Role of prefrontostriatal circuits in effort-based, cost-benefit decision making

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PROJECT SUMMARY Ongoing evaluation of cost-benefit tradeoffs guides action selection during adaptive decision making. When outcomes change, the utility of potential actions is re-evaluated to determine whether to persist or deviate from an existing strategy. Disturbances in the neural mechanisms underlying cost-benefit decision making can lead to pathological behavior (e.g., addiction, OCD, depression/anxiety). Effort-based decision making is specifically disrupted in patients with depression, schizophrenia and substance use disorders. Although pathological behavior in these conditions is linked to dysfunction in the prefrontal cortex and striatum, we lack the detailed neurobiological understanding necessary to design targeted therapeutic interventions. We will address this deficit using cutting edge tools for measuring and manipulating neural activity in freely behaving animals. We will test the specific hypothesis that anterior cingulate cortex (ACC) to nucleus accumbens (NAc) projection neurons encode updates to action selection policies based on new effort-reward tradeoffs, and that inputs to the NAc instantiate new, effortful choice strategies. In Aim 1, we will use miniaturized head-mounted microscopes to determine how ACC and ACCàNAc projection neuron activity is organized to represent effort-related cost- benefit computations influencing action selection. In Aim 2, we will manipulate the activity of ACCàNAc projection neurons with optogenetics, during flexible decision making driven by changes in effort-related value. Finally, in Aim 3, we will focus on prefrontal projections to the NAc, measuring and inhibiting activity at ACCàNAc terminals and comparing with inputs from the orbitofrontal cortex (OFC). We will do this during decision making in the context of both effort and delay-costs as a tool to further refine our understanding of how NAc integrates prefrontal inputs and translates these into action selection. This proposal directly addresses a pressing need to understand the cell-type and circuit-specific mechanisms that mediate cost-benefit decision making. Our research can inform pharmacological, psychotherapeutic and brain stimulation interventions for a variety of psychiatric conditions characterized by disordered cost-benefit evaluations and decision making.