Team "Physiopathology of Motivation" *

Manager : Sébastien CARNICELLA

The major aim of our group is to uncover the physiopathological mechanisms underlying the development of neuropsychiatric symptoms in neurological disorders such as Parkinson’s disease (PD).

Keywords

Dopamine, Parkinson’s disease, deep brain stimulation, psychiatry, addictions, animal behavior, translational

Themes of research

Beyond the cardinal motor features of the disease, PD is indeed associated with a plethora of behavioral complications ranging from apathy (defined as a loss of motivation), anhedonia, depression and anxiety to an heterogeneous group of impulsive-compulsive behaviors (including pathological gambling, hypersexuality, …) that resembles addiction in terms of phenomenology and putative psychobiological mechanisms.

This cluster of symptoms, which was largely neglected in the past, severely impairs patients’ quality of life and is now recognized as a major contributor to morbidity. However, their underlying neurobiological and cellular mechanisms remain unclear, as well as the influence on these symptoms of the gold-standard pharmacological and neurosurgical treatments of the disease, namely dopamine replacement therapies (DRTs) and deep brain stimulation of the subthalamic nucleus (STN-DBS).

In a multidisciplinary and translational strategy, we address these questions through two main research projects:

  • Pathophysiology of apathy, depression and impulsive-compulsive behaviors in PD: investigating with a rodent model of non-motor symptoms of PD developed in the laboratory and experimental deep brain stimulation the implication of nigrostriatal dopamine and corticostriatal circuits dysfunctions in abnormal motivational and impulsive behaviors. Evaluating the therapeutic and side effects of DRTs on such behaviors in rats and humans.
  • Identification of transcriptomic and metabolomic markers of PD-related neuropsychiatric symptoms: psychiatric and neurodegenerative disorders are accompanied with profound modifications of the expression of microRNAs (small non-coding RNA sequences that powerfully regulate the translation of mRNAs) and metabolites. In a collaborative and translational project with Barbier’s team, the clinical transcriptomic facility and the Movement Disorder Unit of the Grenoble University Hospital, analyzing microRNAs and metabolites levels in in specific brain regions (rats) and blood samples (rats and patients) to identify specific markers of apathy and impulsive-compulsive behaviors, in order to develop innovative predictive medical tools and therapeutic approaches.

 

Techniques used :

 

  • Animal behavior: evaluation of mood-related, Pavlovian, operant and motor behaviors.
  • Experimental deep brain stimulation: implantable microstimulators for chronic and long-term stimulation in freely-moving rats.
  • Histology and neuroanatomy: immunohistochemistry, autoradiography, immunofluorescence, optical microscopy.
  • Neurochemistry and neuropharmacology: microdialysis in vivo, HPLC (catecholamines), stereotaxic surgery.

Partners :  

Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks . Magnard R, Fouyssac M, Vachez YM, Cheng Y, Dufourd T, Carcenac C, Boulet S , Janak PH, Savasta M, Belin D and Carnicella S (2024) Translational Psychiatry.

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use . Goutaudier R, Joly F, Mallet D, Bartolomucci M, Guicherd D, Carcenac C , Vossier F, Dufourd T, Boulet S,Deransart C, Chovelon B, Carnicella S  (2023). Molecular Psychiatry. Jan;28(1):463-474.

Re-routing Metabolism by the Mitochondrial Pyruvate Carrier Inhibitor MSDC-0160 Attenuates Neurodegeneration in a Rat Model of Parkinson's Disease.  Mallet D, Goutaudier R ,Barbier EL, Carnicella S, Colca JR, Fauvelle F, Boulet S (2022) Molecular Neurobiology Oct;59(10):6170-6182

Dopamine D3 Receptors: A Potential Target to Treat Motivational Deficits in Parkinson's Disease . Favier M, Carcenac C, Savasta M, Carnicella S (2022) Current Topics in Behavioral Neurosciences. 60:109-132

A metabolic biomarker predicts Parkinson's disease at the early stages in patients and animal models. Mallet D, Dufourd T, Decourt M, Carcenac C, Bossù P,Verlin L, Fernagut PO, Benoit-Marand M, Spalletta G, Barbier EL,Carnicella S , Sgambato V , Fauvelle F  , Boulet S (2022) Journal of Clinical Investigation 15;132(4):e146400

Ventral arkypallidal neurons modulate firing to promote reward consumption . Vachez YM, Tooley J, Abiraman K, Matikainen-Ankney B, Casey E, Earnest T, Silberberg H, Godynyuk E, Uddin O, Marconi L, Le Pichon C and Creed MC. (2021). Nature Neuroscience. Mar;24(3):379-390.

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats. Goutaudier R, Coizet V, Carcenac C, Carnicella S (2020) Plos One Sep 18;15(9):e0238156.

Subthalamic Nucleus Stimulation Impairs Motivation: Implication for Apathy in Parkinson's Disease . Vachez Y, Carcenac C, Magnard R, Kerkerian-Le Goff L, Salin P, Savasta M, Carnicella S, Boulet S (2020) Mov Disord Apr;35(4):616-628.

GPCR and Alcohol-Related Behaviors in Genetically Modified Mice. Neasta J, Darcq E, Jeanblanc J, Carnicella S, Ben Hamida S. (2020) Neurotherapeutics. Jan;17(1):17-42

DREADDs: The Power of the Lock, the Weakness of the Key. Favoring the Pursuit of Specific Conditions Rather than Specific Ligands . Goutaudier R, Coizet V, Carcenac C, Carnicella S. (2019) eNeuro. Oct 14;6(5):ENEURO.0171-19.2019

Nigrostriatal Dopaminergic Denervation Does Not Promote Impulsive Choice in the Rat: Implication for Impulse Control Disorders in Parkinson's Disease . Magnard R, Vachez Y, Carcenac C, Boulet S, Houeto JL, Savasta M, Belin D, Carnicella S. (2018) Front Behav Neurosci. Dec 13;12:312.

Reversing dopaminergic sensitization . Castrioto A, Carnicella S, Fraix V, Chabardes S, Moro E, Krack P. (2017) Mov Disord. Dec;32(12):1679-1683

Motivation and apathy in Parkinson's disease: implication of dopaminergic D3 receptors . Favier M, Carcenac C, Savasta M, Carnicella S. (2017) Med Sci (Paris). Oct;33(10):822-824.

Psychostimulant effect of dopaminergic treatment and addictions in Parkinson's disease . Delpont B, Lhommée E, Klinger H, Schmitt E, Bichon A, Fraix V, Castrioto A, Quesada JL, Pélissier P, Kistner A, Carnicella S, Lüscher C, Broussolle E, Pollak P, Thobois S, Krack P (2017). Mov Disord. Nov;32(11):1566-1573

Implication of dorsostriatal D3 receptors in motivational processes: a potential target for neuropsychiatric symptoms in Parkinson's disease . Favier M, Carcenac C, Drui G, Vachez Y, Boulet S, Savasta M, Carnicella S. (2017) Sci Rep. Jan 30;7:41589

Trait Impulsivity and Anhedonia: Two Gateways for the Development of Impulse Control Disorders in Parkinson's Disease? . Houeto JL, Magnard R, Dalley JW, Belin D, Carnicella S. (2016) Front Psychiatry May 30;7:91

Emotional manifestations of PD: Neurobiological basis . Castrioto A, Thobois S, Carnicella S, Maillet A, Krack P (2016) Mov Disord Aug;31(8):1103-13

Apathy and Impulse Control Disorders: Yin & Yang of Dopamine Dependent Behaviors . Sierra M, Carnicella S, Strafella AP, Bichon A, Lhommée E, Castrioto A, Chabardes S, Thobois S, Krack P. (2015) J Parkinsons Dis 5(3):625-36

Subthalamic deep brain stimulation differently alters striatal dopaminergic receptor levels in rats . Carcenac C, Favier M, Vachez Y, Lacombe E, Carnicella S, Savasta M, Boulet S (2015) Mov Disord. Nov;30(13):1739-49

  •     Sabrina BOULET
  •     M. Sebastien CARNICELLA
  •     Maurice DEMATTEIS
  •     M. Colin DERANSART
  •     Fanny JOLY
  •     Vanille MILLASSEAU
  •     Margaret PRAS
  •     Lucinda SPEERS
  •     Yvan VACHEZ
  •     Yury VELHO MARTINS LAGES
  •     Mylène WILT

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