Abstract

Mental health disorders are a pressing global health-threat, affecting millions of people world-wide, which has already cost the world economy over 2.5 trillion dollars, making it a critical burden to society. These psychiatric disorders, including major depressive disorders, anxiety disorders and posttraumatic stress disorders, commonly arise as a combination of genetic and environmental factors. In the past decades, these gene by environment interactions (GxE) have increasingly been studied in both clinical and pre-clinical settings. Exposure to early life adversity has often been associated with negative outcomes on brain and behaviour and it has frequently been described as a risk factor for developing psychiatric disease. Nevertheless, there is also cumulative evidence that exposure to early life stress (ELS) in a milder form can result in adaptive responses that prepare an individual to cope with future life challenges. One gene that has repeatedly been implicated in the risk for psychiatric disease development is the FK506-binding protein 5 (FKBP5) gene, that encodes the glucocorticoid receptor (GR) co-chaperone FKBP51. FKBP51 plays an important role in regulating the sensitivity of the GR to the stress-hormone cortisol in humans or corticosterone in rodents. Interestingly, polymorphisms in the FKBP5 gene were found to interact with traumatic early life events to increase the risk for developing psychiatric disorders. In recent years, FKBP51 has extensively been studied in relation to stress resilience and vulnerability, however the mechanisms by which it contributes to these processes, particularly in combination with ELS, are not yet fully understood. Apart from genetic factors and early life events, there are a number of additional environmental factors that can be of great influence on mental health, such as age or sex. In fact, research from the past decades has shed an increasing light on the pivotal role that sex plays in the resilience to (early life) stress. Nevertheless, since many studies historically only included males, there is unfortunately still a large gap in information on the female sex when it comes to stress resilience and vulnerability mechanisms. In this thesis, the importance of including both sexes in rodent stress research study designs is emphasized, by demonstrating sex-differential phenotypes of chronic social defeat stress using a recently developed hands-on protocol for chronic social defeat in females. Moreover, using genetic mouse models, this thesis demonstrates not only clear sex-dependent, but also cell-type specific functionality of FKBP51, either under baseline conditions in an older aged sample or in interaction with ELS stress exposure. Furthermore, it underlines the FKBP51-mediated beneficial effects of ELS exposure in female mice and proposes novel underlying pathways in this process. Ultimately, this thesis corroborates the notion that FKBP5 is not per se a psychiatric risk factor, but rather a highly dynamic stress-responsive gene that interacts with the environment in shaping stress resilience.