title: 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.
authors.affiliation: The Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.affiliation: The Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Mozi
authors.initials: M
authors.lastname: Chen
authors.affiliation: The Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Zhilan
authors.initials: Z
authors.lastname: Pu
authors.affiliation: Department of Pharmacology, Fudan University Shanghai Medical College, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Molecular Biology Center, Research Institute of Surgery and Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: The Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: The Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Fudan University Shanghai Medical College, Shanghai, China.
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Huang
authors.affiliation: The Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Li
authors.affiliation: The Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Department of Neurology, Boston University, School of Medicine, Boston, MA, USA.
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003216:Conditioning, Operant / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006040:Goals; D020935:MAP Kinase Signaling System; D051379:Mice; D009474:Neurons / Q000502:physiology*; D062308:Optogenetics; D043705:Receptor, Adenosine A2A / Q000378:metabolism / Q000502:physiology*; D012201:Reward
chemical_list: D043705:Receptor, Adenosine A2A