Fronto-thalamic interactions in value-based decision making under uncertainty

This project is a continuation of the original funded K99/R00 application. Having secured a tenure- track assistant professor role, jointly at the Children’s Hospital of Philadelphia and the University of Pennsylvania, the remaining aims will be pursued at these institutions. The aims proposed here have not been changed substantively from the ones originally proposed for the independent phase of the award. Real world decisions have to be made in environments that are noisy and uncertain. The frontal cortex—the brain’s principal center for cognitive control—must account for such uncertainty to guide adaptive decision-making. From a translational perspective, failure to resolve uncertainty is thought to represent a core computational deficit in schizophrenia, contributing to abnormal perceptions, distorted beliefs, and psychotic symptoms. While an extensive body of literature from humans as well as preclinical models have established a causal role of the frontal cortex in such decision making, recent work, including my own have also highlighted an important role of thalamocortical interactions between the frontal cortex and the medio dorsal (MD) thalamus in perceptual decision making under uncertainty. Building on this foundation, I will test whether MD–frontal cortex circuits also support value based decision making with uncertainty in the expected value of rewards/outcomes. First, we will train tree shrews on an object valuation task that introduces trial-by-trial uncertainty in the subjective value of two options, while recording neural activity from the frontal cortex to identify representations of subjective value. Second, we will employ multisite electrophysiological recordings and causal optogenetic perturbations to examine the mechanistic role and circuit substrates of MD-frontal cortex interactions in this paradigm. The insights developed here on the mechanistic basis of object valuation under conditions of uncertainty will form the basis of my future research program dissecting the circuit substrates of maladaptive beliefs and motivational anhedonia that underlie schizophrenia.