Sleep-wake states and cortical synchronization control by pregnenolone sulfate into the pedunculopontine nucleus

Cholinergic neurons of the pedunculopontine tegmentum nucleus (PPT) are crucial for initiation and maintenance of electroencephalographic (EEG) desynchronization states like paradoxical sleep and wakefulness. These neurons are regulated by classical neurotransmitter systems from the pontomesencephalic reticular formation and basal ganglia. In addition to this regulation, PPT neuron activity could be modulated by endogenous neurosteroids and particularly by pregnenolone sulfate (PREG-S) because synthesis enzymes of this neurosteroid are present in this area and peripheral administrations of PREG-S affect sleep-wakefulness states. To test this hypothesis, we studied the effects of different doses of PREG-S infusion into the PPT on sleep-wakefulness states in rats. Our results show dose-dependent effects of PREG-S on sleep-wakefulness states. Low concentration of PREG-S (5 ng) increased the amount of paradoxical sleep without any modification of slow wave sleep and wakefulness. High level of PREG-S (10 and 20 ng) increased paradoxical sleep and slow wave sleep together with an increase of delta power and a decrease of theta power during wakefulness. Dependent on the doses used, PREG-S thus can promote paradoxical sleep alone or the global propensity to fall asleep, impairing the quality of wakefulness. These results unveil a new regulation pathway for PPT neurons and strengthen the role of PREG-S in sleep-wakefulness regulation.