Medial Prefrontal Dopamine Dynamics Reflect Allocation of Selective Attention

Abstract

Mesocortical dopamine signaling is widely implicated in cognitive function and psychopathology, yet our functional and mechanistic understanding of this pathway remains less understood relative to the other major dopaminergic pathways. This gap reflects not only the intrinsic complexity of its primary target, the prefrontal cortex, a highly integrated hub that supports diverse cognitive operations, but also longstanding technical limitations that, until recently, made it prohibitively difficult to measure dopamine release in the prefrontal cortex of freely-moving animals on behaviorally discrete timescales. This dissertation begins with a focused review of dopamine biology and the major dopaminergic pathways, highlighting key similarities and differences that motivate the work that follows. To directly observe mesocortical dopamine dynamics in real time, this dissertation leverages a genetically encoded fluorescent dopamine sensor combined with fiber photometry to monitor dopamine release in the medial prefrontal cortex of freely behaving mice. Using this approach, we initially observed robust prefrontal dopamine responses to novel, appetitive, and aversive stimuli, but we saw little evidence that learning-induced changes occurred throughout either simple or more complex tasks. Across stimuli, we consistently observed a decline in prefrontal dopamine responses with repeated exposure, but this attenuation could be reversed when novelty was reintroduced or when task contingencies were altered. In addition to stimulus-evoked transients, dopamine activity ramped in anticipation of expected outcomes and tracked second-to-second variation in behavioral engagement, including in the absence of discrete stimuli, suggesting that prefrontal dopamine may be involved in internal processes. From these findings, we hypothesized that prefrontal dopamine reflects the allocation of attentional resources. To test this hypothesis, we developed a behavioral task that systematically manipulated attentional demand and observed that prefrontal dopamine was engaged during the allocation of selective attention. Moreover, optogenetic activation of dopamine terminals in the prefrontal cortex was sufficient to augment task performance exclusively under conditions of high attentional demand. Together, these results support a model in which prefrontal dopamine serves as a selective attention signal grounded in direct observation of time-resolved dopamine dynamics, helping to reconcile decades of competing theories regarding mesocortical dopamine function.