Mental disorders, including schizophrenia, obsessive compulsive disorder (OCD) and drug addiction are linked to pathology in the prefrontal cortico-ventral striatal-thalamic circuit by imaging studies, post mortem anatomical studies, and basic research. Not only do these illnesses have a common circuitry, but they all emerge relatively early in life, primarily during adolescence or young adulthood. Anatomical, physiological and pharmacological studies in this circuit have been central in gaining insight into the mechanisms underlying mental health disorders. The structures involved include the prefrontal cortex, the ventral striatum (VS), the ventral pallidum/substantia nigra, pars reticulata (VP/SNr), and the medial dorsal N. of the thalamus (MD), which links the circuit back to cortex. During the previous funding period we: 1. defined the territory of the VS in primates, 2. identified important and unique cellular features of the VS, including BCL-2 positive cells and newly formed cells from the subventricular zone, and 3. identified the afferent connections to the midbrain dopamine. We also demonstrated a mechanism by which the limbic component of the basal ganglia impacts on other basal ganglia circuits through striato-nigro-striatal pathways. Finally, place of the thalamus in cortical regulation emphasizes newer concepts in control of cortico-cortical activity through its complex connections. We showed that an integrative network exists for the dorsal basal ganglia through its thalamic projections to different cortical layers and through a non-reciprocal cortico-thalamic projection. The general hypothesis of this proposal is that the combination of the impact of the ventral BG thalamocortico-thalamic network several cortical areas along with the unique cellular features of the ventral striaturn place this circuit in a position to be particularly vulnerable during adolescence. The experiments proposed here will test this hypothesis by: 1. delineating the thalamo-cortical network to determine how pathways through the ventral BG circuit can both reinforce its own loop and also impact on other cortical areas and BG circuits; 2. characterize bcl-2-positive neurons and newly formed cells and determine whether the unique cellular characteristics of the VS differ during adolescence, and whether they are particularly vulnerable to stimulation.
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