Bidirectional and context-dependent changes in theta and gamma oscillatory brain activity in noradrenergic cell-specific Hypocretin/Orexin receptor 1-KO mice

Abstract

Noradrenaline (NA) and hypocretins/orexins (HCRT), and their receptors, dynamically modulate the circuits that configure behavioral states, and their associated oscillatory activities. Salient stimuli activate spiking of locus coeruleus noradrenergic (NALC) cells, inducing NA release and brain-wide noradrenergic signalling, thus resetting network activity, and mediating an orienting response. Hypothalamic HCRT neurons provide one of the densest input to NALC cells. To functionally address the HCRT-to-NA connection, we selectively disrupted the Hcrtr1 gene in NA neurons, and analyzed resulting (Hcrtr1Dbh-CKO) mice, and their control littermates electrocortical response in several contexts of enhanced arousal. Under enforced wakefulness (EW), or after cage change (CC), Hcrtr1Dbh-CKO mice exhibited a weakened ability to lower infra-{theta} frequencies (1-7 Hz), and mount a robust, narrow-bandwidth, high-frequency {theta} rhythm (~8.5 Hz). A fast-{gamma} (55-80 Hz) response, whose dynamics closely parallelled {theta}, also diminished, while {beta}/slow-{gamma} activity (15-45 Hz) increased. Furthermore, EW-associated locomotion was lower. Surprisingly, nestbuilding-associated wakefulness, inversely, featured enhanced {theta} and fast-{gamma} activities. Thus HCRT-to-NA signalling may fine-tune arousal, up in alarming conditions, and down during self-motivated, goal-driven behaviors. Lastly, slow-wave-sleep following EW and CC, but not nestbuilding, was severely deficient in slow-{delta} waves (0.75-2.25 Hz), suggesting that HCRT-to-NA signalling regulates the slow-{delta} rebound characterizing sleep after stress-associated arousal.