Role of the locus coeruleus-norepinephrine system in arousal and circadian regulation of the sleep–wake cycle

A variety of previous results indicate that the norepinephrine (NE) locus coeruleus (LC) system is integrally involved in regulation of sleep and waking. In particular, LC activation promotes wakefulness. This appears to be one of the major arousal systems in the brain. The LC was also found to be critical for rebound sleep following sleep deprivation, and increased sleep that occurs following a stressor. We recently identified a circuit from the suprachiasmatic nucleus (SCN) to the LC, in which the dorsomedial hypothalamus (DMH) serves as a relay. The functionality of this circuit was confirmed in our studies, showing that LC neurons have a circadian rhythm in their firing activity and that this circadian fluctuation in the LC requires an intact DMH. Other recent studies have also shown that lesions of the LC decrease the amplitude of the circadian rhythm in the sleep–wake cycle. These results indicate that the LC may be an important component in SCN efferent circuitry for driving circadian rhythms in sleep–wake cycles. Other recent results in our lab have revealed that light deprivation produces a profound loss of NE in the frontal cortex in rats, and this NE loss in dark-maintained animals is associated with decreased amplitude of the circadian sleep–wake rhythm. The dependence of the LC system on light for normal function has implications for clinical disorders such as seasonal affective disorder. Other disorders that are comorbid with sleep anomalies and associated with LC dysfunction are discussed.