In this R21 grant, entitled “Causal Roles of Dorsolateral Prefrontal and Dorsal Premotor Cortex in Perceptual Decision Making,” we will test the causal roles of the dorsolateral prefrontal cortex (DLPFC) and dorsal premotor cortex (PMd) in the macaque monkey during perceptual decision making. Perceptual decision making is the ability to discriminate and integrate cues from different sensory systems to produce an action that supports behavioral goals. Our current studies demonstrate distinct neural dynamics in DLPFC and PMd during our novel red-green perceptual decision- making task. In this task, monkeys discriminate the dominant color of a central static checkerboard cue composed of red and green squares and report their decision with an arm movement to a left or right target. By randomizing the color identity of the target across trials, we can differentiate action choices (left vs. right) from color choice (red vs. green). We find that neural population dynamics in DLPFC encode the color choice, action choice, and target configuration, whereas neural population dynamics in PMd are only associated with the action choice. In addition, PMd firing rates closely covary with the reaction time (RT) of the animal before and after cue onset, suggesting a role for PMd in planning and executing an action choice. However, such correlative experiments are unable to fully answer whether these brain areas are differentially and causally involved in these aspects of decision-making. The goal of this research is to causally establish the roles of DLPFC or PMd during perceptual decision-making. Our central hypothesis based on our physiological recordings is that inactivation of DLPFC should bias color and action choice, whereas inactivation of PMd should only bias action choice and alter RT. To test this hypothesis, we will use custom-made cortical cooling deactivation to focally and temporarily silence PMd (Aim 1) or DLPFC (Aim 2) in monkeys trained to perform our behavioral task. Our overall approach is as follows: we will implant bilateral recording chambers over the DLPFC and PMd into which we will introduce a linear multicontact electrode and cooling devices. While monkeys perform our behavioral task, we will perform simultaneous electrophysiological recording before, during and after cooling of DLPFC or PMd. We will use various measures of task performance (psychometric curve, RT curve, kinematics of eye and arm movements etc.) to evaluate the impact of cooling on decision making behavior. Sessions will use unilateral or bilateral cooling and either complete cooling or mild cooling. Based on our physiological experiments, we predict three effects. First, we anticipate that cooling PMd will lead to slower RTs and biases in action choice but no biases in color choice. Second, we anticipate DLPFC deactivation will produce biases in both color choice and action choice behavior and lead to profound deficits in task performance. Finally, we anticipate bilateral deactivation to produce deficits of larger magnitude than unilateral deactivation. These data are first of its kind causal tests of the specific roles of DLPFC and PMd in perceptual decision-making behavior. Impact: our results could help better understand behavioral deficits that occur in these clinically relevant brain areas because of psychiatric and neurological disorders as well as in normal aging.

NARRATIVE Perceptual decision-making, our capacity to use information from our senses to guide our behaviors, is an essential aspect of interacting with the world, and it is an ability that is disrupted in numerous psychiatric and neurological disorders and normal aging. We propose to examine for the first time the unique and causal contributions of two regions of the frontal lobe of the cerebral cortex on decision-making behavior. Insights from this study will help us better understand the behavioral impact of alterations to these brain areas by neurological and psychiatric orders, and in the long term help us develop better therapies for these disorders.