Clues on the coding of reward cues by the nucleus accumbens

Abstract

The study by Calipari et al. in PNAS provides a glimpse into the in vivo pattern of neuronal activation in the mouse nucleus accumbens during the acquisition and expression of learned reward-context associations (1). The nucleus accumbens sits in the ventral part of the mouse striatum, and is required for reward-motivated learning. The activity of neurons in this region is thought to code information on the reward value of cues and contexts. Two distinct subpopulations of striatal neurons can be identified based on their anatomical projections and the degree of expression of dopamine D1 and D2 receptors. Striatal neurons expressing D1 receptors (D1-expressing neurons) have been shown to enhance reward learning, whereas striatal neurons expressing D2 receptors (D2-expressing neurons) have been shown to reduce reward learning when activated via optogenetic stimulation (2, 3). These manipulations, together with decades of experimentation in the field, have led to consensus around a general model in which the outputs of D1-expressing neurons and D2-expressing neurons exert opposing actions on coding of reward value and where the balance of activity between these outputs determines the final state (Fig. 1A). Based on this conceptual framework, predictions can be made about the activity of D1-and D2-expressing neurons during reward learning. However, recording the activity of the striatal neurons in a cell-specific manner has been very difficult. To this end, Calipari et al. (1) introduce the genetically coded calcium indicator GCaMP6 selectively in D1-or D2-expressing neurons of the nucleus accumbens, and use fiber photometry to monitor the calcium signals generated in this cell-specific fashion during the acquisition of condition place preference for cocaine. It is important to stress that although each detected calcium signal is generated by the firing of one or more action potentials in the neuron, not every action potential appears to lead to a detectable calcium signal. The evidence for this arises from the fact that the frequency of recorded calcium signals (5-25 events per minute, see also ref. 4) is at least an order-of-magnitude lower than the frequency of action potentials recorded with implanted electrodes in the nucleus accumbens (5).That said, Calipari et al. (1) make several significant observations that directly test core predictions from the general model. When animals are placed in a context with little or no rewarding value, the frequency of calcium signals is larger in D2-expressing neurons than D1-expressing neurons. Noncontingent administration of cocaine produces opposite changes on the frequency of the calcium events in the two subpopulations of striatal neurons. During these conditioning sessions, cocaine decreases the frequency of calcium signals in D2-expressing neurons while increasing the frequency in D1-expressing neurons, likely through the well-described enhancement of dopamine extracellular concentration by cocaine. Interestingly, the study also shows that only a decrease in the frequ...

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