Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control.
Details
Serval ID
serval:BIB_0015D8648854
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control.
Journal
Molecular psychiatry
ISSN
1476-5578 (Electronic)
ISSN-L
1359-4184
Publication state
Published
Issued date
02/2024
Peer-reviewed
Oui
Volume
29
Number
2
Pages
327-341
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
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.
Keywords
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
Yes
Create date
21/12/2023 15:51
Last modification date
09/08/2024 14:55