While it is clear that genetic alterations may predispose individuals to be more or less prone to develop a stress-induced disease, the nature of these genetic alterations remains largely unknown. Some individuals are vulnerable to stress, but many others show a remarkable resilience to adverse experiences. Our research has revealed that the impact of specific genetic variants on stress vulnerability and resilience depends on the stress context and, importantly, on the life history of the individual (Fig. 1). This means that most common genetic variants can be both beneficial and detrimental in the development of stress-related psychiatric disorders. We are working to further elucidate this complex 'gene' with 'early environment' with 'adult environment' interaction using two main approaches:
(1) Candidate gene-driven approaches
Clinical studies in depression and other stress-related psychiatric disorders have identified a number of candidate genes or pathways that were altered in patients compared to control subjects. To unravel the function of these genes in relation to varying environmental conditions, transgenic or conditional knockout mouse models are subjected to various paradigms of adverse environmental stimuli (postnatal stress paradigms, chronic adolescence stress, chronic adult stress, etc.). Alternatively, candidate genes are directly modulated genetically (e.g. using viral vectors) or pharmacologically. Overall, we test the hypothesis that differences in the expression of these genes alter the sensitivity of an individual to react to adverse stimuli. Consequently, increased stress vulnerability and a disease-like phenotype would be observed under either mismatched environmental conditions or following repeated (cumulative) stress exposure.
(2) Screening approaches
By utilizing complex animal models for stress vulnerability or resilience we can identify novel molecular targets involved in stress vulnerability and disease, based on gene expression profiling, DNA analysis (SNPs, next generation sequencing, etc.), proteomics or metabolomics. The resulting new candidate genes or molecular pathways are then further analyzed in detail and cross-linked with the observations in clinical samples.
Our overall goal is to understand the molecular basis of stress vulnerability, thereby creating the possibility to effectively predict, prevent and treat stress-related disorders. Our work is closely connected to the clinical and translational research efforts at our Institute, trying to bridge the gap from the bench to the clinic.