult maladaptive behavior via epigenetic modifications. Altogether, the studies described in this thesis suggest that the trajectory of anorexia nervosa is likely defined by an ongoing gene and environment interplay starting at an early stage. Close to the onset of illness, the role of excessive exercise or excessive physical activity as a risk factor becomes prominent and it should also be considered as a factor of illness severity. These results warrant further studies to investigate what modifications of brain structures i.e. neuronal organizations or/and connections, have occurred with the epigenetic modifications under the environmental and how these dynamic brain changes affect susceptibility to adult mal-adaptive behavior