Nucleus accumbens dynamics underlying cue-reward learning - Project Summary / Abstract Learning to associate environmental cues with rewards, such as food, is critical to survival, but maladaptive cue- reward learning is thought to underlie cardinal features of substance use disorder by driving craving and relapse in the presence of drug associated cues. Rewarding environments contain many stimuli that could be potentially serve as cues. How does the brain learn to selectively discriminate and respond to reward-predictive cues and ignore irrelevant ones? As a primary target of mesolimbic dopamine signaling, the nucleus accumbens core (NAc) is a critical brain region involved in both the learning of cue-reward associations and the ability of learned predictive cues to evoke or invigorate appetitive behavior. Compared to the research on dopamine signaling in this region, however, the role of NAc neuronal activity is considerably understudied. During cue driven reward seeking, NAc neurons exhibit heterogeneous firing patterns: many neurons increase in activity while many other neurons decrease in activity. These activity modulations reflect many different task variables and differ in duration within a trial. Due to this complexity, understanding the activity profiles contributing to NAc function and cue-driven reward seeking remains a challenge. Rapid cue excitation responses are important for cue-induced approach behaviors, but sustained non-selective reduction of NAc activity reduces the ability to discriminate meaningful versus distractor cues, which suggests an important role for inhibition in selective behavior responses to reward paired cues. In this proposal, I test the hypothesis that precisely timed inhibitions of activity in a subset of NAc neurons during cue-driven reward seeking develops over learning to serve a crucial role in selective conditioned responses to reward paired cues. To answer this, I will use an auditory Pavlovian discrimination task in head-fixed mice to study the selective learning and response to reward paired cues. In Aim 1, I will optogenetically inhibit D1 or D2 receptor expressing NAc projection neurons during either the cue presentation or reward reciept/outcome phase of both reward associated cue and neutral cue trials. Based on preliminary experiments, I expect D2 neuron inhibition during the reward period to drive rapid, indiscriminate conditioned responding to both rewarded and unrewarded cues. In Aim 2, I will use two-photon imaging to track the activity dynamics of the same visually identified D1 and D2 neurons across the entire phase of learning. I predict that inhibitory responses specifically during rewarded trials will develop in a subset of NAc neurons immediately preceding or concurrent with the emergence of conditioned responding. These experiments will greatly enhance our understanding of the NAc dynamics that contribute to cue-driven reward seeking.
