Study of brain metabolic dysfunctions in animal models of mood disorder using magnetic resonance spectroscopy

Mood disorders, in particular depression, are a major burden of our society. Due to the poor knowledge of the biological basis of these diseases, classification remains based on arbitrary symptomatic parameters. As a result, the existing pharmacological treatments have difficulties targeting relevant pathophysiological processes leading to high level of non-responding patients. Magnetic resonance spectroscopy (MRS) provides an outstanding means of measuring biochemical processes in vivo and can help identifying metabolic pathways that are associated with a given pathological condition. In this thesis, we have taken advantage of state-of-the-art MRS technologies at high field for studying metabolic dysfunctions associated with behavioral impairments in animal models of mood disorder. The overall goal consisted in finding potential biomarkers and endophenotypes (i.e. heritable biomarkers) with MRS, associate them with a molecular/physiological mechanism and evaluate the effect of a treatment targeting the observed dysfunction. We have successfully identified neuroenergetic abnormalities in different limbic regions of the brain in two mouse models of mood disorders; with a genetic or an environmental origin. Genetic deletion of an important metabolic regulator in mouse brain led to hippocampal neuroenergetic impairment and susceptibility to environmental stressors. Treating the animals with ebselen, an energy boosting mood stabilizer, allowed us to reduce the animal’s sensitivity to stress. With the same approach, we observed energy-related biomarkers associated with susceptibility to stress in the nucleus accumbens of genetically identical mice. We found that social hierarchy can predict the response to a chronic stressor and that behavioral impairments could be prevented by administering an energy stimulating compound, acetyl-L-carnitine. Finally, in an additional project, we have used MRS in an embryonic model in ovo to investigate for markers related to metabolic remodeling during neurogenesis. Our results support the idea that mood disorders arise from energy metabolism fragility in different regions of the limbic system with both environmental and genetic origin. Due to the high translational potential of MRS into clinics, our findings provide new biological targets or routes to study for a better understanding of mood disorders.