Noradrenergic Modulation Of Cortical And Hippocampal Activity During Natural Sleep In Rats

The activity of noradrenergic (NA) neurons of the brain stem neuromodulatory nucleus Locus Coeruleus (LC) fluctuates across sleep/wake cycle; LC firing being highest during awake, substantially decreased during slow-wave sleep (SWS) and essentially absent during REM. Due to reduced level of NA during sleep, little attention has been given to the NA modulation of sleep-associated brain rhythms. We recently reported that LC firing is tightly related to the cortical slow oscillations in naturally sleeping rats. Psychiatric disorders, which are characterized by enhanced activity of NA system, are often accompanied by sleep disturbances. Neurophysiological mechanisms underlying this phenomenon remain unknown. The present study aimed to characterize changes in cortical and hippocampal activity produced by increased tonic firing of LC during sleep. Extracellular electrophysiological recordings in cortex and hippocampus were made using linear electrode arrays. The LC activity was modulated by electrical microstimulation via chronically implanted electrode in LC. Trains of pulses (100-500ms, 20-100Hz) were delivered to the LC unilaterally at the onset of SWS every 10s continuously for 10 min. None of the stimulation parameters resulted in behavioral waking up or any visible discomfort of the animal. The LC stimulation with relatively long (50Hz, 500ms) trains of pulses or high-frequency LC stimulation with relatively short trains (100Hz, 100ms) immediately reduced slow wave (1-4Hz) and sigma (12-15Hz) activity in cortex. It resulted in complete elimination of the sleep spindles, characteristic for normal SWS. The slow activity in hippocampus was also strongly affected by LC stimulation. The effect of a single train lasted for up to 6 sec until recovery of neural activity to the baseline level. Our results demonstrate that a mildly elevated LC activity affects a microstructure of the sleep pattern, as indicated by electrophysiological correlates of sleep, without influencing the sleep/awake cycle or inducing behavioral arousal