Circadian regulation of arousal:: Role of the noradrenergic locus coeruleus system and light exposure

Study Objectives: Noradrenergic locus coeruleus (LC) neurons regulate arousal. Previous studies have shown that noradrenergic LC neurons exhibit a circadian rhythm in impulse activity, which peaks during the active period. This is mediated by an indirect circuit projection from the suprachiasmatic nucleus (SCN) to the LC. Here we sought to evaluate the hypothesis that the LC regulates the circadian properties of the sleep-wake cycle. \ Design: Sprague-Dawley rats maintained on a light-dark (LD) schedule or in constant darkness (DD) for 3 to 4 weeks were treated with DSP-4, a neurotoxic agent specific for noradrenergic-LC projections. Vigilance states were analyzed before and 3 weeks after LC lesion. The DSP-4 lesion was verified by immunohistochemistry of noradrenergic fibers in the frontal cortex. Setting: University of Pennsylvania. Patients or Participants: N/A. Interventions: N/A. Measurements and Results: DSP-4 decreased the amplitude of the sleep-wake rhythm in LD animals by significantly decreasing wakefulness and increasing sleep during the active period. However, DSP-4 had no effect on the sleep-wake cycle of DD animals. Moreover, DD itself decreased the amplitude of the sleep-wake cycle similar to that of the neurotoxic lesion of the noradrenergic system in LD animals. Analysis of noradrenergic fiber staining in the frontal cortex revealed that this effect was associated with fewer fibers or boutons in nonlesioned DD rats than in nonlesioned LD animals. Conclusions: Noradrenergic LC neurons provide a circadian regulation of the sleep-wake cycle, and the maintenance of LC function depends on light exposure. Light deprivation induces a loss of noradrenergic fibers, which in turn decreases the amplitude of the sleep-wake rhythm.