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 A(2A) receptors (A(2A)Rs) are highly enriched in the striatopallidal neurons and are implicated in instrumental behavior control. However, the temporal importance of the A(2A)R signaling in relation to the reward and specific contributions of the striatopallidal A(2A)Rs 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 optoA(2A)R signaling precisely at the time of the reward to the control of instrumental learning, using our newly developed rhodopsin-A2AR chimeras (optoA(2A)R). We demonstrated that transient light activation of optoA(2A)R signaling in the striatopallidal neurons in 'time-locked' manner with the reward delivery (but not random optoA(2A)R 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 A(2A)R signaling in the DMS suppressed goal-directed behaviors, as focally genetic knockdown of striatopallidal A(2A)Rs in the DMS enhanced goal-directed behavior by the devaluation test. By contrast, optogenetic activation or focal AAV-Cre-mediated knockdown of striatopallidal A(2A)R in the DLS had relatively limited effects on instrumental learning. Thus, the striatopallidal A(2A)R 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.

Habit Formation after Random Interval Training Is Associated with Increased Adenosine A2A Receptor and Dopamine D2 Receptor Heterodimers in the Striatum

“…This novel molecular correlate of the RI training and possibly habit formation would be useful in molecular dissecting and monitoring habit formation. Moreover, our detailed analysis of A 2A R-D 2 R heterodimer changes on anterior-posterior axes indicated that the A 2A R-D 2 R heterodimers in the DMS showed more dynamic changes after RI training in agreement with our recent finding that the DMS A 2A R signaling plays a major role in control of instrumental learning (Li et al, 2016). …”

“…The increased association of the A 2A R-D 2 R heterodimers was seen selectively after the RI schedule (to promote habit), but was not seen in the mice trained by the RR schedule (to promote goal-directed behavior). Genetic and pharmacological studies have implicated several neurotransmitter and neuromodulator receptors take effects on development of goal-directed and habit behaviors, including D 1 R, D 2 R (Yin et al, 2009), CB 1 R (Hilário et al, 2007), NMDAR (Yin et al, 2005), A 2A R (Yu et al, 2009; Li et al, 2016), and Gpr6 (Lobo et al, 2007), by alteration of instrumental behaviors. However, to the best of our knowledge, this is the first report on the molecular marker of habitual formation that is selectively induced by the RI (but not the RR) training schedule.…”

Understanding the Functional Plasticity in Neural Networks of the Basal Ganglia in Cocaine Use Disorder: A Role for Allosteric Receptor-Receptor Interactions in A2A-D2 Heteroreceptor Complexes

“…It can lead to the differential dopaminergic signaling observed in the ventral and dorsal striatum with selective A2AR agonist induced inhibition of D2R signaling in the ventral striatum (Figure 2). The loss of the antagonistic allosteric A2AR-D2R interactions in the dorsal striatopallidal GABA neurons of the dorsal striatum found in cocaine self-stimulation can have an impact on novel habit formation versus goal-directed behavior that remains to be determined [78]. …”

“…However, A2ARs appear to have a different role in the dorsal striatum where a striatum-specific A2AR deletion led to selective impairment of habit formation [77]. Later on, it was demonstrated that dorsomedial striatopallidal GABA neurons upon optogenetic activation of their A2ARs diminished goal-directed behavior [78]. Thus, in this circuit, A2AR signaling when linked to reward may favour habit formation.…”

“…Neuronal plasticity induced by cocaine at the molecular level through allosteric mechanisms can therefore produce changes in the brain circuits involved. According to the work of Li et al [78], increases in A2AR signaling should lead to suppression of goal-directed behavior. Therefore, the increased balance of A2AR and D2R signaling in the dorsomedial striatopallidal GABA neurons through loss of the inhibitory allosteric mechanism should reduce, if anything, the appearance of abnormal habit formation.…”