机构：[1]Molecular Pharmacology Lab,School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou[2]Wincon TheraCells Biotechnologies, Nanning[3]Department of Neurobiology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China老年医学科首都医科大学宣武医院[4]Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts.
BACKGROUND: Working memory (WM) taps into multiple executive processes including encoding, maintenance, and retrieval of information, but the molecular and circuit modulation of these WM processes remains undefined due to the lack of methods to control G protein-coupled receptor signaling with temporal resolution of seconds. METHODS: By coupling optogenetic control of the adenosine A(2A) receptor (A(2A)R) signaling, the Cre-loxP-mediated focal A(2A)R knockdown with a delayed non-match-to-place (DNMTP) task, we investigated the effect of optogenetic activation and focal knockdown of A(2A)Rs in the dorsomedial striatum (n = 8 to 14 per group) and medial prefrontal cortex (n = 16 to 22 per group) on distinct executive processes of spatial WM. We also evaluated the therapeutic effect of the A(2A)R antagonist KW6002 on delayed match-to-sample/place tasks in 6 normal and 6 MPTP-treated cynomolgus monkeys. RESULTS: Optogenetic activation of striatopallidal A(2A)Rs in the dorsomedial striatum selectively at the delay and choice (not sample) phases impaired DNMTP performance. Optogenetic activation of A(2A)Rs in the medial prefrontal cortex selectively at the delay (not sample or choice) phase improved DNMTP performance. The corticostriatal A(2A)R control of spatial WM was specific for a novel but not well-trained DNMTP task. Focal dorsomedial striatum A(2A)R knockdown or KW6002 improved DNMTP performance in mice. Last, KW6002 improved spatial WM in delayed match-to-sample and delayed match-to-place tasks of normal and dopamine-depleted cynomolgus monkeys. CONCLUSIONS: The A(2A)Rs in striatopallidal and medial prefrontal cortex neurons exert distinctive control of WM maintenance and retrieval to achieve cognitive stability and flexibility. The procognitive effect of KW6002 in nonhuman primates provides the preclinical data to translate A(2A)R antagonists for improving cognitive impairments in Parkinson's disease.
基金：
the Start-up Fund from Wenzhou Medical University Grant Nos. 89211010, 89212012, and KYQD121004;
National Natural Science Foundation of China Grant Nos. 81630040, 31771178, 31600854, 81600991, and 31600859;
Zhejiang Provincial Special Funds Grant No. 604161241;
Key Laboratory of Vision Science, Ministry of Health, China Grant No. 601041241;
Central Government Special Fund for Local Universities’ Development Grant No. 474091314;
Zhejiang Provincial Natural Science Foundation Grant Nos. LQ15H090007, LY15H090020, and LY17C090009, Wenzhou Science and Technology Program Grant Nos. Y20150003 and Y20150254;
U.S. National Institutes of Health Grant Nos. DK095862, HL095556, and HL108922;
Boston University School of Medicine special research fund Grant No. DTD 4-30-14.
医学