This Research career Award application is from an Associate Professor in the Departments of Neuroscience and Psychiatry at the University of Pittsburgh. The candidate has established a successful early career and seeks to be released from excessive teaching and administrative responsibilities, in order to devote additional time to mental health research. The candidate has outlined a plan of professional growth along multiple dimensions, including expansion of research into new methodologies, extension of existing collaborative research, increased involvement in clinically-based training, and enhanced leadership in the national and international scientific communities. The candidate's environment ins nearly ideal for developing professional growth, as it provides ample opportunities for advanced training experiences and clinical exposure, particularly within a Center for the Neuroscience of Mental Disorders in schizophrenia. The candidate's research focuses on the cortical and monoamine systems that are reportedly disrupted in schizophrenia. The prefrontal cortex (PFC) guides complex cognitive behaviors, and disruption of the cortical dopamine (DA) innervation, such as reported in schizophrenic patients, causes behavior consistent with PFC damage. Thus, an intact mesocortical DA innervation appears to be essential for proper functioning of the PFC, although the cellular mechanisms underlying DA's crucial modulation are not known. This proposal seeks to address several critical issues regarding the synaptic organization of the rat mesocortical DA system using a combined immunocytochemical, tract-tracing and electron microscopic approach to identify: the GABA interneuron subclasses synaptically innervated by Daterminals (Q1.1); the sources of excitatory glutamate afferents that target the interneurons receiving DA input (Q1.2); the populations of PFC pyramidal neurons synaptically innervated by DA terminals (Q2.1); the sources of excitatory glutamate afferents that converge synaptically with DA terminals onto pyramidal cell dendrites (Q2.2); and potential differences in the distribution of DA terminal synapses onto apical versus basilar dendrites of physiologically characterized neurons (Q3.1). the central hypothesis of these studies is that DA terminals exhibit specificity in their synaptic targets and do not associate uniformly with all cell types, afferents, and dendritic compartments. These studies will provide valuable information regarding extrapolation to humans of anatomical, physiological, and neurochemical data collected in experimental animals. Elucidating the synaptic organization of the mesocortical DA system will improve knowledge of the cellular mechanisms of DA modulation in cognition and the pathophysiology and treatment of major psychiatric disorders.
