Periodic Reporting for period 1 - MitoDyaD (The role of the glucocorticoid receptor in dopaminoceptive neurons in mitochondrial dysfunction and vulnerability to depression)
Reporting period: 2017-05-01 to 2019-04-30
Individuals differ in their ability to cope with stress and are either prone (vulnerable) or resistant (resilient) to develop psychopathologies. Therefore, there is a great interest in understanding the molecular mechanisms for stress-resilience and vulnerability. Previous studies indicated that individual differences in mitochondrial function and brain energy metabolism in a brain region critically implicated in reward and motivation, the Nucleus accumbens (NAc), can modulate vulnerability to stress. Importantly, the glucocorticoid receptor (GR) that is activated upon stress has been suggested as a key regulator of mitochondrial function. In this project, we have investigated the molecular mechanisms involved in GR-mediated mitochondrial dysfunction in the NAc and their role in the development of psychopathologies. Our final goal is to provide a profound basis for the development of future therapeutic approaches to better prevent and/or treat psychopathologies.
Our work first has investigated the role of the GR in the vulnerability for psychopathology. To this end, we made use of mice lacking the GR in all neurons or in specific neuronal cell types of the NAc. Behavioral characterization of these mice showed that GR actions in NAc neurons and in the mesolimbic dopamine system are indeed important for the development of psychopathology. We, then, evaluated the impact of the GR on mitochondrial function in the NAc by performing molecular analysis in these mice and observed that the lack of the GR in NAc neurons leads to impaired mitochondrial respiration. In parallel to these studies, we have also investigated the underlying molecular pathways. Furthermore, we have found the capacity of GR antagonists to revert stress-induced behavioral alterations
The MitoDyaD project has led to the understanding of the contribution of the GR in the NAc for mitochondrial function-related psychopathology and the underlying molecular mechanisms.