Orexin System Dynamics in Neurophysiological Processes

The orexin system, comprising the neuropeptides orexin A and B (hypocretins) and their receptors (OX1R and OX2R), is centred in the lateral hypothalamus and exerts widespread influence across the central nervous system. Orexin neurons integrate metabolic, environmental and emotional cues to regulate arousal, sleep–wake transitions, feeding behaviour and reward processing. Dynamic firing patterns of these neurons encode moment-to-moment changes in physiological state, orchestrating transitions between wakefulness and sleep, modulating autonomic outputs and shaping cognitive and motivational processes. Cross-talk with monoaminergic and cholinergic systems underpins the maintenance of sustained attention and the consolidation of wakeful states, while interactions with GABAergic and dopaminergic circuits mediate feeding and reward-related adaptations. Disruption of orexin signalling is implicated in narcolepsy, insomnia, metabolic disorders and epilepsy, highlighting its therapeutic potential through pharmacological modulation or targeted neuromodulation.

Research from Nature Portfolio

Recent studies have demonstrated that the activity of orexin neurons closely tracks rapid fluctuations in arousal and reward states, as evidenced by correlative and causal links to pupil dilation metrics in awake mammals. These findings reveal that individual orexin cells multiplex information on alertness and motivational valence, supporting a unified framework for momentary state control. In parallel, temporally precise optogenetic silencing of lateral hypothalamic orexin populations in rodent models of acute epilepsy has uncovered a pre-seizure window during which orexin activity predicts and drives seizure onset. Targeted deep brain stimulation during this window attenuates orexin cell firing and yields significant seizure protection, establishing a proof of concept for seizure intervention via modulation of orexin dynamics.

Orexin System Dynamics in Neurophysiological Processes publication trend

The graph below shows the total number of articles in orexin system dynamics in neurophysiological processes across all publications each year (not limited to Nature Index journals).

Technical terms

Orexin (hypocretin): Neuropeptides synthesised by lateral hypothalamic neurons that regulate arousal, feeding, reward and energy homeostasis.

OX1R and OX2R: G-protein-coupled receptors for orexin A and B, mediating their physiological effects.

Optogenetic silencing: Technique using light-activated proteins to inhibit the activity of genetically defined neurons with temporal precision.

Deep brain stimulation (DBS): Therapeutic approach involving electrical stimulation of specific brain regions to modulate neural activity.

Feedforward inhibition: Circuit motif in which excitatory inputs activate inhibitory interneurons that suppress downstream targets.

Theta–gamma coupling: Cross-frequency interaction between theta (4–8 Hz) and gamma (30–100 Hz) brain rhythms associated with cognitive processing and arousal.

References

1. Control and coding of pupil size by hypothalamic orexin neurons. Nature Neuroscience (2023).
2. Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy. Nature Communications (2024).
3. Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control. Molecular Psychiatry (2023).
4. The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases. Frontiers in Molecular Neuroscience (2018).
5. Inhibitory Interplay between Orexin Neurons and Eating. Current Biology (2016).