Restless legs syndrome (RLS) and periodic leg movements disorder (PLMD) are present in 5 percent and 11 percent of the population, respectively and can cause a severe sleep disruption; however, no animal model exhibits key aspects of the human syndrome. We hypothesize that the ventral mesopontine junction (VMPJ), including the rostroventral pons and the caudal part of the dopaminergic retrorubral nucleus and ventral tegmental area, plays a crucial role in the etiology of this disorder, as well as in REM sleep behavior disorder (RBD), which is present in 0.5 percent of the population. Our previous studies found that NMDA lesion of the VMPJ area produces periodic leg movement (PLM) in the decerebrate cat, and that this can be attenuated by glutamate injection into the medullary magnocellularis nucleus. This suggests that descending projections from the VMPJ are important in the control of muscle activity. Our pilot data in the intact freely moving cat indicates that 6-hydroxydopamine (6-OHDA) lesions of the dopaminergic neurons of the VMPJ elicit PLM's during slow wave sleep (SWS). The PLM's in SWS seen in the otherwise intact 6-OHDA lesioned cat resemble those seen in PLMD in humans. Our pilot data also suggest that NMDA lesions of the VMPJ cause PLM's during SWS, as well as an increase in tonic and phasic muscle activities during REM sleep and an increase in total sleep time. These effects duplicate the syndrome seen in RBD in humans. We hypothesize that VMPJ projections to the caudal brainstem regulate motor activity in SWS and REM sleep. We propose to investigate the role of the VMPJ in motor control across the sleep-wake cycle with cytotoxic lesion, anatomical, microinjection and dialysis techniques. In contrast to the well-established ascending midbrain dopaminergic mechanism of motor control via the basal ganglia, the role of the descending dopaminergic system in the control of motor activity has received little attention. This proposed work is of critical importance for the understanding of RLS/PLMD, RBD and other motor pathologies of sleep and for the design of therapeutic strategies to reverse these disorders.
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