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Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control

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Název: Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control
Autoři: Mojtaba Bandarabadi, Sha Li, Lea Aeschlimann, Giulia Colombo, Stamatina Tzanoulinou, Mehdi Tafti, Andrea Becchetti, Benjamin Boutrel, Anne Vassalli
Zdroj: Mol Psychiatry
Molecular psychiatry, vol. 29, no. 2, pp. 327-341
Informace o vydavateli: Springer Science and Business Media LLC, 2023.
Rok vydání: 2023
Témata: Male, Mice, Knockout, Orexins, Animals, Mice, Dopaminergic Neurons/physiology, Dopaminergic Neurons/metabolism, Cognition/physiology, Orexin Receptors/metabolism, Orexin Receptors/physiology, Wakefulness/physiology, Electroencephalography/methods, Arousal/physiology, Mice, Inbred C57BL, Orexins/metabolism, Orexins/physiology, Sleep, REM/physiology, Signal Transduction/physiology, Theta Rhythm/physiology, Reward, Dopamine/metabolism, Dopaminergic Neurons, Dopamine, Sleep, REM, Electroencephalography, Article, 3. Good health, Cognition, Orexin Receptors, Hypocretin, orexin, dopamine, HcrtR1, HcrtR2, Wakefulness, Theta Rhythm, Arousal, Signal Transduction
Popis: 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). DAHcrtr2-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 DAHcrtr2-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, DAHcrtr2-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 DAHcrtr2-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 DAHcrtr2-deficient mice were seen in DAHcrtr1-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.
Druh dokumentu: Article
Other literature type
Popis souboru: application/pdf
Jazyk: English
ISSN: 1476-5578
1359-4184
DOI: 10.1038/s41380-023-02329-z
DOI: 10.21203/rs.3.rs-2938625/v1
Přístupová URL adresa: https://pubmed.ncbi.nlm.nih.gov/38123729
http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_0015D86488541
https://serval.unil.ch/resource/serval:BIB_0015D8648854.P001/REF.pdf
https://serval.unil.ch/notice/serval:BIB_0015D8648854
Rights: CC BY
Přístupové číslo: edsair.doi.dedup.....d624e82d1d933f143b2764cb8a70d210
Databáze: OpenAIRE
Popis
Abstrakt: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). DAHcrtr2-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 DAHcrtr2-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, DAHcrtr2-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 DAHcrtr2-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 DAHcrtr2-deficient mice were seen in DAHcrtr1-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.
ISSN:14765578
13594184
DOI:10.1038/s41380-023-02329-z