title: Cortical areas involved in behavioral expression of external pallidum dysfunctions: A PET imaging study in non-human primates.
abstract: The external pallidum (GPe) is a component of the indirect pathway centrally placed in the basal ganglia. Studies already demonstrated that the pharmacological disinhibition of the sensorimotor, associative, and limbic GPe produced dyskinesia, hyperactivity, and compulsive behaviors, respectively. The aim of this study was to investigate the cortical regions altered by the disinhibition of each GPe functional territory. Thus, 5 macaques were injected with bicuculline in sensorimotor, associative, and limbic sites of the GPe producing dyskinesia, hyperactivity, and compulsive behaviors, and underwent in vivo positron tomography with18F-2-fluoro-2-deoxy-D-glucose to identify cortical dysfunctions related to GPe disinhibition. Blood cortisol levels were also quantified as a biomarker of anxiety for each condition. Our results showed that pallidal bicuculline injections in anesthetized animals reproducibly modified the activity of specific ipsilateral and contralateral cortical areas depending on the pallidal territory targeted. Bicuculline injections in the limbic GPe led to increased ipsilateral activations in limbic cortical regions (anterior insula, amygdala, and hippocampus). Injections in the associative vs. sensorimotor GPe increased the activity in the ipsilateral midcingulate vs. somatosensory and parietal cortices. Moreover, bicuculline injections increased blood cortisol levels only in animals injected in their limbic GPe. These are the first functional results supporting the model of opened cortico-striato-thalamo-cortical loops where modifications in a functional pallidal territory can impact cortical activities of the same functional territory but also cortical activities of other functional territories. This highlights the importance of the GPe as a crucial node in the top-down control of the cortico-striato-thalamo-cortical circuits from the frontal cortex to influence the perception, attention, and emotional processes at downstream (or non-frontal) cortical levels. Finally, we showed the implication of the ventral pallidum with the amygdala and the insular cortex in a circuit related to aversive processing that should be crucial for the production of anxious disorders.
authors.affiliation: UMR INSERM U930, Université François Rabelais de Tours, Tours, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Galineau
authors.affiliation: AP-HP, Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, UPMC Paris 06, CNRS UMR 7371, INSERM U1146, 75013 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Kas
authors.affiliation: Department of Neurology, Pitié-Salpêtrière Hospital, Sorbonne University, UMPC Paris 06, ICM, 75013 Paris, France.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Worbe
authors.affiliation: MIRCEN, CEA UMR 9199, 18 route du Panorama, 92260 Fontenay-aux-Roses, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Chaigneau
authors.affiliation: MIRCEN, CEA UMR 9199, 18 route du Panorama, 92260 Fontenay-aux-Roses, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Herard
authors.affiliation: MIRCEN, CEA UMR 9199, 18 route du Panorama, 92260 Fontenay-aux-Roses, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Guillermier
authors.affiliation: MIRCEN, CEA UMR 9199, 18 route du Panorama, 92260 Fontenay-aux-Roses, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Delzescaux
authors.affiliation: UPMC Université Paris 6, UMR-S975, CRICM-Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Féger
authors.affiliation: MIRCEN, CEA UMR 9199, 18 route du Panorama, 92260 Fontenay-aux-Roses, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.affiliation: CNRS, UMR 5229, Université de Lyon 1, Centre de Neurosciences Cognitives, 67 Boulevard Pinel, Cedex, 69675 Bron, France. Electronic address: leon.tremblay@isc.cnrs.fr.
authors.forename: Léon
authors.initials: L
authors.lastname: Tremblay
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001640:Bicuculline / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003192:Compulsive Behavior / Q000378:metabolism; D020820:Dyskinesias / Q000378:metabolism; D019788:Fluorodeoxyglucose F18; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism*; D006948:Hyperkinesis / Q000378:metabolism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D049268:Positron-Emission Tomography
chemical_list: D058787:GABA-A Receptor Antagonists; D019788:Fluorodeoxyglucose F18; D001640:Bicuculline
keywords: Aversive processing; Cortex; External globus pallidus; Opened cortico-striato-thalamo-cortical loops; PET imaging