Optogenetic Activation of Adenosine A2A Receptor Signaling in the Dorsomedial Striatopallidal Neurons Suppresses Goal-Directed Behavior

Abstract

The striatum has an essential role in neural control of instrumental behaviors by reinforcement learning. Adenosine A2A receptors (A2ARs) are highly enriched in the striatopallidal neurons and are implicated in instrumental behavior control. However, the temporal importance of the A2AR signaling in relation to the reward and specific contributions of the striatopallidal A2ARs in the dorsolateral striatum (DLS) and the dorsomedial striatum (DMS) to the control of instrumental learning are not defined. Here, we addressed temporal relationship and sufficiency of transient activation of optoA2AR signaling precisely at the time of the reward to the control of instrumental learning, using our newly developed rhodopsin-A2AR chimeras (optoA2AR). We demonstrated that transient light activation of optoA2AR signaling in the striatopallidal neurons in 'time-locked' manner with the reward delivery (but not random optoA2AR activation) was sufficient to change the animal's sensitivity to outcome devaluation without affecting the acquisition or extinction phases of instrumental learning. We further demonstrated that optogenetic activation of striatopallidal A2AR signaling in the DMS suppressed goal-directed behaviors, as focally genetic knockdown of striatopallidal A2ARs in the DMS enhanced goal-directed behavior by the devaluation test. By contrast, optogenetic activation or focal AAV-Cre-mediated knockdown of striatopallidal A2AR in the DLS had relatively limited effects on instrumental learning. Thus, the striatopallidal A2AR signaling in the DMS exerts inhibitory and predominant control of goal-directed behavior by acting precisely at the time of reward, and may represent a therapeutic target to reverse abnormal habit formation that is associated with compulsive obsessive disorder and drug addiction.