The central hypothesis of our Center focuses on the nature, mechanisms and consequences of dorsolateral prefrontal cortical (DLPFC) dysfunction in schizophrenia. In order to test one aspect of this hypothesis, the studies proposed in this project are designed to identify which components of DLPFC circuitry may be most affected by the pathophysiology of schizophrenia. The proposed research strategy integrates three lines of investigation. The first group of studies (Specific Aim 1) extends ongoing work that evaluates, in on-human primates, the circuitry that may serve as neuroanatomical substrate for the sustained firing of DLPFC neurons during the delay period of delayed-response tasks, behaviors which are impaired in individuals with schizophrenia. Specific emphasis is placed on the organization and synaptic targets of the excitatory inputs from the mediodorsal thalamus and on the mesocortical dopamine projections in relationship to intrinsic elements of DLPFC circuitry. The second set of studies (Specific Aim 2) assesses the refinements in primite DLPFC circuitry that occur during adolescence and early adulthood, the developmental epoch when mature levels of function on delayed-response tasks are achieved and when schizophrenia subjects typically first manifest the clinical symptoms of the disorder. The results of these studies in monkeys are then used to predict which elements of DLPFC circuitry are most likely to be compromised in schizophrenia, and to guide a third set of studies (Specific Aim 3) designed to examine these predictions in postmortem human brain. These investigations have a number of conceptual and technical links with other Center projects and depend upon support provided by the Human Brain Bank and Statistics and Data Management Cores.
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