Gene regulation and adaptative behaviors

Animals adapt their behavior to environmental changes. The general objective of the “Gene Regulation and Adaptive Behaviors” team is to elucidate the physiological and molecular mechanisms whereby life experiences that have an emotional impact, produce long-term behavioral modifications and may lead to disease. To sustain behavioral adaptations, the most probable assumption is that environmental stimulations cause modifications of gene expression in the brain, stabilized by epigenetic mechanisms, which reflect changes in nuclear organization.

To address this question, we investigate the functions of transcription factors, such as steroid receptors or STATs, induced by hormones released upon environmental challenges or the functions of epigenetic modifiers recruited by these transcription factors.We generate mutations of these factors in selected brain cell populations (specific neuronal populations, neural precursors, microglia, astrocytes, ...) and combine behavioral, physiological and molecular approaches to study the consequences.

In this context, we are particularly interested in studying how stress response remodels gene expression to modify behaviors, such as addiction or emotions; and how stress may lead to pathological situations including behavioral disorders or neurological diseases, such as Parkinson’s disease. We also investigate how hormonal control of gene expression shape sexual and social behaviors.

Highlights and future directions

Physical and emotional stress induces a rapid release of glucocorticoids from the adrenal glands that orchestrates adaptive metabolic, physiological and behavioral responses. Beneficial when functioning normally, stress exposure may however trigger metabolic and behavioral pathologies in individuals with frequent or prolonged demands, or in hypersensitive individuals. Glucocorticoids activate the glucocorticoid receptor (GR) a transcription factor. We previously provided the first direct genetic evidence that brain GR are key modulators of stress-related behaviors in mice. Brain-specific GR gene inactivation reduces anxiety, despair, a depression-like behavior, and responses to cocaine. The action of GR on distinct behaviors probably involves GR from different cell populations and brain structures. Dopaminergic neurotransmission shapes behaviors ranging from motivation to reward and cognition. We demonstrated that GR in dopaminoceptive neurons is essential for the behavioral responses to cocaine, and for social aversion, a response acquired in the context of a chronic stress induced by repeated social defeats. Remarkably, the same mutation does not affect other aspects of depression, such as despair, or anxiety (Ambroggi et al. 2009 Nature Neuroscience, Barik et al. 2010 Biol. Psy., Barik et al. 2013 Science).

Stress response modulates also the appearance and the progression of neurological disorders. Combining conditional GR gene inactivation and experimental model of Parkinson’s disease, we showed that microglial GR preserves neuronal degeneration (Carrillo de Sauvage et al. 2013 Cell Death & Diff, Ros-Bernal et al. 2011 PNAS).

GR is closely related to other steroid receptors, including the androgen (AR) and the progesterone (PR) and the progesterone receptors.We developed a similar strategy to precisely define the contribution of brain AR in shaping male specific behaviors (Raskin et al. 2009, J of Neuroscience).

Our actual effort aims to refine the anatomical dissection of steroid receptor genes function and to uncover the underlying molecular mechanisms. In the most pertinent models, we analyse the transcriptome to identify target genes. Among various strategies, GR controls gene expression by interacting with other transcription factors and by recruiting chromatin modifiers. We investigate the role of these partners by conditional gene inactivation.

Collaborations
  • International collaborations:

Daniela Kaufer (UC Berkeley, California, USA)

Jan-Wilhelm Kornfeld (Max-Planck Institute, Cologne, Germany)

Alban de Kerchove d’Exaerdre (Université Libre de Bruxelles, Belgium)

  • National collaborations:

Philippe Faure (IBPS, UPMC, Paris)

Pier-Vincenzo Piazza, Jean-Michel Revest (Institut Magendie, INSERM, Bordeaux)

Michael Schumacher (INSERM UMR 788, le Kremlin-Bicêtre)

Etienne Hirsch, Stéphane Hunot (ICM, UPMC, Paris)

Christian Giaume (Collège de France, Paris)

Patrice Mollard, Agnès Martin (IGF, CNRS, Montpellier)