The research that is described in this proposal is designed to examine the cellular mechanisms that control the excitability of executive neurons that are involved in the production and maintenance of the behavioral states of active sleep and wakefulness. We hypothesize that these key neurons are located within the nucleus pontis oralis and that their excitability is regulated by the interaction of GABA and hypocretin, as well as other neurotransmitters/neuromodulators, which control an intracellular cascade of events involving cAMP, cGMP and IP3-DAG, etc. The result is the state-dependent discharge of active sleep-on and waking-on neurons in the nucleus pontis oralis that, in turn, determines the state of the animal and the control of motoneuron activity. A multidisciplinary approach will be employed to study the excitability of nucleus pontis oralis neurons based upon the use of different but complimentary neurobiological preparations in the guinea pig, which is a unique species insofar as it can be utilized in a coordinated fashion for acute in vitro and chronic in vivo studies of sleep and wakefulness. Other species that have been used to study behavioral states can be employed only for certain studies, but are unsuitable for others, e.g., the cat cannot be used for slice experiments; the rat is unsuitable for chronic intracellular recording, etc. Therefore, we propose to develop a series of animal preparations to study sleep and wakefulness in which the data from each experiment can be directly applied to information obtained in other preparations in the same species. The demonstration that the guinea pig can be utilized for a variety of coordinated multidisciplinary studies examining cellular mechanisms from a behavioral perspective will be a significant contribution to the field of sleep research. In addition, the complementary set of hypotheses to be examined requires the use of a single species in order to validate the results of the interdisciplinary studies vis-a-vis the executive role of nucleus pontis oralis neurons and the intracellular events that are responsible for their control of active sleep and wakefulness Resolution of our hypotheses will provide important foundational bases for understanding the neuronal mechanisms that control active sleep and wakefulness. We also believe that these data will be directly applicable to the development of rational therapies for the treatment of sleep and waking disorders that arise as a result of the pathological functioning of these neuronal mechanisms
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