“纹状体-外侧苍白球-运动皮层”通路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 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 the aging process, and in many neuropsychiatric disorders, however, its specific neuromodulation mechanism is not yet clear. At present, it is considered that: 1) The basal ganglia Indirect pathways are important pathways that regulate different information processing stages of working memory; 2) External globus pallidus may be the regulatory juncture of the basal ganglia system and “striatum-external globus pallidus-motor cortex" pathway. This loop (compared to the traditional indirect pathway) can achieve flexible and stable information transfer and meet the characteristics of real-time stable maintenance and flexible regulation of working memory information processing; 3) We have previously used the optogenetics activation of the external globus pallidus neurons to improve the ability of working memory information processing in the maintenance period (Delay period). Therefore, we propose a hypothesis that the external globus pallidus and its connective fibers are the key neural circuit nuclei that regulate the processing of working memory information. In this project, we will use two different delayed non-match working memory behavior detection paradigms(DNMTP), using optogenetics methods coupled with fiber photometry to activate the external globus pallidus and its connective fibers to study its neuromodulation effect on the working memory information processing (Encoding phase, Delay phase, Retrieval phase) and loop selection mechanism. The progress of this project will elucidate the new mechanism of neural circuits based on the regulation of working memory processing information by the exteral globus pallidus and its associated fibers, thus providing an important circuit mechanism to treat WM disorders upon neuropsychiatric diseases.

工作记忆是基本认知机能系统，其功能障碍见于多种神经精神疾病。WM保持短暂、容量有限，信息加工过程包括编码、保持、提取，神经机制未明。目前发现:1)基底神经节间接通路调控WM不同信息加工阶段；2)外侧苍白球可能是基底神经节系统的调控枢纽，而“纹状体-外侧苍白球-运动皮层”环路比传统的间接通路可实现信息灵活、稳定的传递，符合WM信息加工的特点；3）我们前期发现，WM信息加工保持期（Delay phase）操控外侧苍白球改善WM信息加工的能力。据此提出假说：外侧苍白球及联络纤维是调控WM信息加工过程关键神经环路。本项目中，光遗传学技术结合两种延迟非匹配行为范式和光纤记录技术，在WM信息加工的不同阶段操控外侧苍白球及其联络纤维，研究其对WM信息加工过程的调控作用及环路选择机制。项目进展将阐明基于外侧苍白球及联络纤维调控WM信息加工过程的新的神经环路机制，为神经精神疾病WM障碍治疗提供机制基础。

工作记忆（Working memory，WM）是脑内在短时间内对信息进行暂时加工和有限容量的贮存并对正在或将要进行的行为调节的基本记忆机能系统，与各种认知功能密切相关，具有认知和目标导向性行为、持续时间段和储存信息容量有限等特点。工作记忆的功能障碍是阿尔兹海默症、精神分裂症等多种神经退行性疾病和精神疾病常见病理现象，但其神经机制不明确。本课题组前期研究发现:（1）基底神经节间接通路调控工作记忆不同信息处理阶段；（2）外侧苍白球可能是基底神经节系统的一个调控枢纽，研究新发现的“纹状体-外侧苍白球-运动皮层”环路可能较传统的间接通路可实现灵活和稳定的信息传递，符合工作记忆信息处理的特点；据此提出假说：外侧苍白球上下游环路是调控工作记忆信息处理过程关键神经环路。.结果：.（1）保持期光激活前部GPe,而非后部GPe胞体显著增强低认知负荷下工作记忆表现。.（2）在工作记忆的保持期光激活间接通路DMS至GPe通路的投射末梢抑制了低认知负荷下工作记忆表现，而高认知负荷下无差异，同时影响运动表现。.（3）在工作记忆的保持和提取阶段抑制GPe至STh通路的投射神经元末梢，显著损害低认知负荷下工作记忆表现.（4）在工作记忆保持阶段抑制GPe至M2的投射末梢，损害低认知负荷下工作记忆表现.结论：前部GPe较后部GPe更可能参与工作记忆等行为的调控；间接通路上的DMS至GPe通路参与低认知负荷下工作记忆处理过程的保持阶段的调控并影响小鼠的运动表现；GPe至STh通路参与低认知负荷下工作记忆处理过程的保持和提取阶段的调控；GPe至M2通路参与低认知负荷下工作记忆处理过程的保持阶段的调控。.本研究中，我们使用光遗传学技术结合两种延迟非匹配行为范式和光纤记录技术，在工作记忆信息处理的不同阶段操控外侧苍白球及上下游环路，研究其对工作记忆信息处理过程的选择性调控作用，为神经精神疾病的工作记忆障碍治疗提供机制基础。