PT - JOURNAL ARTICLE AU - Carina Soares-Cunha AU - Bárbara Coimbra AU - Ana Verónica Domingues AU - Nivaldo Vasconcelos AU - Nuno Sousa AU - Ana João Rodrigues TI - Nucleus Accumbens Microcircuit Underlying D2-MSN-Driven Increase in Motivation AID - 10.1523/ENEURO.0386-18.2018 DP - 2018 Mar 01 TA - eneuro PG - ENEURO.0386-18.2018 VI - 5 IP - 2 4099 - http://www.eneuro.org/content/5/2/ENEURO.0386-18.2018.short 4100 - http://www.eneuro.org/content/5/2/ENEURO.0386-18.2018.full SO - eNeuro2018 Mar 01; 5 AB - The nucleus accumbens (NAc) plays a central role in reinforcement and motivation. Around 95% of the NAc neurons are medium spiny neurons (MSNs), divided into those expressing dopamine receptor D1 (D1R) or dopamine receptor D2 (D2R). Optogenetic activation of D2-MSNs increased motivation, whereas inhibition of these neurons produced the opposite effect. Yet, it is still unclear how activation of D2-MSNs affects other local neurons/interneurons or input terminals and how this contributes for motivation enhancement. To answer this question, in this work we combined optogenetic modulation of D2-MSNs with in loco pharmacological delivery of specific neurotransmitter antagonists in rats. First, we showed that optogenetic activation of D2-MSNs increases motivation in a progressive ratio (PR) task. We demonstrated that this behavioral effect relies on cholinergic-dependent modulation of dopaminergic signalling of ventral tegmental area (VTA) terminals, which requires D1R and D2R signalling in the NAc. D2-MSN optogenetic activation decreased ventral pallidum (VP) activity, reducing the inhibitory tone to VTA, leading to increased dopaminergic activity. Importantly, optogenetic activation of D2-MSN terminals in the VP was sufficient to recapitulate the motivation enhancement. In summary, our data suggests that optogenetic stimulation of NAc D2-MSNs indirectly modulates VTA dopaminergic activity, contributing for increased motivation. Moreover, both types of dopamine receptors signalling in the NAc are required in order to produce the positive behavioral effects.