Abstract
Recent experimental studies investigating the neuronal regulation of rapid eye movement (REM) sleep have identified mutually inhibitory synaptic projections among REM sleep-promoting (REM-on) and REM sleep-inhibiting (REM-off) neuronal populations that act to maintain the REM sleep state and control its onset and offset. The control mechanism of mutually inhibitory synaptic interactions mirrors the proposed flip-flop switch for sleep-wake regulation consisting of mutually inhibitory synaptic projections between wake- and sleep-promoting neuronal populations. While a number of synaptic projections have been identified between these REM-on/REM-off populations and wake/sleep-promoting populations, the specific interactions that govern behavioral state transitions have not been completely determined. Using a minimal mathematical model, we investigated behavioral state transition dynamics dictated by a system of coupled flip-flops, one to control transitions between wake and sleep states, and another to control transitions into and out of REM sleep. The model describes the neurotransmitter-mediated inhibitory interactions between a wake- and sleep-promoting population, and between a REM-on and REM-off population. We proposed interactions between the wake/sleep and REM-on/REM-off flip-flops to replicate the behavioral state statistics and probabilities of behavioral state transitions measured from experimental recordings of rat sleep under ad libitum conditions and after 24 h of REM sleep deprivation. Reliable transitions from REM sleep to wake, as dictated by the data, indicated the necessity of an excitatory projection from the REM-on population to the wake-promoting population. To replicate the increase in REM-wake-REM transitions observed after 24 h REM sleep deprivation required that this excitatory projection promote transient activation of the wake-promoting population. Obtaining the reliable wake-nonREM sleep transitions observed in the data required that activity of the wake-promoting population modulated the interaction between the REM-on and REM-off populations. This analysis suggests neuronal processes to be targeted in further experimental studies of the regulatory mechanisms of REM sleep.
Highlights
Theories on the neuronal control for rapid eye movement (REM) sleep have been dominated by the cholinergic hypothesis
This hypothesis is synthesized in the reciprocal interaction model [3,4] for REM sleep in which regular transitions between REM and nonREM (NREM) sleep are generated by excitatory and inhibitory synaptic projections between the cholinergic REM-promoting (REM-on) LDT/PPT and monoaminergic, REM-suppressing (REM-off) neuronal populations including the locus coeruleus (LC) and the dorsal raphe (DR)
Lu and colleagues [5] propose that REM regulation is controlled by a core REM-on/ REM-off flip-flop switch composed of mutually inhibitory (GABAergic) synaptic projections between REM-off neurons in the ventrolateral periaqueductal gray matter (vlPAG) and adjacent lateral pontine tegmentum (LPT), and REM-on neurons in the sublaterodorsal tegmental nucleus (SLD)
Summary
Theories on the neuronal control for rapid eye movement (REM) sleep have been dominated by the cholinergic hypothesis (see [1] for review). Based on a wealth of experimental evidence collected since the identification of REM sleep in the 1950s [2], the cholinergic hypothesis posits that the REM sleep state is initiated and maintained by the activity of cholinergic neurons in areas of the pons, including the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT) This hypothesis is synthesized in the reciprocal interaction model [3,4] for REM sleep in which regular transitions between REM and nonREM (NREM) sleep are generated by excitatory and inhibitory synaptic projections between the cholinergic REM-promoting (REM-on) LDT/PPT and monoaminergic, REM-suppressing (REM-off) neuronal populations including the locus coeruleus (LC) and the dorsal raphe (DR). Luppi and colleagues [8] propose that REM sleep transitions are controlled by a more distributed network of inhibitory projections among REM-off neurons in the vlPAG and dDPME, and REM-on neurons in the vlPAG, LH and DPGi
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