| Three components of the dopaminergic mesotelencephalic system have been recognized: mesocortical, mesolimbic, and mesostriatal. They directly influence motor, cognitive and emotive behaviors and are thought to indirectly regulate thalamocortical output via basal ganglia circuitry. This heuristic model does not account for how or why degeneration of the mesostriatal dopaminergic pathway in Parkinson's disease disrupts thalamocortical arousal and results in the loss of sleep spindles, 12-14Hz electroencephalographic activity reflective of thalamocortical bursting activity. The most parsimonious explanation posits that these disturbances reflect a loss of dopaminergic tone upon the thalamus. Accordingly, the major goals of this study were (1) to delineate the anatomical characteristics of the mesothalamic system, a novel pathway originating from the mesencephalon providing dopaminergic innervation to the thalamus and (2) to elucidate the physiological features of how this system might participate in sleep/wake regulation.; The dopamine transporter was histochemically visualized in thalamic regions that modulate behavioral state, as well as motor and limbic-related nuclei, in rats, nonhuman primates, and humans. Anatomical tracing established that this innervation arises via mesostriatal axon collaterals. Therefore, individual mesencephalic dopamine neurons have the potential to modulate behavior through both traditional nigrostriatal pathways and axon collaterals innervating the thalamus.; Previously, dopaminergic neurons had not been thought to innervate the thalamus and evidence for dopaminergic regulation of arousal had been underappreciated. Re-evaluation of dopaminergic substrates underlying arousal was imperative considering findings that: (1) thalamic dopamine loss accompanies striatal dopamine depletion in the nonhuman primate 1-methyl-4-phenyl-2,3-tetrahydropyridine (MPTP) and rodent 6-hydroxydopamine (6-OHDA) parkinsonian models (Freeman et al., 2001), as well as in human Parkinson's Disease (PD) (personal observations); and (2) excessive daytime sleepiness and rapid eye movement (REM) sleep dyscontrol is evident in both PD and animal models (Daley et al., 1999; Decker et al., 2000; Rye et al., 2000).; Physiology consistent with the tenet that dopamine modulates thalamocortical rhythms in the context of behavioral state (i.e., sleep/wake), was investigated through in vivo microdialysis and simultaneous electrophysiological measures of arousal state in nonhuman primates. A diurnal rhythm of extracellular dopaminergic concentration, independent of specific sleep stage, suggests a circadian or homeostatic mechanism for dopamine's regulation of arousal. |
