Gene Regulation and Adaptive Behaviors

Research center

9 Quai Saint-Bernard Université Pierre et Marie Curie, Campus Jussieu, Bâtiments A-B-C
75005 Paris
Michel Labouesse

Institution

Inserm
CNRS
Université Pierre et Marie Curie

Laboratory

Neuroscience Paris Seine
U1130 UMR8246 UMCR18

Keywords

behavior
Epigenetics
Stress response
Molecular genetics
Glucocorticoid Receptor
Available to host a PhD student

Publications

#Barik J, Marti F, Morel C, Fernandez SP, #Lanteri C, #Godeheu G, #Tassin JP, Mombereau C, Faure P, #Tronche F. Chronic stress triggers social aversion via GR in dopaminoceptive neurons. Science, 2013 339(6117):332-5

#Carrillo MA, #Pasco M, Arnoux I, #Maatouk L, Sanz Diez A, Delahaye M, Herrero MT, Newman TA, Calvo CF, Audinat E, #Tronche F, #Vyas S. Potent and multiple regulatory actions of microglial glucocorticoid receptors during CNS inflammation. Cell Death & Differentiation, 2013 20(11):1546-1557.

Revest JM, Le Roux A, Roullot-Lacarriere V, Kaouane N, Vallee M, Kasanetz F, Rouge-Pont F, #Tronche F, Desmedt A and Piazza PV. BDNF-TrkB signaling through Erk1/2MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids. Molecular Psychiatry, 2013, doi: 10.1038, in press

Valtat B, Riveline JP, Zhang P, Singh A, Armanet M, Venteclef N, Besseiche A, Kelly D, #Tronche F, Ferré P, Gautier JF, Bréant B, Blondeau B. Fetal PGC-1? Overexpression Programs Adult Pancreatic ?-cell Dysfunction. Diabetes. 2013 62:1206-16

Romanò N, Yip SH, Hodson DJ, Guillou A, #Parnaudeau S, #Tronche F, Bonnefont X, Bunn SJ, Grattan DR, Mollard P, Martin AO. Electrical robustness during phenotypic plasticity of hypothalamic dopaminergic neurons. J Neuroscience, 33(10):4424-4433.

Fields of research

Neurophysiology / systems neuroscience

Research Theme

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.