Individual Differences in Nucleus Accumbens Activity and Cue-Reward Learning

Abstract

The nucleus accumbens (NAc) and its population of GABAergic medium spiny neurons (MSNs) converge inputs from cortical and subcortical structures to modulate behavioral responses associated with reward and motivation. In particular, the NAc plays a crucial role in cue-reward learning by linking appetitive unconditioned stimuli with external and internal cues to later drive conditioned responses (CR). For decades, much attention has been focused on understanding this carefully coordinated process that supports elemental associative learning mechanisms. We hypothesize that variations in NAc activity can contribute to aberrant and maladaptive behaviors. For example, evidence suggests that behavioral endophenotypes such as impulsivity and heightened cue reactivity – traits that have a neurobiological footprint on NAc activity during cue-reward learning – may predispose certain individuals to develop disorders like addiction. “Sign-tracker” (ST) and “goal-tracker” (GT) rats can be used as a behavioral model of individual differences in cue reactivity. During a Pavlovian conditioned approach (PavCA) procedure, GTs only use the reward cues as predictors, resulting in a CR directed toward the site of impending reward delivery (“goal-tracking”). In contrast, STs also attribute cues with incentive salience and find them rewarding, resulting in increased motivation towards and fixation on these cues measured by a CR directed toward the cue (“sign-tracking”). STs are more impulsive as well as susceptible to cue-induced reinstatement or “relapse” of drugs of abuse compared to GTs, making them an excellent model to study predisposition to addiction-like behaviors. Sign- and goal-tracking behaviors exhibit different levels of dependence on NAc activity, and this is reflected by differences in cue- and reward-evoked patterns of neuronal activity and dopamine release during Pavlovian learning. Why these distinct patterns of activity emerge is unknown, but we hypothesize that both the excitability state of MSNs in the NAc as well as the synaptic influence from glutamatergic sources, such as the ventral hippocampus (vHPC), could impact how sensitive the NAc is to input signals carrying cue-related information. To test this hypothesis, we began by establishing a physiological profile of the subregional membrane excitability of MSNs in the core and shell subdivisions of the NAc of naïve and behaviorally experienced rats. We found that MSNs in the shell consistently exhibited greater intrinsic excitability than those in the core, which supports that subregional excitability across the NAc may be important for understanding differences in NAc dynamics and reward-processing. We also found that STs had significantly lower firing capacity than GTs only in the NAc core, suggesting that individual differences in NAc excitability may be important for different expressions of conditioned responses toward rewarding cues and addiction susceptibility. Focusing on the vHPC-NAc projection, which is thought to regulate conditioned responses based on contextual information processing during cue-reward learning, we found that sign-tracking behavior is associated with reduced vHPC-NAc activity compared to goal-tracking. Collectively, these findings demonstrate that differences in NAc neuronal excitability and synaptic activity are present between STs and GTs. This work highlights the importance of individual differences in NAc physiology and activity during cue-reward learning for understanding how properties of emotionally salient cues are encoded and contribute to disease susceptibility.