There was an established consensus, until the 1990's, that muscle atonia during REM sleep was due to the glycinergic postsynaptic inhibition of motoneurons. This consensus, from different laboratories, was based on experiments wherein neurotransmitter agonists and antagonists where administered juxtacellularly to intracellularly-recorded motoneurons during naturally-occurring states of sleep and wakefulness. Subsequently, extracellular recording studies began to appear which called into question the preceding consensus; data were presented indicating that the atonia of REM sleep was due a variety of other mechanisms, such as disfacilitation, and other neurotransmitters, such as serotonin and noradrenaline. Consequently, despite 50 years of research, currently there is no agreement regarding the neurochemical mechanisms that are responsible for atonia during REM sleep. An innovative research approach is proposed that is designed to resolve the present irreconcilable data involving the state-dependent control of motor activity during REM sleep. In the proposed experiments, we will place an equal emphasis on exploring the contributions of disfacilitation and postsynaptic inhibition with respect to the control of motoneurons during REM sleep. To accomplish our objectives, hypoglossal activity motoneuron will be examined during spontaneously-occurring REM sleep and compared with data obtained during hypoxic REM sleep in an Animal Model of Obstructive Sleep Apnea. For the first time, intracellular activity of hypoglossal motoneurons and the extracellular activity of the hypoglossal muscle will be simultaneously recorded. Quantitative data will also be obtained during REM sleep in conjunction with the juxtacellular and reverse dialysis administration of neurotransmitter agonists and antagonists. Consequently, the contributions of postsynaptic and disfacilitatory processes to the depression of hypoglossal motoneuron activity will be documented. We hypothesize that the mechanisms that promote the REM sleep-induced depression of hypoglossal motoneurons are the same as those that control the activity of other brainstem and spinal cord motoneurons, except during pathological conditions. Specifically, during normoxic REM sleep, we propose that postsynaptic inhibition is responsible for atonia, whereas disfacilitation results in the depression of hypoglossal motoneuron activity, in addition to postsynaptic inhibition, under hypoxic conditions such as those that occur during Obstructive Sleep Apnea. Verification of our hypotheses and the data that are obtained will provide the necessary foundational bases for understanding the neuronal mechanisms that control atonia during normal and pathological (hypoxic) REM sleep. We also believe that these data will be directly translatable to the development of rational therapies for the treatment of motor disorders of REM sleep, such as Obstructive Sleep Apnea, REM Sleep Behavior Disorder, and cataplexy, among others.
After 50 years of research, we still do not know the mechanisms that are responsible for atonia during REM sleep, and the literature is replete with contradictory data. We will conduct innovative research involving the joint efforts of a group of collaborating investigators in order to develop consensus data regarding the neurochemical mechanisms that control motoneuron activity during normal (normoxic) and pathological (hypoxic) REM sleep. The data emanating from these studies will constitute a basic science foundation for the development of therapeutics to treat REM sleep-related motor disorders, which include Obstructive Sleep Apnea, cataplexy and REM Sleep Behavior Disorder, among others.
