Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control.
Détails
Télécharger: 38123729_BIB_0015D8648854.pdf (4524.80 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_0015D8648854
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control.
Périodique
Molecular psychiatry
ISSN
1476-5578 (Electronic)
ISSN-L
1359-4184
Statut éditorial
Publié
Date de publication
02/2024
Peer-reviewed
Oui
Volume
29
Numéro
2
Pages
327-341
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are both key effectors of salience processing, reward and stress-related behaviors and motivational states, yet their respective roles and interactions are poorly delineated. We inactivated HCRT-to-DA connectivity by genetic disruption of Hypocretin receptor-1 (Hcrtr1), Hypocretin receptor-2 (Hcrtr2), or both receptors (Hcrtr1&2) in DA neurons and analyzed the consequences on vigilance states, brain oscillations and cognitive performance in freely behaving mice. Unexpectedly, loss of Hcrtr2, but not Hcrtr1 or Hcrtr1&2, induced a dramatic increase in theta (7-11 Hz) electroencephalographic (EEG) activity in both wakefulness and rapid-eye-movement sleep (REMS). DA <sup>Hcrtr2</sup> -deficient mice spent more time in an active (or theta activity-enriched) substate of wakefulness, and exhibited prolonged REMS. Additionally, both wake and REMS displayed enhanced theta-gamma phase-amplitude coupling. The baseline waking EEG of DA <sup>Hcrtr2</sup> -deficient mice exhibited diminished infra-theta, but increased theta power, two hallmarks of EEG hyperarousal, that were however uncoupled from locomotor activity. Upon exposure to novel, either rewarding or stress-inducing environments, DA <sup>Hcrtr2</sup> -deficient mice featured more pronounced waking theta and fast-gamma (52-80 Hz) EEG activity surges compared to littermate controls, further suggesting increased alertness. Cognitive performance was evaluated in an operant conditioning paradigm, which revealed that DA <sup>Hcrtr2</sup> -ablated mice manifest faster task acquisition and higher choice accuracy under increasingly demanding task contingencies. However, the mice concurrently displayed maladaptive patterns of reward-seeking, with behavioral indices of enhanced impulsivity and compulsivity. None of the EEG changes observed in DA <sup>Hcrtr2</sup> -deficient mice were seen in DA <sup>Hcrtr1</sup> -ablated mice, which tended to show opposite EEG phenotypes. Our findings establish a clear genetically-defined link between monosynaptic HCRT-to-DA neurotransmission and theta oscillations, with a differential and novel role of HCRTR2 in theta-gamma cross-frequency coupling, attentional processes, and executive functions, relevant to disorders including narcolepsy, attention-deficit/hyperactivity disorder, and Parkinson's disease.
Mots-clé
Animals, Mice, Dopaminergic Neurons/physiology, Dopaminergic Neurons/metabolism, Cognition/physiology, Orexin Receptors/metabolism, Orexin Receptors/physiology, Wakefulness/physiology, Male, Electroencephalography/methods, Arousal/physiology, Mice, Inbred C57BL, Mice, Knockout, Orexins/metabolism, Orexins/physiology, Sleep, REM/physiology, Signal Transduction/physiology, Theta Rhythm/physiology, Reward, Dopamine/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
21/12/2023 15:51
Dernière modification de la notice
09/08/2024 14:55