To decipher the molecular mechanisms that allow brain gene expression to adapt to environmental challenges, we focus on the function of inducible transcription factors. Glucocorticoid hormones (GC) plays a key role in physiological and psychological responses to stress. It has multifaceted functions in the brain, most likely reflecting distinct actions in different brain areas and cell populations. In response to stress, GCs activate the glucocorticoid receptor (GR) that induces both rapid cellular alterations, involving modifications of signal transduction, as well as long-term changes by regulating gene expression. Genetic studies in mice have provided direct evidence that GRs are key players in stress-induced behavioral disorders. However, given a wide range of GCs actions, precise genetic dissection of GR functions, and combinatorial behavioral, physiological, electrophysiological and molecular analyses, is absolutely required.
Our research proposal aims at furthering our understanding of the role of the GR transcription factor and associated proteins in the modulation of behaviors affected by stress and in the pathogenesis of stress-related disorders. Firstly, we plan to expand our ongoing work on the identification of cells in which GR gene activity is required for a specific response and, secondly, we will identify GR target genes underlying changes in behavior and the cellular consequences of their changes in expression.
We established refined transgenic mouse models to examine how abolishing or exacerbating glucocorticoid receptor (GR) signaling in specific subsets of brain cell populations, including those of the dopamine and the serotonin pathways, microglia, astrocytes or adult neural precursors, impinges on behavior and brain physiology in healthy brain or neurodegenerative context, such as Parkinson?s disease.
Detailed comparative behavioural analysis of these models, focusing on addiction, emotional and social behaviors, should uncover the nature of the cells in which GRs may play a role. Electrophysiological, in depth anatomical, biochemical and molecular studies will provide insight into the cellular effects of GR modulation. Thus, transcriptome analysis in animal models showing changes in either behavior or cellular functions will allow us to define the molecular mechanisms underlying GR actions. The genes studied will include GR target genes, as well as genes responsible for sustaining long-term effects, including pathological changes induced by stress. We will then use a functional screen, based on targeted overexpression or transduction, to validate a few candidate genes that are of particular interest. Finally, we will investigate the strategies employed by GR to control target genes of interest. Using ChIP, we will identify binding of GR and associated partners. The function of some of these binding partners (STAT5 transcription factor and brm/BRG1 chromatin remodelers) will eventually be studied using conditional mutants recently established.
The expected results of these studies will provide the precise role of GR in the development of stress related pathologies and should elucidate some of the molecular mechanisms by which the emotional life events can lead to long-lasting modifications in behavior. This knowledge about mechanisms leading to stress-related pathologies should provide a new ground for developing more specific therapeutic approaches to neurological and psychiatric disorders.