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An innovative strategy for dissecting the disease process guides the research proposed in this Center.
Given the number of different genetic liabilities and environmental exposures associated with an increased risk of schizophrenia, different combinations of these causal factors probably induce distinct pathogenic events that differ across affected individuals and that are distal from the pathophysiology of a given clinical feature. However, these alterations are likely to converge upon a more limited set of proximal molecular and cellular changes—a final common pathway that directly gives rise to the feature,pathophysiology underlying a given clinicalDiagram of cortical circuitry studied in this Center(CTMHR) and that would be expected therefore to be conserved across individuals who share that clinical feature. Consequently, in the proposed studies we have elected not to focus on the expanding number of putative risk genes for schizophrenia or on their potential pathogenic consequences, although components of the proposed studies are likely to provide novel information regarding pathogenesis (e.g., cell type-specific gene expression profiling in Project 1). Instead, we look downstream in the disease process at the clinical features and pathological markers that appear to be relatively common across individuals diagnosed with schizophrenia. At the clinical level, we focus on well-established, core, cognitive deficits in schizophrenia that are dependent upon the circuitry of the V1-PPC-DLPFC network. At the pathological level, we focus on alterations in PCs that furnish the projections among the cortical regions that mediate visual working memory and attention. The proposed studies are designed to test the idea that these abnormalities are linked by the pathophysiology of altered functional connectivity that subserve both top-down and bottom-up information processing. Thus, the Center structure provides convergent and multidisciplinary probes of the robustness of this model. However, we recognize that disturbances in other domains of information processing and in other brain regions and circuits are present in the illness. Thus, the proposed studies provide a proof-of-concept approach that will provide a strategic model for examining these other phenomena.

The rationale for this strategy is based upon our two-fold goal of 1) identifying novel pathologically-based treatment targets that can be used to guide the development of rational interventions, and 2) developing novel, pathophysiologically-based biomarkers that can be used in clinical trials to assess the extent to which an intervention normalizes the pathophysiology of the illness. Achieving the first goal requires recognizing that molecular alterations observed in association with the disease state could represent any of the following four “Cs”: 1) Cause, an upstream factor related to the disease pathogenesis; 2) Consequence, a deleterious effect of a cause; 3) Compensation, a response to either cause or consequence that helps restore homeostasis; or 4) Confound, a product of factors frequently associated with, but not a part of, the disease process. The molecular alterations most likely to be useful treatment targets are 1) the downstream consequences that are closely tied to, and the direct and powerful determinants of, the brain pathophysiology that mediates the clinical feature of interest; and 2) the homeostatic compensations that could be augmented. Thus, Projects 1-3 employ an integration of postmortem human investigations and studies in non-human primates to provide pathological and physiological bases for identifying and validating potential novel treatment targets. In parallel, Projects 4 & 5 use comparable cognitive tasks and complementary measures of functional connectivity and synchrony in monkeys and in medication-naïve subjects with a first episode of psychosis; this strategy provides a robust assessment of potential biomarkers that reflect (as a consequence of indexing molecular-cellular-circuitry pathology) the underlying pathophysiology of the clinical features of interest.
Silvio O. Conte Center for Translational Mental Health Research
Funded by the National Institute of Mental Health (MH103204)

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