Neurotensin通过调节神经元兴奋性改善认知功能障碍的作用及机制研究

It is a significant issue in neuroscience that how to efficiently improve and cure the cognitive disorders, such as Alzheimer's disease. It is found in recent research that the synaptic plasticity and long-term potentiation could enhance learning and memory function, which could also be an important means to treat Alzheimer's disease. The results in our publication and pre-experiments showed that, neurotensinergic excited dentate gyrus granule cells via Gαq-coupled inhibition of TASK-3 channels. However, the pre-synaptic mechanism of promoting neuronal excitability, and whether it can improve cognitive function require further study. This study would explore in-depth of neurotensin which facilitates neuronal excitability by increasing the size of readily releasable pool and releasing probability, supplemented by patch clamp, light genetics, neurobehavioral test and other experimental methods. It would demonstrate the hypothesis that neurotensin could enhance neuronal excitability, produce long-term potentiation and improve cognitive dysfunction ultimately. This research could also provide the basis for future research on clinical treatment of cognitive disorders upon neurotensin or its acceptor as new drugs. It could be meaningful in both theoretical and clinical area.

如何有效地改善和治疗以阿尔茨海默症为代表的认知功能障碍疾病一直是神经科学界所关注的重要问题。新近的研究认为，突触可塑性调节产生的长时程增强在形成学习记忆功能的同时，有可能作为阿尔茨海默症治疗的重要手段。通过前期研究和预实验，我们发现内源性多肽神经降压素(Neurotensin)通过抑制钾离子通道可诱导海马颗粒细胞去极化并增加突触间兴奋性递质释放，但其促进神经兴奋性增强的突触前机制，和其是否具有改善认知功能的作用仍需进一步研究。本课题辅以膜片钳、光遗传学、行为学等实验手段，将深入探索Neurotensin通过促进递质囊泡转运从而调节神经元兴奋性的突触传递机制，力求证实其在增强神经元兴奋性的基础上可产生长时程增强并改善认知功能障碍这一假说。本研究以Neurotensin或其受体作为新型药物或干预靶点，为未来将其应用于认知功能障碍类疾病的临床治疗奠定了基础，有着积极的理论和临床意义。

如何有效地改善和治疗以阿尔茨海默症为代表的认知功能障碍疾病一直是神经科学界所关注的重要问题。新近的研究认为，突触可塑性调节产生的长时程增强在形成学习记忆功能的同时，有可能作为阿尔茨海默症治疗的重要手段。我们前期的研究证实：内源性多肽神经降压素(Neurotensin，NT)，可通过抑制钾离子通道诱导海马颗粒细胞去极化并增加突触间兴奋性递质释放，产生长时程增强效应。但其促进神经兴奋性增强的突触前、及神经环路机制，和其是否具有改善认知功能的作用仍需进一步研究。本课题辅以膜片钳、形态学、行为学等手段，深入探索了NT通过促进递质囊泡转运从而调节神经元兴奋性的突触传递机制。研究发现，NT通过受体NTS-1激活L型Ca2+通道后通过Calmodulin、磷酸化MLCK和最终激活Myosin、促进突触前膜兴奋性神经递质释放这一全新通路（NT/NTS-MLCK-Myosin-Glutamate），证实了其在增强齿状回颗粒细胞元兴奋性的基础上，可通过Perforant Path途径，对海马CA1区神经元产生长时程增强效应并改善动物学习记忆功能这一生物学现象。本研究将以NT或其受体作为新型药物或干预靶点，为未来其应用于各类认知功能障碍类疾病的临床治疗奠定了基础，有着积极的理论意义和临床价值。

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