Cholinergic mesopontine cell groups, in concert with catecholaminergic (and serotonergic) neurons, participate in the descending control of locomotion and of postural muscle tone (e.g., startle response and atonia of REM sleep). As part of the Reticular Activating System (RAS), ascending projections of these cells modulate changes in state (e.g., sleep-wake cycles) and the response to afferent input (e.g., sensory gating). That is, they are in a crucial position to modulate fight vs flight responses. The applicants' work has implicated these neurons in psychiatric (e.g., schizophrenia, anxiety disorder), neurological (e.g., Parkinson's Disease) and sleep (e.g., narcolepsy, REM behavior disorder) disturbances, all of which have sleep-wake cycle and motor dysregulation in common. Studies during the previous grant period identified the presence of a novel mechanism whereby mesopontine cholinergic neurons may induce changes in state in descending target neurons. The proposed studies will investigate the characteristics and pharmacological control of this mechanism with a view towards determining the manner in which postural and locomotion systems are switched on and off. In addition, the applicants have developed a preparation in the behaving animal allowing the non-invasive recording of a waveform which is a measure of the ascending output of the RAS. Preliminary data suggest that localized injections of neuroactive agents into the mesopontine region can modulate this vertex-recorded waveform. The proposed studies will investigate the characteristics and pharmacological control of this waveform with a view towards determining the manner in which arousal and sensory gating systems are controlled. This work is of critical importance in the understanding of, and design of therapeutic strategies for, a number of psychiatric, neurological and sleep-wake cycle disorders.
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