Locus Coeruleus Optogenetic Stimulation and the Estrous Cycle Manipulate Sleep Characteristics and Memory Consolidation

Abstract

Sleep and is critical for proper memory consolidation. The locus coeruleus (LC) releases norepinephrine throughout the brain except when the LC falls silent throughout rapid eye movement (REM) sleep and prior to each non-REM (NREM) sleep spindle. We hypothesize that these transient LC silences allow the synaptic plasticity necessary to incorporate new information into preexisting memory circuits. We found that spontaneous LC activity within sleep spindles triggers a decrease in sleep spindle power. By optogenetically stimulating norepinephrine-containing LC neurons at 2 Hz during sleep, we reduced sleep spindle occurrence as well as NREM delta power and REM theta power, without causing arousals or changing sleep amounts. Stimulating the LC during sleep following a hippocampus-dependent food location learning task interfered with consolidation of newly learned locations, and reconsolidation of previous locations, disrupting next-day place cell activity. The LC stimulation-induced reduction in NREM sleep spindles, delta, and REM theta, and reduced ripple-spindle coupling all correlated with decreased hippocampus-dependent performance on the task. Thus, periods of LC silence during sleep following learning are essential for normal spindle generation, delta and theta power, and consolidation of spatial memories.

Sleep quantity and quality also impact many physiological and neural processes. Sleep is affected by the menstrual cycle; however, few studies have examined the effects of the estrous cycle on sleep in rodents. Thus, studies of disease mechanisms in females lack critical information regarding estrous cycle influences on relevant sleep characteristics. We recorded electroencephalographic (EEG) activity from multiple brain regions to assess sleep states as well as sleep traits such as spectral power and interregional spectral coherence in males and freely cycling females across the estrous cycle. Our findings show that the high hormone phase of proestrus decreases the amount of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep and increases the amount of time spent awake compared with males and other estrous phases. This spontaneous sleep deprivation of proestrus was followed by a sleep rebound in estrus with increased NREM and REM sleep and rebound-like sleep architecture. Spectral power increased in the delta 0.5-4 Hz) and the gamma (30-60 Hz) ranges during NREM sleep of proestrus, and in the theta range (5-9 Hz) during REM sleep of both proestrus and estrus. Slow wave activity and cortical sleep spindle density also increased in NREM sleep of proestrus. Finally, interregional NREM and REM spectral coherence increased during proestrus. This work demonstrates that the estrous cycle affects more facets of sleep than previously thought and reveals further sex differences in feature of the sleep-wake cycle, which are relevant to a myriad of physiological processes influenced by sleep.