We hypothesize that a network of interconnected GABAergic neurons is responsible for controlling and switching between the states of wakefulness, NREM sleep and REM sleep. When this GABAergic Switching Network for Sleep and Wakefulness is activated, wakefulness occurs and REM sleep is suppressed. The proposed GABAergic Switching Network for Sleep and Wakefulness is comprised of a primary population of GABAergic Executive neurons that reside in the pontine tegmentum (nucleus pontis oralis, NPO) and the hypothalamus (VLPO/MnPO). Wakefulness occurs when GABAergic neurons in the NPO are activated, i.e., these neurons inhibit both adjacent REM-on neurons as well as GABAergic neurons in other sites involved in promoting wakefulness, such as the dorsal raphe. REM sleep is controlled by glutamatergic cells in the NPO, called REM sleep-on neurons (that comprise the REM Generator). NREM sleep arises when GABAergic neurons in the VLPO/MnPO are activated which results in the inhibition of NPO GABAergic neurons as well as Wake-on neurons in sites such as the dorsal raphe. Therefore, the proposed studies will elucidate the circuitry and mechanisms that are responsible for generating, and switching between, the behavioral states of sleep and wakefulness. These experiments are significant in light of the paucity of research that has addressed the manner in which each of the interdependent, but exclusively-occurring states of sleep and wakefulness arise and manner the fashion in which GABAergic inhibition provides for switching between these states. The information that will be obtained will significantly enhance our understanding of the neuronal mechanisms underlying the states of sleep, in general, and their interactions with wakefulness. In addition, a number of innovative concepts and novel technologies will be incorporated into the proposed studies which will further enhance their basic science and clinically-related significance, such as the use of a novel supraparamagnetic nanotechnology. The data that are derived from the proposed studies will provide a basis for future explorations into the development of therapeutics to treat disorders that are due to pathologies that involve disruption in the circuitry and mechanisms that control wakefulness and NREM sleep and REM sleep, such as cataplexy and REM Sleep Behavior Disorder.
The proposed research is designed to provide key data regarding the neuronal mechanisms that are responsible for switching between the behavioral states of wakefulness and NREM sleep and REM sleep. In addition, these studies will establish a basis for understanding the pathological mechanisms that are responsible for state-dependent disorders of sleep and wakefulness, such as cataplexy and REM Sleep Behavior Disorder, as well as facilitate the development of efficacious therapies to treat these and related disorders.
