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Free keywords:
Stress, gene x environement interaction, HPA-axis, Arc, Arg3.1
Abstract:
Stress is part of everyday life. And while acute and short periods of stress can help to overcome challenges, exposure to chronic - and especially uncontrollable - stress can lead to maladaption of the organism, which can ultimately increase the risk of disease. However, vulnerability to stress and vulnerability to risk increases are strongly dependent on the individual. The molecular underpinnings of this vulnerability and resilience are still largely unknown. Therefore, the present thesis aims at identifying novel molecules involved in modulating individual stress vulnerability in the brain of male mice. In a first step, we investigated long-term gene expression changes in the hippocampus of male mice that underwent chronic social stress. Adolescent male CD1 mice were subjected to 7 weeks of chronic social stress and were investigated after 5 weeks of recovery via an unbiased whole-genome approach utilising microarray technology. Here, we did not find strong differences caused by the stress exposure, possibly because not all animals were affected by the stress exposure. Nevertheless, we identified Iffo1 as a gene that seems to be affected by at least acute stress and might also be involved in the long-term effect of chronic stress exposure. In the next step, we classified the animals from the same paradigm into stress-vulnerable and stress-resilient individuals based on their corticosterone levels after recovery. Animals which still showed elevated levels of corticosterone 5 weeks after stress were defined as vulnerable, while animals in which levels returned to baseline comparable to controls were termed stress resilient. With an additional whole-genome experiment, we were able to show distinct patterns of gene expression between the groups, including genes like Arc, Gria1 and Gria2. In addition, we also investigated differences in peripheral lymphocytes, which showed regulation in genes like Hsp90b1 or SLA. When we compared the expression profiles between brain and peripheral blood, we showed that stress-vulnerable and stress-resilient animals show different patterns of correlations. In the final part of the thesis, we decreased the expression of Arc, one of the genes we found overrepresented in vulnerable individuals, in the hippocampal formation of male mice via AAV-mediated shRNA knockdown. As we performed the modulation of Arc before the stress exposure, we were able to investigate the causal influence of Arc expression on stress exposure. Animals that were subjected to 3 weeks of chronic social defeat, showed an increase in anxiety-related behaviour, impairment in spatial memory, an increase in social behaviour and did not differ in depression-like behaviour. Concomitant with the behavioural alterations, stressed animals showed alterations in multiple physiological parameters, like increased adrenal glands or corticosterone response. Intriguingly, we were able to prevent most of the behavioural, but not the physiological, changes with the Arc knockdown. This strongly suggests that Arc is at least partly causally involved in the molecular machinery that underlies stress vulnerability. As Arc is a downstream molecule in multiple pathways already connected to stress vulnerability or stress in general, it might be that Arc actually is one of the major molecular factors that translate the effects of these pathways.
