Early life stress reprograms DARPP-32 signaling and determines behavioral pathology and resilience

Major depressive disorder (MDD) is one of the most disabling and potentially life-threatening diseases. The lifetime prevalence of MDD is 15-20%, and women suffer from MDD about twice more often than men. MDD is a complex multifactorial disorder, with both genetic and environmental factors playing an important role in its development. Despite decades of research and efforts to collect cohorts for genetic studies, we still lack a fundamental understanding of the pathophysiology for any of the classical psychiatric disorders, including MDD. Although heritability is estimated to be approximately 37%, DNA sequence variations cannot fully explain the susceptibility to MDD, exposure to known environmental risk factors, such as early life adversity (ELA), also significantly contribute to the aetiology of MDD. It is widely accepted that early life adversities (ELA) such as stress, trauma, abuse and neglect are critical risk factors contributing to the aetiology various mental disorders including major depressive disorder and suicidal behavior. This project is guided by the hypotheses that
· exposure to early life adversity (ELA) such as early life stress induces - depending on the duration of stress exposure - either stress vulnerability or stress resilience;
· ELA exposure induces epigenetically regulated changes in the expression of genes encoding proteins that are critically involved in synaptic plasticity, and
· resilient individuals display elevated synaptic plasticity, which enables them to better cope with stress challenges and to continuously adapt to environmental changes;
· vulnerable individuals show reduced synaptic plasticity ,which impairs stress coping and the competence to adapt to the environment.
Since in human patients the level of analysis is limited to peripheral cells or to postmortem brain tissue, we have established animal models, in which peripheral and brain tissue can be analyzed in parallel, as well as other body organs, e.g. to unveil potential comorbidities