Linda Amarante - US grants

PROJECT SUMMARY To flexibly execute behavior, choices are made based on previous outcomes that will maximize reward. Crucially, learning the value of each action to obtain a reward is thought to drive this decision making process. In a value-based decision making framework, these values are first computed and then used to select and execute actions. Dysfunction in this decision making process is evident in many neuropsychiatric disorders including addiction and in patients with frontal cortical damage who show an inability to flexibly adjust or adapt their behavior. The corticostriatal pathway, from the medial prefrontal cortex (mPFC) to its downstream target, dorsomedial striatum (DMS), is a candidate circuit implicated in promoting flexible behavior. Neural correlates of value have been found in mPFC across species, and DMS is traditionally thought to be involved in action selection, where representations of action values have been found in DMS neurons. However, it is unclear exactly how representations of value are then transformed into actual movements for adaptive behavior. Similarly, many studies that have described representations of value in either region have done so using discrete binary measures of behavior and correlate neural activity only to the action's endpoint (e.g. emitting a lick at a left or right spout, or making a saccade to a target). This project will investigate the transformation of value into actions in mice by investigating how mPFC and DMS neural activity represent value during ongoing movements (Aim 1), and will reveal the specific cell types and pathways within the corticostriatal pathway that are necessary for value representation and action selection (Aim 2). In both aims, action potentials from mPFC and DMS will be recorded as thirsty head-fixed mice perform in a dynamic foraging task that requires a joystick movement to search for the high-probability reward, where the location of the high-probability reward changes over time. Value-based decision variables, such as action values and relative value, will be quantified by correlating the animal's joystick movement behavior to neural activity in both areas (Aim 1). This will reveal how mPFC and DMS compute decision variables during ongoing movements. Aim 2 will reveal the specific neural circuitry between mPFC and DMS; perturbations of mPFC layer 5 pyramidal tract neurons will reveal how value-based decision variables are represented in the corticostriatal pathway, and by using transgenic mouse lines paired with antidromic stimulation, direct and indirect pathway neurons in DMS will be identified to determine each cell type's role in representing value and transforming value into action. This project overall will provide a better understanding of how values are attributed to actions during the decision making process, and will identify how specific cells in the corticostriatal pathway compute and transform information about value to make optimal choices.