Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control-Reference-Cited by-同舟云学术

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

Published:2023-06-01 Issue: Volume: Page:
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Author:

Bandarabadi Mojtaba¹^ORCID,Li Sha¹,Aeschlimann Lea,Colombo Giulia^ORCID,Tzanoulinou Stamatina²^ORCID,Tafti Mehdi¹^ORCID,Becchetti Andrea^ORCID,Boutrel Benjamin,Vassalli Anne¹^ORCID

Affiliation:

1. University of Lausanne

2. Department of Fundamental Neuroscience, CMU, University of Geneva, Geneva, Switzerland.

Abstract

Abstract Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are two key effectors of salience processing, reward and stress-associated behavior and motivational states, yet their respective roles and interactions are poorly delineated. We inactivated HCRT-to-DA connectivity by genetic disruption of Hypocretin receptor type-1 (Hcrtr1), Hypocretin receptor type-2 (Hcrtr2), or both receptors (Hcrtr1&2) in dopamine 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, led to dramatic increases in theta (7-11 Hz) electroencephalographic (EEG) activity during both wakefulness and rapid-eye-movement (REM) sleep. Compared to controls, DAHcrtr2-deficient mice spent more time in an active (or theta activity-enriched) substate of wakefulness, as well as exhibited prolonged REM sleep. Additionally, both wake and REM sleep 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, which however were found to be uncoupled from the mice’ locomotor activity. Upon exposure to novel, either rewarding or stress-inducing environments, DAHcrtr2-deficient mice’ waking state featured more pronounced surges in theta and fast-gamma (52-80 Hz) EEG activities compared to their littermate controls, further suggesting increased alertness. Cognition was next evaluated using an operant conditioning paradigm, demonstrating that DAHcrtr2-ablated mice exhibit faster learning, and once performance was stable and attentional demands were increased, they manifested higher attentional capabilities. Concomitantly, the mice however displayed maladaptive patterns of reward-seeking, with behavioral indices of increased impulsivity as well as compulsivity. None of the EEG changes observed in DAHcrtr2-deficient mice were seen in dopaminergic Hcrtr1-ablated mice, which tended to show opposite EEG phenotypes. Our findings establish a clear, genetically-defined link between monosynaptic HCRT-to-dopaminergic neurotransmission and theta oscillations, with a differential and novel role of HCRTR2 in cross-frequency coupling, attentional processes, and executive functions, relevant to disorders including narcolepsy, attention-deficit/hyperactivity disorder, and Parkinson’s disease.

Publisher

Research Square Platform LLC

Reference157 articles.

1. ABSTRACT

2. Hypocretin/Orexin (HCRT/OX) and dopamine (DA) are two key effectors of salience processing, reward and stress-associated behavior and motivational states, yet their respective roles and interactions are poorly delineated. We inactivated HCRT-to-DA connectivity by genetic disruption of Hypocretin receptor type-1 (Hcrtr1), Hypocretin receptor type-2 (Hcrtr2), or both receptors (Hcrtr1&2) in dopamine 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, led to dramatic increases in theta (7–11 Hz) electroencephalographic (EEG) activity during both wakefulness and rapid-eye-movement (REM) sleep. Compared to controls, DAHcrtr2-deficient mice spent more time in an active (or theta activity-enriched) substate of wakefulness, as well as exhibited prolonged REM sleep. Additionally, both wake and REM sleep 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, which however were found to be uncoupled from the mice’ locomotor activity. Upon exposure to novel, either rewarding or stress-inducing environments, DAHcrtr2-deficient mice’ waking state featured more pronounced surges in theta and fast-gamma (52–80 Hz) EEG activities compared to their littermate controls, further suggesting increased alertness. Cognition was next evaluated using an operant conditioning paradigm, demonstrating that DAHcrtr2-ablated mice exhibit faster learning, and once performance was stable and attentional demands were increased, they manifested higher attentional capabilities. Concomitantly, the mice however displayed maladaptive patterns of reward-seeking, with behavioral indices of increased impulsivity as well as compulsivity. None of the EEG changes observed in DAHcrtr2-deficient mice were seen in dopaminergic Hcrtr1-ablated mice, which tended to show opposite EEG phenotypes. Our findings establish a clear, genetically-defined link between monosynaptic HCRT-to-dopaminergic neurotransmission and theta oscillations, with a differential and novel role of HCRTR2 in cross-frequency coupling, attentional processes, and executive functions, relevant to disorders including narcolepsy, attention-deficit/hyperactivity disorder, and Parkinson’s disease.

3. INTRODUCTION

4. Neuromodulators are master levers of brain circuits which shape brain states and functional output by tuning neuronal firing or synaptic strength. Hypocretin (HCRT, also known as Orexin, OX) and dopamine (DA) are both major neuromodulators of arousal and motivated states. Their interactions, however, remain ill defined. A small population of glutamatergic neurons in the lateral and dorsomedial hypothalamus synthesizes the neuropeptides HCRT-1 and HCRT-2 (OXA and OXB), and sends axonal projections to all wake-promoting monoaminergic (including dopaminergic) and cholinergic nuclei of the ascending arousal system, as well as directly innervates their targets, the neocortex, thalamus, hippocampus, amygdala, and spinal cord1. HCRT neurons thus establish a brain-wide neural network, with extraordinarily pleiotropic functions, spanning multiple physiological, behavioral, emotional, and temporal domains2,3. HCRT peptides act through two genetically independent and differentially expressed G-protein-coupled-receptors, HCRTR1 and HCRTR2. HCRTR2 binds both peptides, whereas HCRTR1 only binds HCRT-1 with high affinity. Brain level of each peptide, differential signaling via the two receptors, and how each uniquely impacts vigilance states and behavior remain elusive.

5. HCRT neurons fire maximally during active wakefulness, in line with their role in maintaining heightened arousal4, but can also show burst firing during phasic REM sleep (REMS)4, and occasional bursting during non-REMS5¸ consistent with their role in sleep-to-wake transitions6. An unexpected role of HCRT neurons in REMS was recently discovered7. Disrupting the HCRT system in mice8, dogs9, and humans10 causes narcolepsy-type-1, a disease characterized by excessive daytime sleepiness, vigilance state fragmentation, hypnagogic/hypnopompic hallucinations, and emotionally-driven sudden muscle atonia, or cataplexy11. Inactivation of the Hcrt gene, or combined loss of the two receptors, are sufficient to induce narcolepsy in mice12,13, indicating that narcolepsy stems from deficient HCRTR signaling. However, a circuit-based understanding of the unique role of each HCRTR1 or HCRTR2-expressing target population is still lacking. Among HCRT targets, DA neurons are particularly interesting because of their established prime role in regulating arousal and arousal-dependent behaviors, and apparent functional overlap with HCRT.