Grant: Project Grant

Major depressive disorder is a debilitating condition resulting from a combination of alterations affecting the activity of the brain. The prefrontal cortex is a brain region showing important molecular and functional alterations in humans with MDD but also in animal models of chronic stress. The higher executive functions exerted by the mPFC over stress and emotional responses is believed to be controlled by its output to limbic regions. Amongst limbic regions, the mPFC projects densely to the nucleus accumbens and ventral tegmental area which are well known for their processing of rewarding and emotional information. The activity of these cortico-limbic circuits is controlled by complex transcriptional programs having distinct functional impact on the activity of both pathways. Importantly, we previously showed that chronic stress interferes with the activity of gene programs differently in the prefrontal cortex of males and females suggesting that these two pathways may be controlling stress responses differently in stressed males and females. The main objective of our research program is to define the contribution of these two pathways to the expression of stress responses in males and females. To address this question, we developed a series of experiments to define how stress changes the activity of both pathways in males and females. We also propose to investigate the gene programs modified by chronic stress and test how these genes modulate stress responses by altering the activity of both pathways in males and females. Overall, our research program will allow us to identify the molecular and functional mechanisms by which chronic stress induces behavioral stress responses in order to develop better therapeutic strategies for the treatment of mood disorders in males and females.