Neuronal signaling and gene regulation

We aim at pinpointing cellular and molecular events shaping long-lasting neuronal and behavioral adaptations encountered in preclinical models of psychiatric disorders (addiction and depression) and Huntington’s disease (HD).

We intend to identify alterations in enzymatic and metabolic pathways and design tools to alleviate pathological adaptations. We primarily analyze these mechanisms within the striatum, a key target structure of addictive substances and the most vulnerable brain region to neurodegeneration in HD. Using a combination of multidisciplinary approaches ranging from a molecular standpoint, to imaging and behavioral studies in rodents, our overall goals are:

·To understand how signal transduction within basal ganglia can govern neuronal adaptations and long-term behavioral changes.

·To study how these pathways, by regulating epigenetic and genetic responses, can control persistent neuronal and behavioral alterations induced by drugs of abuse or striatal dysfunction in HD.

·To identify, from the plasma membrane to the nucleus, therapeutic targets and overcome dysfunction encountered in diseases such as psychiatric disorders and HD.


Drug addiction is characterized by compulsive patterns of drug-seeking and drug-taking behavior in spite of detrimental consequences and a high rate of relapse after abstinence. A hallmark of addictive drugs is their ability to increase dopamine concentration in discrete brain regions, which persistently shapes excitatory glutamate transmission within the reward circuit, thereby hijacking natural reward processing. This imbalance between dopamine and glutamate transmissions is key for drug-evoked activation of signaling pathways and downstream epigenetic and genetic responses in specific neuronal populations, which are mandatory for the persistence of addictive behavior. Drugs of abuse increase dopamine in the striatum, where it triggers molecular alterations within striatal projection neurons (SPN), which fall into two subpopulations depending on the dopamine receptor subtype they express (D1R or D2R). SPN receive converging glutamate inputs from the cortex, thalamus, amygdala and hippocampus that encode contextual and emotional information together DA signals, which modulate the efficacy of glutamate synapses. Over the past years, we have been studying the molecular and cellular basis by which cocaine alters the integration of dopamine/glutamate signals to persistently usurp the neural circuitry of reward.

By contrast, HD is a genetic disease characterized by abnormal expansion of poly CAG repeats in the gene encoding Huntingtin characterized by a progressive loss of plasticity and neurodegenerescence of SPN. Multiple attempts have been made over the past few years in order to unravel the cellular and molecular mechanisms that underlie this neuronal vulnerability in HD. Among these, altered gene expression, mitochondria dysfunctions, cellular metabolism and dopamine/glutamate signaling have been incriminated. We participated to these studies notably by showing that alterations of cholesterol metabolism play a key role in cellular and behavioral dysfunctions encountered in HD.


·From mice to humans, we showed that psychostimulants increase DA receptors (DAR) heteromerization (i.e interaction) with glutamate NMDA receptors (NMDAR) in NAc SPNs. Disruption of D1R-NMDAR or D2R-NMDAR interaction alters the development and maintenance of cocaine-induced adaptations, respectively, while sparing natural reward processing (Andrianarivelo et al. (2021) Science Advances)

·Cocaine-evoked D1R-NMDAR heteromerization drives nuclear calcium transients in D1R-D1R-SPN, which play key roles in cocaine-evoked rewarding effects and transcriptional regulations of plasticity-related genes (Saint-Jour et al. in prep), including npas4 (Lissek et al. (2021) EMBO Rep).

·We identified the transcription factor Elk-1, downstream the MAPkinase/ERK signaling pathway, as a biomarker of depression state in humans and mice, and demonstrated that inhibiting Elk-1 phosphorylation alleviates symptoms of depression and anhedonia in mice (Apazoglou et al., (2018) Nature Medicine)

·We highlighted the cell-type-specific role of epigenetic responses in cocaine-adaptive behavior through the modulation of multiple microRNA, including miRNA1, which overexpression in D1R-SPN of the dorsal striatum modulates cocaine-seeking behavior (Forget et al. (2021) Mol. Psychiatry).

·The development of a 3D-analysis of dendritic spinesand synaptic contacts revealed that cocaine-evoked activation of the MAPK/ERK induces an increase in dendritic spines in D1R-SPN leading to an enhancement glutamate synapses and dopaminergic connectivity of NAc (Dos Santos et al. (2017) Biol. Psychiatry; Dos Santos et al. (2018) Brain Struct. Funct ).

·We highlighted that targeting cholesterol metabolism is a promising HD-modifier strategy in HD. We found that restoring CYP46A1 expression, which converts cholesterol into 24S-OH cholesterol, prevents neuronal dysfunctions, alleviates motor behavior phenotype and restores cholesterol homeostasis. (Boussicault et al. (2016) Brain; Boussicault et al. (2018) Biochimie; Kacher et al. (2019) Brain).

Future direction

Based on the literature and our previous work, the main objectives of the team are to:

·Study the role of DAR-NMDAR heteromers in opiate-induced adaptations, evaluate whether these heteromers are common substrates for addiction and depression and identify new inhibitors of DAR-NMDAR heteromerization (Funds: ANR DROPSTRESS and IReSP AAP-addiction).

·To study the role of Elk-1 inhibitors in psychiatric disorders associated with anhedonia, and decipher their cellular and molecular properties in neuronal circuit rewiring.

·Characterize the molecular determinants of the 3D organization of SPN post-synapse, glutamate and dopamine boutons and its remodeling by cocaine(Fund: ANR DopamineHub)

·Determine regional and cellular specificity of cocaine-induced miRNA expression in preclinical models of addiction and human brain samples from addict patients along with their blood expression levels at different stages of addiction, as biomarkers of susceptibility to addiction (Fund: FHU NOR-SUD).

·Target cholesterol metabolism for efficient striatal protection in HD. Strategies to best target cholesterol metabolism in HD remain to be established, we aim at dissecting cell-type-specific mechanisms (MSN/astrocytes) underlying CYP46A1-mediated regulation of brain cholesterol metabolism and neuroprotection in HD. We will consider small molecule development in HD therapy using new modulators of cholesterol metabolism such as Liver X receptor (LXR) beta ligands. The impact of restoring striatal CYP46A1 levels and LXR beta ligands will also be analyzed on psychiatric symptoms encountered in HD, including depression and addiction (Funds: AFM and ANR Stero-HD).


  • Hilmar BADING - Interdisciplinary Center for Neurosciences, University of Heidelberg, Germany
  • Jonathan A JAVITCH - Department of Psychiatry, Columbia University New York, USA
  • Naguib MECHAWAR - Department of Psychiatry, McGill University, Douglas-Bell Canada Brain bank, Canada
  • Bruno GIROS – Department of Psychiatry, Douglas Hospital, McGill University, Canada/ Integrative Neuroscience and Cognition Research Center, Paris Descartes University, France
  • Ernest FRAENKEL - Department of Biological Engineering, MIT, Boston, USA
  • Ferah YILDIRIM - Department of experimental Neurobiology, University of Berlin, Germany
  • Maura MARINOZZI – Department of Pharmaceutical Sciences, Perugia University, Italy
  • Rafael MALDONADO - Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain
  • Pierre TRIFILIEFF - INRAE, Nutrineuro, Bordeaux University, France
  • Jacques BARIK – Institute of Molecular and Cellular Pharmacology, Côte d’Azur University, France
  • Etienne HERZOG & David PERRAIS – Interdisciplinary Institute for Neuroscience, Bordeaux University, France
  • Nathalie THIRIET & Marcello SOLINAS – Laboratory of Experimental and Clinical Neuroscience, Poitiers University, France.
  • Jean-Antoine GIRAULT - Institut du Fer à Moulin, France
  • Laurent VENANCE & Nicolas GERVASI - Collège de France, France
  • Franck BELLIVIER &Florence VORSPAN - F. Widal hospital, Department of Adult Psychiatry, France
  • Guiseppe GANGAROSSA – Fonctional and Adaptive Biology, Paris-Cité University, France.
  • Nathalie CARTIER – ICM, Paris, France
  • Alexis BEMELMANS - CEA, MirCen laboratory; Paris-Saclay University, France
  • Frederic SAUDOU – Grenoble: Institute for Neurosciences; Grenoble University, France.
  • Marie-Claude POTIER - ICM, Paris, France
  • Delphine CHARVIN – formerly Prexton therapeutics, Suisse
  • Anne ROUMIER – Institut du Fer à Moulin, Paris, France
  • Antonin LAMAZIERE – Sorbonne University, Faculté de Médecine, AP-HP, Saint Antoine Hospital, France
  • Carole ESCARTIN - CEA, MirCen laboratory; Paris-Saclay University, France
  • Karine MERIENNE – Laboratory of Adaptive and Cognitive Neurosciences (LNCA), Strasbourg University, France
  • Charbel MASSAAD – Paris-Cité University.
  • Nicolas PIETRANCOSTA – Laboratory of Biomolecules and Neuroscience Paris-Seine, Sorbonne University, France.
  • IBPS collaborations: Emmanuel BROUILLET &Christian NERI (Department of Biological Adaptations and Aging); Thomas BOUDIER, Jean-François GILLES, Thomas BOUDIER (currently CENTURI facility, Marseille), Susanne BOLTE (IBPS Imaging Facility); Christophe PIESSE, Tahar BOUCEBA (Protein Engineering Facility).
  • NPS collaborations: François TRONCHE & Sébastien PARNAUDEAU (Team Gene Expression and Adaptive Behavior); Vincent VIALOU (Team: Neurobiology of Psychiatric disorders); Isabelle DUSART (Team: Development and Plasticity of Neuronal Networks); Jean-Michel PEYRIN (Team: Axonal Growth and Regeneration); Régine HEPP & Ludovic TRICOIRE (Team: Synaptic Networks and Neuroenergetics).

About the Team

·In the newspaper “Les Echos”:

·In the radio program “ La méthode scientifique” on France Culture radio : In the newspaper “Les Echos”:

·In the radio program “ La méthode scientifique” on France Culture radio :


·In the highlights of the French Neuroscience Society:

·Brain week inaugural conference:

·In the radio program “La méthode scientifique on France Culture radio :

·Guess of France 24 radio

·In the newspaper “Les Echos”

·In the newspaper l’Express :

·In the newspaper Sciences et Avenir

·In the highlights of the French Neuroscience Society 2019 : (

·In the newsletter of INSB CNRS : (