Mechanistic dissection of cognitive thalamocortical engagement in attention and hierarchical reasoning.

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Abstract Higher order thalamic regions play critical roles in cognitive processing by regulating their cortical targets. Data from both such regions, the pulvinar and mediodorsal thalamus, indicate that their engagement in decision making increases in challenging conditions, including perceptual uncertainty. Schizophrenia is a disorder characterized by heightened susceptibitly to uncertainty on one end and perturbed connectivity between higher order thalamus and associative cortical targets, on another. Therefore, identifying the mechanistic links between higher order thalamic engagement and cognitive processing is translationally- relevant; higher order thalamic regions may be viable targets for neurostimulation in treatment-resistant schizophrenia. This project will utilize Tupaia Bellangeri (Tree shrews) as a model organism to contribute to the overall Aims of this Center. Tupaia is a basal primate with a brain size amenable for optical perturbations that can be readily observed at the level of behavior, tightening the casual inferences that can be made about brain-behavior relationships. In Aim I of this project, we will build upon our extensive preliminary data on MD thalamic function. This will be in close collaboration with P3, which will perform analogous experiments in macaque collectively identifying the mechanisms by which the MD regulates interactions between frontal cortical areas in the context of hierarchical reasoning. In Aim II, we will use the visual system of Tupaia to ask analogous questions on pulvinar regulation of dorsal versus ventral visual stream engagement in a motion vs. color switching task; this will be coordinated closely with P1, which will target the pulvinar in the macaque. Lastly, Aim III will leverage a pharmacological model relevant to the pathophysiology of schizophrenia (chronic methamphetamine) to examine brain-behavior relationships in the context of task performance. This will be done in close coordination with P5, which will interrogate higher order thalamic structure in humans with schizophrenia and healthy controls. In all Aims, there will be close collaboration with P4, Cores B and C, to ensure that the data contributes general insights for building a biologically-plausible model of the human thalamus. Altogether, successful completion of our Aims promises to contribute to the overall vision of this Center in propelling the basic understanding of thalamocortical processing and cognition forward, as well as deriving translational insights for treatment of schizophrenia.