Grant: Project Grant

Major depressive disorder (MDD) is a debilitating condition resulting from a combination of alterations affecting the activity of the brain differently in men and women. These alterations interfere with our capacity to cope with stress but differently in men and women. At the molecular level, these alterations refer to changes affecting gene activity specifically in men and women. When modified, these genes change neuronal activity resulting in inadequate responses to chronic stress and ultimately to the expression of depressive-like behavior. Importantly, the different neuronal populations in the brain are affected differently by stress in men and women. However, the contribution of these different neuronal populations to stress responses remains poorly understood and the transcriptional mechanisms underlying their activity in both sexes unexplored. Here, we propose a multidisciplinary approach to define the transcriptional mechanisms underlying the dynamic contribution neuronal populations in the mPFC mediating the behavioral impact of chronic stress. To do so, we will combine the use of micro-endoscopic devices, advanced molecular techniques and cutting edge functional approaches in a mouse model of chronic variable stress known to reproduce the behavioral and molecular impact of chronic stress in males and females with MDD. Overall, our analyses will provide exciting new insights into the sexual differences underlying cellular activity in response to chronic stress, identify neuronal populations more significantly involved in stress responses, reveal the critical time windows during which stress induces its impact and define the molecular mechanisms underlying these effects in order to develop better therapeutic strategies for the treatment of mood disorders in males and females.