Zhihui Li1, Xingjun Chen1, Tao Wang2, Ying Gao1, Fei Li1, Long Chen1, Jin Xue1, Yan He1, Yan Li1, Wei Guo1, Wu Zheng1, Liping Zhang1, Fenfen Ye1, Xiangpeng Ren1, Yue Feng3, Piu Chan3, Jiang-Fan Chen4. 1. Molecular Pharmacology Lab, School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, China. 2. Wincon TheraCells Biotechnologies, Nanning, China. 3. Wincon TheraCells Biotechnologies, Nanning, China; Department of Neurobiology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China. 4. Molecular Pharmacology Lab, School of Optometry and Ophthalmology, Wenzhou Medical University, Wenzhou, China; Department of Neurology, School of Medicine, Boston University, Boston, Massachusetts. Electronic address: chenjf555@gmail.com.
Abstract
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 A2A receptor (A2AR) signaling, the Cre-loxP-mediated focal A2AR knockdown with a delayed non-match-to-place (DNMTP) task, we investigated the effect of optogenetic activation and focal knockdown of A2ARs 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 A2AR antagonist KW6002 on delayed match-to-sample/place tasks in 6 normal and 6 MPTP-treated cynomolgus monkeys. RESULTS: Optogenetic activation of striatopallidal A2ARs in the dorsomedial striatum selectively at the delay and choice (not sample) phases impaired DNMTP performance. Optogenetic activation of A2ARs in the medial prefrontal cortex selectively at the delay (not sample or choice) phase improved DNMTP performance. The corticostriatal A2AR control of spatial WM was specific for a novel but not well-trained DNMTP task. Focal dorsomedial striatum A2AR 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 A2ARs 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 A2AR antagonists for improving cognitive impairments in Parkinson's disease.
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 A2A receptor (A2AR) signaling, the Cre-loxP-mediated focal A2AR knockdown with a delayed non-match-to-place (DNMTP) task, we investigated the effect of optogenetic activation and focal knockdown of A2ARs 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 A2AR antagonist KW6002 on delayed match-to-sample/place tasks in 6 normal and 6 MPTP-treated cynomolgus monkeys. RESULTS: Optogenetic activation of striatopallidal A2ARs in the dorsomedial striatum selectively at the delay and choice (not sample) phases impaired DNMTP performance. Optogenetic activation of A2ARs in the medial prefrontal cortex selectively at the delay (not sample or choice) phase improved DNMTP performance. The corticostriatal A2AR control of spatial WM was specific for a novel but not well-trained DNMTP task. Focal dorsomedial striatum A2AR 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 A2ARs 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 A2AR antagonists for improving cognitive impairments in Parkinson's disease.
Authors: Alfredo Oliveros; Ki Hyun Yoo; Mohammad Abdur Rashid; Ana Corujo-Ramirez; Benjamin Hur; Jaeyun Sung; Yuanhang Liu; John R Hawse; Doo-Sup Choi; Detlev Boison; Mi-Hyeon Jang Journal: Proc Natl Acad Sci U S A Date: 2022-07-07 Impact factor: 12.779
Authors: Lora J Kasselman; Heather A Renna; Iryna Voloshyna; Aaron Pinkhasov; Irving H Gomolin; Isaac Teboul; Joshua De Leon; Steven E Carsons; Allison B Reiss Journal: J Tradit Complement Med Date: 2022-02-01