皮层-纹状体通路腺苷A2A受体对工作记忆信息加工过程的选择性调控及环路机制研究

Working memory is a short-term (usually within seconds) and limited (usually 3-4 items) memory system that is fundamental to human cognition and intelligence. WM comprises multiple cognitive subcomponents, which tap into several executive processes including encoding, maintenance and retrieval of information. WM decline and impairment is common during aging process and in many neuropsychiatric disorders. Our recent studies suggest the adenosine A2A receptor (A2AR) is an important therapeutic target for controlling cognition (including WM) impairment in neuropsychiatric disorders. However, the mechanistic understanding of the A2AR control of the distinct temporal phases associated with multiple cognitive subcomponents of WM (i.e. encoding, maintenance and retrieval) is limited, due to the lack of methods to control A2AR signaling with required spatiotemporal resolution to establish their casual roles in specific phase. Using our newly developed optogenetic method (optoA2AR) to control A2AR signaling in the cortico-striatal pathway with the second resolution, coupled with a delayed non-match-to-place task, we seek to demonstrate that A2AR signaling in dorsomedial striatum and frontal cortex is required for the maintenance and retrieval (but not the encoding) of SWM information. Using optoA2AR coupled with fiber photometry, we will further test the hypothesis that the A2AR signaling in prefrontal cortex and dorsomedial striatum during the delay and retrieval phases exert opposite control of SWM maintenance and updating to achieve cognitive stability and flexibility. These findings will identify the cortico-striatal A2AR signaling as a critical neuromodulator for pharmacological control of SWM information flow.

工作记忆（WM）是认知功能的根本能力之一，其功能障碍是多种神经精神疾病常见病理现象。WM持续时间短暂、容量有限，需复杂信息加工过程完成。我们前期研究表明皮层-纹状体通路腺苷A2A受体（A2AR）是调控WM等多种认知功能的新靶点。但由于缺乏在特定神经元上瞬时调控A2AR信号的技术，A2AR调控WM信息加工过程和神经环路机制不清。本项目利用我们新近开发光控A2AR信号技术（opto-A2AR）瞬时性激活A2AR的特点，结合两种延迟非匹配行为范式和活体钙成像光纤记录系统，探讨中心工作假说：前额叶皮层和纹状体神经元的A2AR信号选择性调控WM 信息加工 (编码、保持和提取) 过程，通过两脑区A2A受体信号对WM的不同调控来实现WM信息的稳定保持和灵活更新之间的平衡。本项目鉴定出皮层-纹状体通路A2AR为WM信息平衡控制的全新调节位点，为改善老年化和神经精神疾病WM障碍提供重要新药物靶点。

工作记忆（WM）是认知功能的根本能力之一，其功能障碍是多种神经精神疾病常见病理现象。WM虽持续时间短暂、容量有限，但需复杂信息加工过程完成。我们前期研究表明皮层-纹状体通路腺苷A2A受体（A2AR）是调控WM等多种认知功能的新靶点。但由于缺乏在特定神经元上瞬时调控A2AR信号的技术，A2AR调控WM信息加工过程和神经环路机制不清。本项目利用我们新近开发光控A2AR信号技术（optoA2AR）瞬时性激活A2AR的特点，结合T迷宫延迟非匹配工作记忆行为范式，系统解析了背内侧纹状体（DMS）、内侧前额叶皮层（mPFC）两个关键脑区的A2A受体分别在高低不同认知负荷下，对SWM的不同信息处理过程（编码、保持、提取）的选择性调控作用，揭示出内侧前额叶皮质（mPFC）、背内侧纹状体两脑区的A2AR对工作记忆具有显著不同的调控特征：纹状体-苍白球通路神经元的A2A受体信号不影响WM信息编码，而选择性调控WM信息的保持和提取，mPFC A2AR选择性调控WM信息保持，且mPFC和DMS两脑区的A2A受体对WM具有相反的调控作用，提示A2A受体作为神经内稳态调节分子，可协同调控WM信息稳定性和灵活性，调节两者间平衡以实现行为最优化。此外，皮层-纹状体A2A受体信号对WM的调控作用有认知负荷依赖性,该通路上的A2A受体选择性调控较低认知负荷（delay 10s）而非较高认知负荷（delay 20-60s）下的WM，提示伴随着认知负荷改变，神经环路及分子机制可能显著不同。在此基础上，腺苷A2A受体特异性拮抗剂KW6002可显著提高正常小鼠、正常非人灵长类动物及非人灵长类PD病理模型工作记忆表现，提示KW6002具有潜在临床改善认知的应用价值。本项目鉴定出皮层-纹状体通路A2AR为WM信息平衡控制的全新调节位点，为改善老年化和神经精神疾病WM障碍提供重要新药物靶点。