Synapsin-Cre-GFP AAV (Serotype 8)

Dopamine release in striatal circuits, including the nucleus accumbens (NAc), tracks dissociable features of reward, such as motivation and reinforcement. Here, researchers show that dopamine D3 receptor (D3R) signaling in the NAc drives motivated behavior by modulating local NAc microcircuits. Furthermore, D3Rs are co-expressed with dopamine D1 receptors (D1Rs), which modulate reinforcement but not motivation. Parallel to the dissociable roles in reward function, researchers report non-overlapping physiological actions for D3R and D1R signaling in NAc neurons. These findings establish a new cellular framework in which dopamine signaling within the same NAc cell type is physiologically distinguished by actions at distinct dopamine receptors. This structural and functional organization provides neurons in limbic circuits with a unique ability to coordinate dissociable aspects of reward-related behaviors that are relevant to the etiology of neuropsychiatric disorders.

To specifically assess whether D3Rs acting on MSNs within the NAc microcircuitry are drivers of motivation, researchers implemented novel functional disconnection procedures, including pharmacological antagonism and cKO of NAc D3Rs (Figure 1c). In these experiments, control Drd3fl/fl mice were microinfused directly with SB-277011A and injected with AAV-hSyn-GFP-Cre into the NAc (Figure 1d). In this group, the unmanipulated hemisphere still had intact D3R signaling, thus supporting motivated behaviors (Figure 1e-f). The experimental group (contralateral Drd3fl/fl mice) underwent a functional disconnection in which unilateral NAc microinjections of SB-277011A and AAV-hSyn-GFP-Cre were performed in the contralateral hemisphere. Under these conditions, only D3R signaling in MSNs within the NAc underwent bilateral disruption (Figure 1d). Researchers hypothesized that if motivated running behavior is independent of local D3R signaling, then manipulating D3R activity in each hemisphere independently should not disrupt NAc D3R-mediated motivation. On the other hand, if motivation is mediated by local D3R signaling, then contralateral disconnection should disrupt motivation. Indeed, contralateral Drd3fl/fl mice exhibited motivational deficits as evidenced by reduced running behavior and preference for a freely moving disk compared to ipsilateral mice (Figure 1e-f). These results suggest that D3Rs acting on local MSNs within the NAc microcircuit are necessary for motivated behavior in mice.

Figure 1. Motivated behavior requires local D3R signaling within the NAc. (Enriquez-Traba J, et al., 2023)