NMDA receptor-dependent plasticity in the nucleus accumbens connects reward-predictive cues to approach responses

Abstract

Learning associations between environmental cues and rewards is a fundamental adaptive function. Via such learning, reward-predictive cues come to activate approach to locations where reward is available. The nucleus accumbens (NAc) is essential for cued approach behavior in trained subjects, and cue-evoked excitations in NAc neurons are critical for the expression of this behavior. Excitatory synapses within the NAc undergo synaptic plasticity that presumably contributes to cued approach acquisition, but a direct link between synaptic plasticity within the NAc and the development of cue-evoked neural activity during learning has not been established. Here we show that, with repeated cue-reward pairings, cue-evoked excitations in the NAc emerge and grow in the trials prior to the detectable expression of cued approach behavior. We demonstrate that the growth of these signals requires NMDA receptor-dependent plasticity within the NAc, revealing a neural mechanism by which the NAc participates in learning of conditioned reward-seeking behaviors.

Reward versus motoric activations in nucleus accumbens core of rats during Pavlovian conditioning

“…While the present results indicate, with respect to each of the three behavioural events, that is, cue, approach and consumption, that NAc core processing was unrelated to inflexion point, cue-evoked excitations emerged over the first 3 days. This finding is in keeping with findings of (1) Dobrovitsky et al (2019), who demonstrated acquisition of cued approach within the first 3 days on this task and (2) Vega-Villar et al (2019), who showed that cue processing in NAc core anticipated the behavioural change point (analogous to inflexion point of the present report). We also found that core responses to the tone CS did not differ on hits versus misses, implying that NAc core may not be involved in the decision to respond or not respond to a single tone cue but does respond more strongly to an S+ than to an SÀ tone (Vega-Villar et al, 2019).…”

“…This finding is in keeping with findings of (1) Dobrovitsky et al (2019), who demonstrated acquisition of cued approach within the first 3 days on this task and (2) Vega-Villar et al (2019), who showed that cue processing in NAc core anticipated the behavioural change point (analogous to inflexion point of the present report). We also found that core responses to the tone CS did not differ on hits versus misses, implying that NAc core may not be involved in the decision to respond or not respond to a single tone cue but does respond more strongly to an S+ than to an SÀ tone (Vega-Villar et al, 2019). Our findings are similar to those of Ghitza et al (2003), in which NAc core neurons responded equally to a conditioned tone as well as a novel tone.…”

“…Thus, while the core is indeed activated by the tone, its 'cue processing' may actually reflect a premotor process. Other groups have observed similar cue-evoked elevations in NAc FR that endured throughout approach (Cerri et al, 2014;Sugam et al, 2014;Vega-Villar et al, 2019) or that triggered approach (McGinty et al, 2013;Morrison & Nicola, 2014). In further support, we have previously demonstrated a double dissociation whereby the NAc shell processed a discriminative stimulus but not the instrumental response, whereas the core processed motoric aspects of approach to, and execution of, the instrumental response but did not discriminate the cue (Ghitza et al, 2003(Ghitza et al, , 2004.…”

“…Alternatively, increased seeking when rewards are available could reflect greater core influence during shell glutamate blockade. It has further been shown that NAc core NMDA receptors play an important role in learning conditioned reward‐seeking behaviours (Vega‐Villar et al, 2019). NAc core also has an important role in cue‐induced reinstatement of natural reward seeking (Floresco et al, 2008).…”

Activity-Based Anorexia Dynamically Dysregulates the Glutamatergic Synapse in the Nucleus Accumbens of Female Adolescent Rats

“…Experiences, such as addictive drug exposure [48,52] or ABA induction, are likely to reverse the switch toward GluN2B-containing NMDA receptors, thus re-opening a critical period of vulnerability and re-programming the accumbal excitatory synapse toward immature or silent synapse. Besides, since NMDA receptor-dependent plasticity is required for learning association between environmental cues and reward-related behaviors [53], this phasic plasticity of NMDA receptor subunits observed in the NAc of ABA rats suggests that the consequent potential alteration in neurotransmission might be a signature of the ABA-induced vulnerability. Interestingly, in the acute phase of the pathology, despite the increase in GluN2A/2B ratio in the membrane fraction both anchoring proteins specific for NMDA receptor, SAP102 and PSD95, were reduced, thus suggesting NMDA receptor instability and altered NMDA-dependent neurotransmission.…”