There is a consensus that active (REM) sleep occurs as a result of the discharge of executive active sleep-on neurons that are located in and/or within the vicinity of the nucleus pontis oralis (NPO); these neurons comprise the active sleep generator (AS-Generator). It is also universally accepted that the AS-Generator is activated by excitatory cholinergic projections from the laterodorsal and pedunculopontine nuclei (LDT/PPT). However, a variety of data suggest that other sites may also be capable of directly inducing active sleep by activating the AS-Generator. The direct electrophysiological and neurotransmitter bases for the control of active sleep-on neurons of the AS-Generator by these sites has not been examined, nor have interactions between the LDT/PPT and other sources of activation of the AS-Generator been explored. The research described in the proposal is designed to determine the veracity of the concept that, in addition to input from the LDT/PPT, neurons that are located in other sites, such as the central nucleus of the amygdala, are capable of directly activating the AS-Generator. Thus, we hypothesize that the central nucleus of he amygdala and the LDT/PPT not only function independently, but also work cooperatively, to control the onset, duration, termination and characteristics of the tonic and phasic periods of active sleep. Guided by the preceeding hypotheses and our Preliminary Studies, we intend to examine the control of the membrane properties, synaptic mechanisms and patterns of discharge of AS-Generator neurons in the NPO by neurons in the central nucleus of the amygdala. We will also examine the manner in which putative glutamatergic projections from neurons in the central nucleus of the amygdala interact with cholinergic projections from the LDT/PPT in initiating and maintaining active sleep. A multidisciplinary approach will be employed based upon the use of complementary techniques, procedures and neurobiological preparations in the chronic in vivo guinea pig preparation during spontaneously occurring states of sleep and wakefulness as well as during pharmalogically-induced active sleep. The data that are obtained and the verification of our hypotheses will provide important foundational bases for understanding the sites and neuronal mechanisms that control active sleep. We believe that these data will also be directly translatable to the development of rational therapies for the treatment of disorders of active sleep including REM Behavior Disorder, narcolepsy/cataplexy, and Restless Legs Syndrome. This knowledge will also provide a key foundation for a comprehensive approach to translational research to treat diverse pathologies that involve amygdala functions, especially those related to emotion and mood disorders, such as depression and PTSD, that also involve disruptions in the control of active sleep. ? ? ?
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