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.

Grant Number: 3F32DA060044-02S1
NIH Institute/Center: NIH
Principal Investigator: Dennis Burke