Functional and behavioral dissection of higher order thalamocortical circuits in schizophrenia.

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ABSTRACT Project 5 (P5) will address Center Aim 2 by characterizing mediodorsal (MD) nucleus and pulvinar (PUL) circuit dysfunction in schizophrenia across levels of analysis, including functional connectivity with cortex, localized activation during cognition, and behavior. The structure, connectivity, and function of the thalamus are abnormal in schizophrenia. Thalamic abnormalities are especially pronounced in the MD nucleus and PUL. How MD and PUL dysfunction contributes to the symptoms and associated features of schizophrenia is largely unknown posing a significant challenge to developing effective interventions. One of the motivating factors of this Center application is that the MD and PUL are not only causally involved in cognition, but anatomically and functionally heterogenous. Consequently, dissecting higher-order thalamocortical circuits across levels of analysis is essential for understanding the functional consequences of thalamic dysfunction in schizophrenia and identifying targets for intervention. Working synergistically with P4 resting-state fMRI studies in healthy individuals and supporting by Core C, Aim 1 will use innovative methods to test the hypothesis that functional connectivity of MD and PUL subdivisions is abnormal in schizophrenia and further determine if the alterations are diffuse, or isolated to specific MD and PUL subdivisions. Informed by basic neuroscience discoveries motivating P1 and P2, Aim 2 will characterize dorsal and ventral pulvinar circuits during attention in schizophrenia. Deficits in attention are ubiquitous in schizophrenia and may serve as a viable biomarker. We hypothesize that such deficits may be caused by aberrant engagement of the PUL in regulating information flow across the dorsal and ventral visual streams. We will test this hypothesis by acquiring simultaneous brain (fMRI) and behavior measurements in patients and healthy individuals. Aim 3 will use a variant of the Center’s Hierarchical Decision Making (HDM) paradigm to investigate MD-PFC pathways for regulating cortical excitation/inhibition. Animal models developed by P3 indicate that resolving sensory uncertainty during decision making depends on different MD-PFC pathways: one for suppressing noise (conflict) by increasing cortical inhibition, the other for enhancing signal (sparseness) by decreasing inhibition. Building on preliminary behavioral data with leaders of P3 implicating impaired decision making under sensory conflict, we will determine if schizophrenia is associated with impaired decision making under uncertainty when task cues are sparse (low signal), conflicting (high noise), or both. Furthermore, we will test the hypothesis that MD dysfunction is associated with impaired attentional control under uncertainty in schizophrenia and determine whether MD dysfunction is more prominent in sparseness- or conflict-based uncertainty. Core B will provide critical support for modelling behavioral data (Aims 2, 3) to allow cross-species comparisons. The overall outcomes of P5 will provide the foundation for developing interventions for correcting thalamocortical dysfunction and cognitive impairment in schizophrenia.