Neuropathology of the mesolimbic dopamine system remains a major focus in the study of neurochemical correlates of schizophrenia. Research has generally focused on the dopamine neurons of the ventral tegmental area (VTA) and their projection to the ventral striatum, the main components of the basal ganglia limbic loop. Recently, studies have turned to areas of the prefrontal cortex that receive dopamine input. These studies suggest that the differential regulation of dopamine in the ventral striatum and in cortex might underlie the pathology of the disease. The midbrain dopamine cells are unique in basal ganglia circuitry in that they are in a position to integrate different cortical/basal ganglia loops. They receive amygdala and ventral striatal input and project to wide areas of both the cortex and striatum. The basal ganglia limbic loop is both a closed and open system. As such it is able to influence the limbic system specifically (closed loops) and, at the same time, integrate limbic, cognitive and motor functions (open loops), primarily through the midbrain dopamine neurons. The general goal of these experiments is to understand how the midbrain dopamine system can integrate information from several functional domains of striatum and cortex. Results from the tracing experiments, as well as other anatomical and physiological studies, demonstrate that the midbrain DA neurons are in a unique position to integrate several basal ganglia circuits. Furthermore, pharmacological studies suggest that dopamine effects in the striatum and cortex may be regulated differently. During the previous funding period we found two populations of dopamine cells that have different levels of the dopamine transporter and the D2 receptor. These two groups may have different cortical targets. Despite the fact that the midbrain dopamine system is one of the most studied in the CNS and is a prominent player in several diseases, there are surprisingly few studies that address circuitry as it relates to striatal/cortical balance. The proposal addresses the issue of the ventral basal ganglia as a complex structure with both segregated and integrated circuits. The main foci are: 1. how the midbrain dopamine circuitry can integrate different functional domains, and 2. how the midbrain dopamine circuitry can differentially regulate various cortical and striatal pathways through levels of DAT and receptor subtypes.
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