Role of prefrontal dopamine circuits in threat avoidance learning

PROJECT SUMMARY Ongoing evaluation of environmental cues that predict aversive outcomes enable animals to avoid threats. However, learned avoidance can easily become maladaptive. Excessive or inappropriate avoidance is a core feature of numerous psychiatric disorders (e.g., depression, anxiety, PTSD and OCD). Although pathological behavior in these conditions is linked to dysfunction in the prefrontal cortex, we lack the detailed neurobiological understanding necessary to design precisely targeted therapeutic interventions. The medial prefrontal cortex (mPFC) is required for learning associations that drive approach or avoidance behaviors, but the circuit mechanisms that underlie this process are poorly understood. Prefrontal dopamine (DA), in contrast with subcortical DA, most strongly encodes aversive stimuli. DA has a well-established role in plasticity and shapes activity in projection-specific mPFC neuronal populations expressing either D1 or D2 receptors (D1R or D2R). However, the role of prefrontal DA, and D1R+ vs. D2R+ populations, in avoidance learning remains largely mysterious. We will address these deficits using innovative tools that allow us to measure and/or manipulate DA and mPFC neuron populations while mice learn to avoid threats. We will test the specific hypothesis that DA generates an mPFC activity state required for flexibly learning to associate cues with actions that preempt aversive outcomes. In Aim 1, we will use temporally precise measurement and manipulation of prefrontal DA to thoroughly interrogate the timing and causality of DA dynamics during threat avoidance learning. In Aim 2, we will use miniaturized head-mounted microscopes and simultaneous optogenetic silencing of mPFC-projecting DA neurons to determine the causal role of DA in modifying emergent neural activity patterns required for avoidance learning. Finally, in Aim 3, we will focus on D1R+ and D2R+ cell-type specific circuits by recording their activity and electrically silencing them during threat avoidance learning. This proposal directly addresses a pressing need to understand the cell-type and circuit-specific mechanisms that mediate avoidance learning. Our research can inform pharmacological, psychotherapeutic and brain stimulation interventions for a variety of psychiatric conditions characterized by maladaptive avoidance.