基于帕金森病大鼠模型的基底节环路编码时间认知障碍的神经机制研究

The dimension of Time is significant important in cognitive perception and motor process of creatures. More and more studies suggest that dopamine system and striatum, which is primarily damaged in Parkinson's disease, is the core area for coding time information. Attempts to understand the neural mechanism of disfunction in time rhythm on Parkinson's disease, such as freezing of gait (which could be dramaticly relieved underlying timing rhythm cues), tremor, etc, would conduce to illustrate the pathogenic mechanism of the disease, and explore potential methods for diagnosis or even treatment ways. In prior studies, we have already proved evidence in support that the fast-spiking interneurons in striatum prefer on coding action time. However, the corresponding electrophysiological representations under pathophysiological conditions are still lack of data. Above all, we intent to use multichannel recording, electrical stimulation and optogenetic technology to study the firing property and temporal association across cortico-striatal circuits. Further neural activities under pathological condition would be explored to provide evidence for neuromodualtion, such as deep brain stimulus, in clinical patients with Parkinson's disease. Our study aims at illustrating the neural mechanism of time rhythm in motor function and disfunction, which may provide meaningful theoretical framework for further exploring the detection indexes and therapeutic strategys of Parkinsons' disease.

时间节律认知是生物体探究活动及运动执行中至关重要的维度。越来越多的研究显示，帕金森病累及的多巴胺系统暨纹状体是参与时间信息编码的核心区域，研究帕金森病患者的时间节律障碍将有助与阐明疾病发生机制，如冻结步态（时间节奏线索可戏剧性缓解）、震颤等症状，并对潜在的检测、治疗方法进行探索。我们在前期研究中发现纹状体内的快速发放中间神经元倾向于编码运动时间信息，然而该过程在病理生理情况下的表现及更深入的机制及应用仍亟待研究。据此我们拟通过多通道记录、光遗传学等核心技术，在时间感知任务中检测内侧前额叶皮层、背侧纹状体等区域的电活动特性与相位关系。在此基础上研究这些神经活动在帕金森样病理情况下的改变，旨在临床帕金森病患者中开展深部脑刺激等神经调控技术提供症状学上的神经环路机制。本研究拟进一步阐明皮质纹状体环路介导的时间节律在病理、生理情况下的神经机制，为探索新的帕金森病检测指标与治疗策略提供理论基础。

时间节律认知是生物体探究活动及运动执行中至关重要的维度。研究过程中我们深入研究了时间感知过程中背侧纹状体神经元的活动特征，找到其与基底节特定 神经元群活动在时间、强度上的关联性，以及与皮层脑电图电信号间的关联。. 本研究设计了固定时长重现任务的大鼠行为范式，从个体和群集水平上对计时相关的纹状体神经元的动态调控及校对基础进行了探索，初步阐明了该核团编码及处理时间信息的神经机制。或有助于为临床实践中诊断、评估乃至干预帕金森病等存在计时紊乱的疾病提供新的对策。.本研究以实验大鼠为载体，回答了纹状体是否参与编码秒内至秒级的时间信息以及进一步探讨了这种计时相关神经元活动改变的内在机制。结果揭示了短时程内时间校准的潜在机制，有助于揭示帕金森病等运动障碍疾病纹状体时间编码节律异常的神经基础。从而进一步阐明冻结步态、震颤等难治性症状在病理生理情况下可能存在的计时、节奏功能代偿或兼并途径，为优化脑深部电刺激疗效提供理论基础。 . 通过对帕金森病患者的步态评测结合功能磁共振，我们发现帕金森病患者纹状体与额叶之间的脑功能连接异常影响步态的节律，步态变异系数明显高于正常对照，尤其是伴有冻结步态的帕金森病患者。结合前期动物实验，研究表明纹状体病变导致的时间节律编码损害可能与帕金森病患者步态节奏紊乱相关。