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-θ frequencies (1–7 Hz), and mount a robust, narrow-bandwidth, high-frequency θ rhythm (~8.5 Hz). A fast-γ (55–80 Hz) response, whose dynamics closely parallelled θ, also diminished, while β/slow-γ activity (15–45 Hz) increased. Furthermore, EW-associated locomotion was lower. Surprisingly, nestbuilding-associated wakefulness, inversely, featured enhanced θ and fast-γ 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-δ waves (0.75–2.25 Hz), suggesting that HCRT-to-NA signalling regulates the slow-δ rebound characterizing sleep after stress-associated arousal.
Highlights
Electrical brain waves can be used to define behavioral domains called vigilance states
To examine whether NALC cell-specific Hcrtr[1] gene inactivation at an adult stage causes a more severe phenotype than the one we report in CKO mice, a Th-driven Cre-expressing viral vector may be injected in the locus coeruleus (LC) of adult Hcrtr1flox/flox mice
We focus on fear, and reward(VTA) related structures, which receive both direct projections from HCRT and NA cell groups[101,102,103]
Summary
Electrical brain waves (or oscillations) can be used to define behavioral domains called vigilance (or behavioral) states. State-specific oscillations emerge from dynamic neuronal activity in interconnected cortical and subcortical microcircuits responding to external stimuli and a multitude of internal indices of the animal’s circadian, homeostatic, and motivational state Many of these signals are implemented by a set of key neuromodulators (acetylcholine, histamine, noradrenaline [NA], serotonin, dopamine, and hypocretin-1 and 2/orexin-A and B [HCRT]), produced in a set of subcortical arousal ‘hubs’, that are active when the animal is awake, but mostly silent in www.nature.com/scientificreports/. All these neuromodulator-producing neurons regulate waking states and attention, they widely differ in their neuroanatomical and electrophysiological properties, the contexts that activate them, and the downstream effectors they act upon, and their behavioral translation[7,8]. In situ hybridization reveals that the LC, as well as the brainstem’s six other NA cell groups, express Hcrtr[1], in relative absence of Hcrtr[2] expression[20,25,26]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
