Chen Xing-Jun, Li Fei, Zhao Xinyue, Chen Long, Xue Jin, Yao Zhimo, Gan Zuobin, Lian Xiaoyue, Liu Zhenghao, Tong Luyao, Yan Qingshan, Qiu Linan, Wang Qin, Chen Jiang-Fan, Li Zhihui
The Molecular Neuropharmacology Laboratory and the Eye-Brain Research Center, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China.
PLoS Biol. 2025 Jul 24;23(7):e3003289. doi: 10.1371/journal.pbio.3003289. eCollection 2025 Jul.
Working memory (WM) is a fundamental cognitive function crucial adaptive behavior. The intricate interplay between the frontal cortex and striatum in governing WM maintenance and updating remains a central question. In this study, we employed optogenetics to demonstrate that inhibiting both dorsomedial striatum (DMS) D1R- and D2R-neurons enhances WM, while their activation impairs it across T-maze and operant-based delayed-non-match-to-place (DNMTP) paradigms in mice. Notably, these neurons selectively modulate WM maintenance and retrieval, with no impact on encoding. Analysis through signal detection theory (SDT) revealed specific regulation of WM signal detection sensitivity, with no alterations in motivational or motor states during the operant DNMTP task. Interestingly, DMS D2R-neurons govern WM regulation under low cognitive load, switching to D1R-neurons as cognitive load increases. Activation of DMS D1R-neurons during the delay phase severely impairs WM under high cognitive load, a deficit rescued by optogenetic inhibition of dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), or dopaminergic terminals in DMS. Additionally, treatment with the D1R antagonist SCH39166, but not the D2R antagonist Sulpiride mitigates these impairments. Collectively, our findings propose a "relay" model wherein cognitive load-dependent WM control switches from DMS D2R- to D1R-neurons, offering nuanced, complementary, and inhibitory regulation of WM maintenance and retrieval. This study suggests potential strategies to enhance WM by promoting a suppressive state in DMS and to increase WM capacity through specific modulation of DMS D1R-neurons.
工作记忆（WM）是一种对适应性行为至关重要的基本认知功能。额叶皮质和纹状体在控制工作记忆维持和更新方面的复杂相互作用仍然是一个核心问题。在本研究中，我们采用光遗传学方法证明，抑制背内侧纹状体（DMS）中的D1R和D2R神经元可增强工作记忆，而激活这些神经元则会在小鼠的T迷宫和基于操作的延迟非匹配位置（DNMTP）范式中损害工作记忆。值得注意的是，这些神经元选择性地调节工作记忆的维持和提取，而对编码没有影响。通过信号检测理论（SDT）分析发现，工作记忆信号检测灵敏度受到特定调节，在操作性DNMTP任务期间动机或运动状态没有改变。有趣的是，DMS中的D2R神经元在低认知负荷下控制工作记忆调节，随着认知负荷增加则切换为D1R神经元。在延迟阶段激活DMS中的D1R神经元在高认知负荷下会严重损害工作记忆，通过光遗传学抑制腹侧被盖区（VTA）和黑质致密部（SNc）中的多巴胺能神经元或DMS中的多巴胺能终末可挽救这一缺陷。此外，用D1R拮抗剂SCH39166治疗可减轻这些损伤，而D2R拮抗剂舒必利则不能。总的来说，我们的研究结果提出了一种“中继”模型，其中认知负荷依赖性的工作记忆控制从DMS中的D2R神经元切换到D1R神经元，为工作记忆的维持和提取提供了细微、互补和抑制性调节。这项研究提出了通过促进DMS中的抑制状态来增强工作记忆以及通过对DMS中的D1R神经元进行特定调节来增加工作记忆容量的潜在策略。
