| Abstract |
Stress -or even potential stressors- is a common condition influencing the lives of all individuals
and organisms. It is known that exposure to stress can affect emotional and cognitive functions
in several ways as well as physiological processes even on a cellular level. The prefrontal cortex
(PFC) is evolutionarily the most developed brain region, and it is related to an organism’s higher
functions. In other words, it is the main brain region controlling higher cognitive and emotional
functions. The functions of the PFC are differentiated in females and males in many cases. The
sexual dimorphism of several of these functions can be observed either in normal conditions or
in mental disorders The aim of this doctoral thesis was to investigate the effect of systemic and
cellular stress on PFC functions.
In the first part, the study focuses on the effects of stress response on the PFC of both males and
females. In the second part, an attempt was made to investigate the sexual differences observed
during the stress response and in the third part; the interaction of systemic and cellular stress in
the PFC was studied. The results of the first part of the study showed that acute restraint stress
increased stress behavior in female but not in male mice, while negatively affecting PFCmediated cognitive functions in male mice only. The latter effect can last for at least 24 hours,
while the negative effects of stress can be improved by the administration of the GRs antagonist,
mifepristone. Furthermore, we showed that stress conditions cause reduced neuronal activation
of the PFC in males compared to females, and in this case too the administration of mifepristone
leads to improvement. Concurrently, 24 hours after the restraint stress, a relatively reduced
density of dendritic spines was observed in the secondary dendrites in the PFC of male mice.
Subsequently, it was shown that the activation of the CRF system through restraint stress and
through the effect of CRF and corticosterone (CORT), along with the inhibition of the system
through CRFRs antagonism, have a negative effect on the induction of long-term synaptic
potentiation (LTP) only in the PFC of male mice. In contrast, activation of the CRF system through
the effect of CORT causes reduced GABAergic inhibition in the PFC of female mice.
Since the above-mentioned results depict a strong sexual dimorphism in the effect of stress on
the PFC, we proceeded to investigate possible mechanisms of this dimorphism. Initially, we
ensured that the phase of the estrous cycle does not affect the studied functions of the PFC, even
in correlation to stress conditions. Next, we checked the possibility that LTP induction in the PFC
is mediated by different mechanisms, in female and male mice. Specifically, we propose that LTP induction is NMDA-dependent in females and non-NMDA-dependent in males, where GABAA
appears to have a crucial role.
Finally, in the third part, we examined the interaction of systemic and oxidative stress in the PFC.
No effect of restraint stress was observed on the expression of an oxidative stress marker in PFC
cells, but in the presence of the antagonist mifepristone, we detected a significant increase in the
marker’s expression in females undergoing stress. In addition, increased cellular stress appears
to reduce synaptic plasticity in the PFC of female, but not male mice.
In conclusion, sex strongly determines the outcomes of both systemic and cellular stress on the
functions of the PFC. The main hypothesis that emerges from this study is that there seems to
be some protective mechanism in females in terms of the effects of systemic stress on the PFC
functions, while at the same time it is hypothesized that the female PFC is more susceptible to
oxidative stress.
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