Core C

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Research under the current proposal is designed to determine behavioral alterations relevant to schizophrenia (SZ), which is elicited by activation of stress-associated cascades and the E-I imbalance in the prefrontal cortex in mouse models that carry microtubule-associated genetic variants. We will also study how adolescent social isolation exacerbates these changes at the molecular, circuitry, and behavioral levels in collaboration with three Projects. In addition to performing basic behavioral characterization of the mouse models, this Core will conduct behavioral assessments for neurocognitive domains that are mediated by medial prefrontal cortex and orbitofrontal cortex, such as behavioral flexibility, including outcome expectancy in goal directed behavior, and working memory. Our rationale for use of specific behavioral assessments aimed at prefrontal systems is grounded in research that 1) documents the critical role of prefrontal cortex (PFC) circuitry in the information encoding mechanisms required to support behavioral performance in these paradigms across rodent and primate species, 2) implicates PFC systems supporting these functions in SZ by anatomical and physiological/neuroimaging evidence from patients, 3) demonstrates a vulnerability of such PFC-mediated behaviors/networks to stress exposure, including underlying mechanisms in PFC. Importantly, the assessments hold potential for the study of species-conserved cognitive mechanisms in the human brain to provide translational opportunities based on this preclinical research program. As such, the work in Core C is consistent with the Research Domain Criteria (RDoC) approach for advancing a biological understanding of the pathophysiology of major psychiatric illness and creating a platform for discovery of new therapeutics. Core C will consult with the investigators of the Projects both for conducting basic behavioral assays, for implementing behavioral experiments with a focus on analytically powerful protocols targeting PFC-mediated behaviors, and will lead data analysis and interpretation of findings in behavioral studies under the research program. In addition to its scientific value to the immediate objectives of the research program, the work of this Core may have broader translational significance in the neuropsychiatric field. As the molecular pathways under investigation are better understood in the context of behavioral profiling, the work of the core could identify assessments that are best suited to target dysfunctional mechanisms in animal models of SZ. In this way the proposed behavioral research may yield innovative findings of more general preclinical importance.