Program & Abstract Book - EPFL Latsis Symposium 2009
Program & Abstract Book - EPFL Latsis Symposium 2009 Program & Abstract Book - EPFL Latsis Symposium 2009
EPFL Latsis Symposium 2009: Understanding Violence P-30 84 February 11-13 2009 ne u r a l c o r r e l a t e s o f a b n o r m a l a g g r e s s i o n f o l l o w i n g p e r i p u b e r t a l s t r e s s in r a t s Marquez, Cristina 1 ; Vaucher, Angélique 1 ; Sonnay, Aliénor 1 ; Sigmund, Coralie 1 ; Marquis, Julien 2 ; Groner, Anna Claire 2 ; Sandi, Carmen 1 1 Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; 2 Laboratory of Virology and Genetics, School of Life Science, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Early life stress in humans enhances the risk for psychopathologies, including excessive aggression and violence. Adolescence is an important maturation phase during which critical neurodevelopmental events occur in brain regions associated with motivation, emotion and cognition. It is also a relevant period for developing social competences required for adult life. In rodents, stress can induce long-lasting changes in emotional and neuroendocrine responsiveness to stress that can be associated with several psychopathologies. Here we examine behavioral and molecular consequences of exposure to stress during the peripubertal period. Male Wistar rats were subchronically exposed to stress (predator odour and open elevated spaces) during peripuberty (7 days of stress across the P28-P42 period). The long term effects of peripubertal stress were examined when animals were 3 months-old. Peripuberty-stressed animals displayed increased anxiety and aggressive behaviors. In the resident-intruder test, peripuberty-stressed rats attacked more the vulnerable parts of their opponent and showed a lack of inhibitory control of their behavior (continued attacking despite clear signals of submission). In order to elucidate the mechanisms involved in this model of abnormal aggression, we studied (i) basal brain energy metabolism using 14C-2deoxyglucose autoradiography, (ii) the pattern of activation of different brain areas after an aggressive encounter (resident-intruder test) using c-fos immunohistochemistry, (iii) the levels of expression of the serotonin transporter using qPCR. Peripuberty-stressed animals showed an increased basal metabolism in amygdala and bed nucleus of stria terminalis, both areas related to anxiety, and an increase in the basal expression of the serotonin transporter in the prefrontal cortex. The aggressive animals showed increase in c-fos expression in medial amygdala and a lower activation of the medial orbitofrontal cortex, after the resident-intruder test. Our findings highlight the relevance of this peripubertal stress model to investigate the neurobiological correlates of abnormal aggression and confirm the serotonergic system and the interactions between amygdala and prefrontal cortex as key elements in the understanding of violence.
EPFL Latsis Symposium 2009: Understanding Violence P-31 Depicting t h e r o l e o f t h e kap1 e p i g e n e t i c r e g u l a t o r in b e h a v i o u r a l v u l n e r a b i l i t y t o s t r e s s Marquis, Julien 1 ; Jakobsson, Johan 2 ; Bisaz, Reto 1 ; Sandi, Carmen 1 ; Trono, Didier 1 Poster Abstracts 1 Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; 2 Faculty of medicine, Lund university, 22184 Lund, Sweden Growing evidence points to the role of epigenetics in translating environmental stimuli into long-lasting changes of gene expression in the brain. Contrasting with the abundance of data pointing to the key role of epigenetics in animal behaviour, relatively little is known about the molecular mediators of this process. As part of a broad effort to define the roles of the KRAB/KAP1 gene regulation pathways in vivo, we carried out a reverse genetic approach by generating a mouse model in which the KAP1 gene was specifically inactivated in neurons of the adult forebrain. Behavioral studies reveal heightened level of anxiety-like and exploratory activity in these mice, as well as stress-induced alterations in spatial learning and memory (Jacobsson et al., Neuron, 2008, 60, 818-31). At the molecular level, transcriptome analyses detect the dysregulation of a small number of genes correlated with a decrease of H3K9-me3 and an increase of H4Ac, consistent with KAP1-dependent chromatin changes. Our initial molecular studies were performed on whole hippocampus, that is, on a mixture of KAP1-negative and KAP1-positive cells. We are now using laser-dissection to recover selectively KAP1-deleted cells and also analyze separately different hippocampal sub-area. We anticipate that, associated with transcriptome and chromatin analyses, the method should generate robust data to help deciphering the cascade of molecular event linking KAP1 to the observed “stress phenotype”. The Cre mediated hippocampal-KAP1 deletion occurs at approximately 15-30 days of age, that is, when murine macroscopic brain structures are fully developed. Nevertheless, we cannot rule out that KAP1 deletion does not primarily impact on immature, developing neurological networks. To address this point, we have generated a similar mouse model but expressing a tamoxifen-inducible form of Cre. We will now study whether inducing KAP1 deletion at different ages has an impact on the “stress behaviour”. Along the same line, we will study the reversibility of that phenotype by controlling the re-expression of KAP1 through doxycycline treatment of animals carrying an rtTA-regulated expression system. Work performed in our laboratory indicates that KAP1 is an important mediator of stem cell proliferation/differentiation. Interestingly, several observations support the hypothesis that depression could be correlated with an altered adult neurogenesis in the hippocampus. Therefore, through combined labelling with BrdU and several neuronal differentiation marker, we are testing the possibility that adult neuronal maturation could be affected in hippocampal KAP1-deleted animals. The results of this analysis may provide insight into the biology of depression. 85
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<strong>EPFL</strong> <strong>Latsis</strong> <strong>Symposium</strong> <strong>2009</strong>: Understanding Violence<br />
P-30<br />
84<br />
February 11-13 <strong>2009</strong><br />
ne u r a l c o r r e l a t e s o f a b n o r m a l<br />
a g g r e s s i o n f o l l o w i n g p e r i p u b e r t a l s t r e s s<br />
in r a t s<br />
Marquez, Cristina 1 ; Vaucher, Angélique 1 ; Sonnay, Aliénor 1 ;<br />
Sigmund, Coralie 1 ; Marquis, Julien 2 ; Groner, Anna Claire 2 ;<br />
Sandi, Carmen 1<br />
1 Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;<br />
2 Laboratory of Virology and Genetics, School of Life Science,<br />
Ecole Polytechnique Fédérale de Lausanne, Lausanne,<br />
Switzerland<br />
Early life stress in humans enhances the risk for psychopathologies, including<br />
excessive aggression and violence. Adolescence is an important<br />
maturation phase during which critical neurodevelopmental events occur<br />
in brain regions associated with motivation, emotion and cognition. It is<br />
also a relevant period for developing social competences required for adult<br />
life. In rodents, stress can induce long-lasting changes in emotional and<br />
neuroendocrine responsiveness to stress that can be associated with several<br />
psychopathologies. Here we examine behavioral and molecular consequences<br />
of exposure to stress during the peripubertal period. Male Wistar<br />
rats were subchronically exposed to stress (predator odour and open elevated<br />
spaces) during peripuberty (7 days of stress across the P28-P42<br />
period). The long term effects of peripubertal stress were examined when<br />
animals were 3 months-old. Peripuberty-stressed animals displayed increased<br />
anxiety and aggressive behaviors. In the resident-intruder test,<br />
peripuberty-stressed rats attacked more the vulnerable parts of their opponent<br />
and showed a lack of inhibitory control of their behavior (continued<br />
attacking despite clear signals of submission). In order to elucidate the<br />
mechanisms involved in this model of abnormal aggression, we studied<br />
(i) basal brain energy metabolism using 14C-2deoxyglucose autoradiography,<br />
(ii) the pattern of activation of different brain areas after an aggressive<br />
encounter (resident-intruder test) using c-fos immunohistochemistry,<br />
(iii) the levels of expression of the serotonin transporter using qPCR.<br />
Peripuberty-stressed animals showed an increased basal metabolism in<br />
amygdala and bed nucleus of stria terminalis, both areas related to anxiety,<br />
and an increase in the basal expression of the serotonin transporter<br />
in the prefrontal cortex. The aggressive animals showed increase in c-fos<br />
expression in medial amygdala and a lower activation of the medial orbitofrontal<br />
cortex, after the resident-intruder test. Our findings highlight the<br />
relevance of this peripubertal stress model to investigate the neurobiological<br />
correlates of abnormal aggression and confirm the serotonergic system<br />
and the interactions between amygdala and prefrontal cortex as key elements<br />
in the understanding of violence.