Identi cation of novel molecular factors involved in individual stress vulnerability

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.