The research proposed in this competing renewal application for a Research Scientist Development Award will accomplish several objectives, including the acquisition of knowledge regarding the biological psychopathology of schizophrenia and the continued development of the research and mentoring skills of the applicant. Multiple lines of evidence indicate that the prefrontal cortex (PFC) is a site of dysfunction in schizophrenia. This dysfunction is proposed to be a consequence of alterations in the distinctive lattice structure of intrinsic excitatory connections present in PFC. This circuitry appears to be critical for the recruitment of spatially-segregated populations of PFC neurons whose coordinated activity generates specific patterns of output from this region. Thus, abnormalities in these intrinsic connections might be manifest not only as PFC dysfunction, but also as the altered activation of specific neuronal populations distributed across other brain regions. In the proposed studies, this hypothesis will be tested in investigations of postmortem brain specimens from carefully-characterized schizophrenic and control subjects. Other studies will be conducted to test corollary hypotheses regarding the organization and development of the intrinsic lattice, and of the inhibitory local circuit neurons and dopaminergic afferents that may influence the function of lattice circuitry. The proposed research will serve as a vehicle for the continued scientific development of the applicant in several ways. First, these studies involve collaborations with other basic and clinical neuroscience investigators at the University of Pittsburgh (Drs. German Barrionuevo, Gretchen Haas, Tony Plant, Allan Sampson and Susan Sesack) and at other institutions (Drs. Jennifer Lund and Eric Nestler). These collaborations will enhance the applicant's skills in specific research techniques, as well as in the design and conduct of studies of schizophrenia and prefrontal cortical circuitry. Second, the applicant will benefit tremendously from interactions with other well-established neuroscientists. Discussions and visits to the laboratory of Dr. Joaquin Fuster will enable the applicant to maximize the scientific yield from the proposed studies, as well as to plan future studies. Drs. Floyd Bloom and Robert Moore will serve as general consultants on the proposed studies, providing suggestions and critiques of the applicant's program of research. Finally, the proposed studies will serve as the major mechanism for the applicant's continued Involvement in mentoring and science education activities. These plans ensure the applicant's continued development as a clinician-neuroscientist whose research is focused at the interface of clinical and basic neuroscience.
