CRCNS: Mechanisms and consequences of infraslow oscillations in sleep

During sleep, the mammalian brain alternates between two major brain states, rapid eye movement (REM) and non-REM (NREM) sleep. Recent work showed that the electroencephalogram (EEG) during NREM sleep in both humans and mice exhibits a pronounced infraslow (~50s) modulation in the sigma (10-15 Hz) power range Transitions from NREM to REM sleep and spontaneous awakenings are synchronized with this infraslow o power (ISP) rhythm, suggesting that it plays a crucial role in shaping sleep architecture and influencing sleep quality. Yet, the mechanisms underlying the generation of infraslow rhythms remain largely unknown. Importantly, the ISP rhythm also strongly modulates the activity of neurons in REM sleep-regulatory brain areas including the locus coeruleus (LC), dorsomedial medulla (dmM), periaqueductal gray (PAG), and dorsal raphe (DR). However, current models of sleep regulation lack this prominent infraslow rhythm, and a functional understanding of its impacts on sleep architecture therefore remains elusive. The central hypothesis of this proposal is that the dmM controls the ISP rhythm through its interactions with the LC and that infraslow fluctuations in the activity of DR/PAG neurons control the stability of NREM sleep and consequently gate transitions to REM sleep. The specific aims combine experimental studies and biophysical computational modeling to determine mechanisms governing the ISP rhythm, and to understand the consequences of this rhythm on sleep architecture, particularly NREM--+REM transitions. In AIM 1, we will perform Neuropixels recordings along with optogenetic manipulation to identify how network interactions between dmM and LC neurons regulate the ISP rhythm In parallel, we will develop computational models informed by recorded data to identify underlying mechanisms of infraslow rhythm generation in the dmM-LC circuit In AIM 2 we will conduct Neuropixels recordings to identify the functional connectivity among different subclasses of DR/PAG neurons. By optogenetically blocking external infraslow inputs to the DR/PAG and conducting behavioral REM sleep deprivation, we will probe how the infraslow rhythmicity and REM sleep pressure affect the dynamics in the DR/PAG network and state transitions. In parallel, we will construct computational models informed by the recorded data to identify the dynamic interactions among different DR/PAG neuron subclasses and to analyze the effects of infraslow activity and REM sleep pressure on simulated sleep architecture. Our studies will bridge a fundamental gap in our understanding of how the mammalian brain generates infraslow rhythms. Furthermore, results will identify targets for enhancing the ISP rhythm to test its impact on sleep quality, and will lay the groundwork to develop complementary and integrative health approaches to leverage infraslow brain dynamics to promote healthy sleep and thus physiological and emotional well-being.