Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors

TLDR

The basal ganglia–thalamocortical circuitry, including the nucleus accumbens, relies on parallel direct and indirect pathways whose dopaminergic modulation is essential for reward-seeking, aversive avoidance, and cocaine addiction. The study aimed to investigate how dopaminergic modulation of the NAc’s direct and indirect pathways influences reward and aversive learning. An asymmetric reversible neurotransmission-blocking approach was used, unilaterally blocking each pathway with tetanus toxin while locally infusing receptor‑specific agonists or antagonists on the intact side. The results showed that postsynaptic D1 receptor activation and D2 receptor inhibition in the direct pathway drive reward learning and cocaine addiction, whereas D2 inhibition in the indirect pathway mediates aversive learning, which is further promoted by NMDA, A2a, and CB1 receptor activity, demonstrating pathway‑specific neural plasticity in the NAc.

Abstract

The basal ganglia–thalamocortical circuitry plays a central role in selecting actions that achieve reward-seeking outcomes and avoid aversive ones. Inputs of the nucleus accumbens (NAc) in this circuitry are transmitted through two parallel pathways: the striatonigral direct pathway and the striatopallidal indirect pathway. In the NAc, dopaminergic (DA) modulation of the direct and the indirect pathways is critical in reward-based and aversive learning and cocaine addiction. To explore how DA modulation regulates the associative learning behavior, we developed an asymmetric reversible neurotransmission-blocking technique in which transmission of each pathway was unilaterally blocked by transmission-blocking tetanus toxin and the transmission on the intact side was pharmacologically manipulated by local infusion of a receptor-specific agonist or antagonist. This approach revealed that the activation of D1 receptors and the inactivation of D2 receptors postsynaptically control reward learning/cocaine addiction and aversive learning in a direct pathway-specific and indirect pathway–specific manner, respectively. Furthermore, this study demonstrated that aversive learning is elicited by elaborate actions of NMDA receptors, adenosine A2a receptors, and endocannabinoid CB1 receptors, which serve as key neurotransmitter receptors in inducing long-term potentiation in the indirect pathway. Thus, reward and aversive learning is regulated by pathway-specific neural plasticity via selective transmitter receptors in the NAc circuit.