Abnormal patterns of motor behavior are a key component of a number of sleep disorders. These patterns of behavior are evidenced, for example, during wakefulness by cataplectic attacks, in which the motor inhibition that normally occurs during active (REM) sleep is expressed during the waking state. On the other hand, there is a lack of motor inhibition during active sleep that occurs in disorders such as REM Sleep Behavior Disorder. These and various other sleep disorders that involve disrupted motor control during active sleep and wakefulness are the clinical bases for the proposed studies dealing with the paradoxical phenomenon of """"""""reticular response-reversal,"""""""" wherein a brainstem system exerts dual functions that are dictated by the ongoing behavioral state of the animal, i.e., motor activation during wakefulness (and quiet (NREM) sleep) and motor inhibition during active (REM) sleep. We hypothesize that hypocretin, a newly discovered peptide that has been implicated in the generation of narcolepsy/cataplexy, may be the neurotransmitter that is utilized by the system of reticular response-reversal. Our discovery that hypocretin- containing cells in the hypothalamus are active not only during wakefulness, but also during active (REM) sleep, together with our other preliminary studies demonstrating that hypocretin acts at various sites to promote motor activity during wakefulness and to enhance motor inhibition during active sleep, suggest that hypocretin may be the neurotransmitter that sustains this systems' actions at the level of motoneurons as well as supporting its circuitry within the brainstem. Our studies will provide fundamental data, which are currently non-existent, of a) the role of hypocretin in the in vivo control of neuronal (motoneuron) activity, which includes the spontaneous and synaptic drives which are fundamental to determining the activity levels of cells; b) the interaction of hypocretin, in vivo, with classical excitatory and inhibitory neurotransmitters; and c) the role of hypocretin, in vivo, in response-reversal in promoting the non-reciprocal excitation of motoneurons during wakefulness and the non-reciprocal inhibition of motoneurons during active sleep. These data will allow us to determine the veracity of our hypothesis that hypocretin plays a critical role in maintaining active sleep and its physiological components in addition to participating in waking functions and waking control mechanisms.
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