Receptor-specific noradrenergic modulation of oscillatory dynamics during non-rapid eye movement sleep in adult male rats

Cortical slow oscillations (SO, ∼1 Hz), which are hallmarks of non-rapid eye movement (NREM) sleep, temporally organize thalamocortical spindles (10-16 Hz) and hippocampal ripples (∼150 Hz), thereby promoting coordinated activity within the thalamocortical-hippocampal (TCH) network. Although markedly reduced during NREM sleep, the firing of noradrenergic neurons and norepinephrine (NE) release are temporally coordinated with SOs and spindles. We assessed the acute impact of pharmacologically targeting adrenergic receptors (ARs) on the oscillatory dynamics during NREM sleep. We recorded local field potentials from the parietal cortex and the dorsal hippocampus in freely behaving adult male rats. To examine receptor-specific effects, we injected intraperitoneally prazosin (α1-AR antagonist, 0.5 mg/kg), propranolol (β-AR antagonist, 10 mg/kg), or clonidine (α2-AR agonist, 0.05 mg/kg). Adrenergic treatment produced state- and receptor-specific alterations of sleep oscillations and affected their cross-frequency and cross-regional coupling. The most pronounced effects were observed after α2-AR activation and combined blockade of α1-and β-ARs. Namely, these treatments suppressed SOs and ripples while promoting sleep spindles; blockage of β-ARs mainly affected the SO rate, and α1-antagonist alone had no effect. Clonidine and the synergistic action of propranolol and prazosin weakened the hippocampal-cortical coupling (ripple/spindle and ripple/SO, respectively); clonidine also modulated the grouping of sleep spindles around SOs. Our findings revealed the state- and receptor-specific noradrenergic modulation of the oscillatory dynamics within the TCH network during NREM sleep. These alterations may have functional implications for sleep quality, homeostatic regulation, and sleep-dependent cognitive processes, and should be considered when using noradrenergic medication.