Nucleus accumbens neurons dynamically encode positive and aversive associative learning

Abstract

To survive, individuals must learn to associate cues in the environment with emotionally relevant outcomes. This association is partially mediated by the nucleus accumbens (NAc), a key brain region of the reward circuit that is mainly composed by GABAergic medium spiny neurons (MSNs), that express either dopamine receptor D1 or D2. Recent studies showed that both populations can drive reward and aversion, however, the activity of these neurons during appetitive and aversive Pavlovian conditioning remains to be determined. Here, we investigated the relevance of D1- and D2-neurons in Pavlovian associations, by measuring calcium transients with fiber photometry during appetitive and aversive Pavlovian tasks. Sucrose was used as a positive unconditioned stimulus (US) and foot shock was used as a negative US. We show that during appetitive Pavlovian conditioning, D1- and D2-neurons exhibit a general decrease in activity in response to CS and to US across learning, with dynamic, and partially overlapping, activity responses to CS and US. During the aversive Pavlovian conditioning, D1- and D2-neurons showed an increase in the activity in response to the CS and to the US (shock). Our data supports a synchronous role for D1- and D2-neurons in appetitive and aversion processing.

A novel perspective on the role of nucleus accumbens neurons in encoding associative learning

“…In contrast, we showed that D1-and D2-MSNs within the NAc core exhibit a general decrease in activity in response to cues and outcomes throughout Pavlovian learning, with dynamic and partially overlapping activity responses to both stimuli [19]. In aversive Pavlovian conditioning, both D1-and D2-MSNs increase activity in response to the cue and to the negative outcome (mild foot shock) [19]. Other studies report that both NAc shell D1-and D2-MSNs increase activity when mice withhold operant responses to unproductive reward seeking, suggesting that efficient reward seeking relies on complementary activity across NAc cell types [96].…”

“…A very recent study using fibre photometry recordings of calcium signals (bulk activity) in the NAc during a Pavlovian approach task showed that D1-MSNs present multiphasic calcium events during cue presentation and reward delivery (increased activity to both cue and reward), whereas D2-MSNs present a monophasic event only after reward delivery [20]. In contrast, we showed that D1-and D2-MSNs within the NAc core exhibit a general decrease in activity in response to cues and outcomes throughout Pavlovian learning, with dynamic and partially overlapping activity responses to both stimuli [19]. In aversive Pavlovian conditioning, both D1-and D2-MSNs increase activity in response to the cue and to the negative outcome (mild foot shock) [19].…”

“…Initially, akin to dorsal striatal MSNs, D1-MSNs were thought to mediate reward and positive associative learning, while D2-MSNs mediate aversion and negative associative learning. However, evidence from the last few years critically challenged this view [17][18][19]76]. Given this conundrum, here we will discuss data from electrophysiological, optogenetic and calcium imaging studies that contributed to a better understanding of the role of each MSN subtype in reward and aversion.…”

“…Importantly, many early and recent electrophysiological studies [10,11,15,16] and in vivo imaging of calcium signals [17][18][19][20] following the activity of NAc neurons over many days provided a fertile ground for Abbreviations A 2 a, adenosine receptor 2a; AMY, amygdala; BLA, basolateral amygdala; D1-MSN, dopamine receptor D1-expressing medium spiny neuron; D1R, dopamine receptor D1; D2-MSN, dopamine receptor D2-expressing medium spiny neuron; D2R, dopamine receptor D2; GPCR, G-protein coupled receptor; HIPP, hippocampus; LDT, laterodorsal tegmental nucleus; MSN, medium spiny neuron; NAc, nucleus accumbens; PFC, prefrontal cortex; PV, parvalbumin-expressing fast spiking GABAergic interneuron; RPE, reward prediction error; TAN, tonically active cholinergic interneuron; VP, ventral pallidum; VTA, ventral tegmental area. a greater understanding of associative learning encoding in this brain region.…”