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.

中文翻译：

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皮质纹状体腺苷 A 2A 受体控制空间工作记忆的维持和恢复

背景工作记忆 (WM) 涉及多个执行过程，包括信息的编码、维护和检索，但由于缺乏以时间分辨率控制 G 蛋白偶联受体信号传导的方法，这些 WM 过程的分子和电路调制仍未确定秒。方法通过将腺苷 A2A 受体 (A2AR) 信号的光遗传学控制、Cre-loxP 介导的局灶性 A2AR 敲低与延迟非匹配到位 (DNMTP) 任务相结合，我们研究了光遗传学激活和局灶性敲低的影响背内侧纹状体（每组 n = 8 至 14 个）和内侧前额叶皮层（每组 n = 16 至 22 个）中的 A2AR 在空间 WM 的不同执行过程中。我们还评估了 A2AR 拮抗剂 KW6002 对 6 只正常和 6 只 MPTP 治疗的食蟹猴延迟匹配到样本/放置任务的治疗效果。结果 背内侧纹状体中纹状体 A2AR 的光遗传学激活在延迟和选择（非样本）阶段会损害 DNMTP 性能。内侧前额叶皮层中 A2AR 的光遗传学激活在延迟（非样本或选择）阶段选择性地提高了 DNMTP 性能。空间 WM 的皮质纹状体 A2AR 控制是特定于新的但未受过良好训练的 DNMTP 任务。局灶性背内侧纹状体 A2AR 敲低或 KW6002 改善了小鼠的 DNMTP 性能。最后，KW6002 在正常和多巴胺耗尽的食蟹猴的延迟匹配样本和延迟匹配到位置任务中改进了空间 WM。结论纹状体和内侧前额叶皮层神经元中的 A2ARs 对 WM 维持和恢复发挥独特的控制，以实现认知稳定性和灵活性。KW6002 在非人类灵长类动物中的预认知作用为转化 A2AR 拮抗剂以改善帕金森病的认知障碍提供了临床前数据。