海马齿状回S1P/S1PR1信号通路介导慢性疼痛相关记忆损伤的细胞和分子机制

记忆损伤是慢性疼痛常见的伴发症状，因机制不清，导致有效治疗手段缺乏。研究发现海马齿状回突触可塑性变化与记忆损伤相关。1-磷酸鞘氨醇（S1P）受体S1PR1在海马齿状回中高度表达且可能参与学习记忆的调控，但其调控海马齿状回突触可塑性变化的特征与机制、以及在慢性疼痛相关记忆损伤发生中的作用仍需深入探究。我们前期研究发现，S1PR1在海马齿状回门部突触蛋白积聚处表达较高，提示S1P/S1PR1信号通路可能参与调控海马齿状回的突触可塑性。我们将利用秀丽线虫作为信号通路关键分子的筛选工具，慢性疼痛相关记忆损伤小鼠作为疾病模型，综合运用神经示踪、膜片钳、慢病毒shRNA干扰、脑立体定位注射等技术，从行为学、细胞和分子水平系统探索S1P/S1PR1信号通路参与慢性疼痛相关记忆损伤的脑机制。本课题将揭示慢性疼痛致记忆损伤发生的全新机制，为新药研发靶点的确定及临床治疗提供科学依据。

Memory impairment is often comorbid with chronic pain. However, the underlying mechanism is unclear, thus leading to less effective clinical management. Previous studies found that memory impairment is partly attributed to altered synaptic plasticity in the hippocampal dentate gyrus (DG). The sphingosine 1-phosphate (S1P) receptor S1PR1 is highly expressed in the DG and plays a pivotal role in memory formation, but its function in synaptic plasticity and occurrence of chronic pain-related memory impairment still awaits further exploration. Our preliminary data showed that S1PR1 localized in the nerve terminal synapses in DG hilus, suggesting that the S1P/S1PR1 signaling pathway may participate in the regulation of synapse formation in the DG. We will use Caenorhabditis elegans as the screen model organism for identifying key molecules along the signaling pathway, and mice with neuropathic pain-related memory impairment as the disease model. Neuronal tracing, patch clamp recording, lentiviral shRNA interference, stereotaxic surgery and microinjections would be applied to investigate the behavioral, cellular and molecular mechanism of S1P/S1PR1 signaling pathway in the pathogenesis of chronic pain-related memory impairment. This project will reveal a novel mechanism for chronic pain-related memory impairment and identify new targets for drug development.