Effects of different degrees of life time adversity on stress vulnerability and resilience in adulthood in dependence of genetic predisposition.

An individual with a lower sensitivity to its early environment (red line) would therefore benefit most from life histories with a mild overall adversity, while each experienced adverse life event would increase subsequent stress vulnerability and disease probability (e.a. cumulative stress hypothesis). On the other hand, an individual with a high sensitivity to environmental stimuli would adapt its physiology to this kind of environment (match/mismatch hypothesis). Here, a moderate life time adversity would be most beneficial, as this would increase the resilience to subsequent mild or moderate stressors. Exposure to severe adversity would in all cases increase stress vulnerability and disease risk. Our data indicate that such different patterns (red vs. blue) might be a result of different genetic polymorphisms, where one allele favours low sensitivity (red), while the other allele favours a high sensitivity (blue). Therefore, each genotype can have beneficial as well as detrimental effects on stress vulnerability and stress-related disorders, depending on the degree of cumulative life time adversity.

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.

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