Disorders of movement, either in the waking or sleeping state, are common, but their pathophysiologies are ill-defined and treatments are frequently inadequate. Dopaminomimetics remain the mainstay of medical management where their benefit is thought to derive from modulation of basal ganglia output to the thalamus and cerebral cortex. Structure- function relationships are less well established in an alternate structure where basal ganglia outputs converge and movement is modulated: the brainstem pedunculopontine (PPN) region. The major goals of this study are: 1) to define the neural circuits in the PPN regions which relay influences from specific dopamine sensitive basal ganglia subcircuits, to lower motor centers; and 2) to examine their role in modulating one well-defined aspect of movement: the atonia of REM-sleep. Preliminary studies identify the precise neuron(s) in the PPN region postsynaptic to basal ganglia output and demonstrate their activation by systemic dopamine agonists that is dependent on an intact nigrostriatal pathway.
The first aim of these studies employs immuno- electron microscopy to define synaptic targets of basal ganglia output within neurochemically defined subdivisions of the PPN region.
The second aim will determine if dopamine activates these same neurons and the pathways and receptors involved using immediate early gene expression as a marker for """"""""functional activation"""""""" resulting from administration of dopamine agonists and antagonists.
The third aim will combine retrograde anatomical tracing with the above paradigm to determine the projection pattern(s) of the dopamine responsive neurons identified in Aim 2.
The fourth aim will record electrophysiological measures of sleep to determine the patterns of sleep stage specific pathological movement that results from striatal dopamine depletion and whether they are reproduced by lesions of the dopamine responsive projection neurons identified in Aim 3. These studies will for the first time define previously suspected dopamine responsive brainstem circuits and ascribe to them novel roles in modulating movement. Establishing the presence and behavioral import of these circuits should advance further investigation into the pathophysiology and treatment of disorders of waking and nocturnal movement. As dopamine sensitive basal ganglia circuits figure prominently in the pathophysiology of other neuropsychiatric disorders, e.g., OCD, ADD, Tourette's and schizophrenia, the results will also bear relevance to a wider spectrum of disease.
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