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目的硫化氢(H2S)是一种内源性气体信号分子,在生物体内发挥着广泛的生物学效应。中枢神经系统的H2S作为一个突触调节分子,具有神经保护作用。有研究发现,额颞叶退变性疾病和阿尔茨海默病患者可出现杏仁核依赖的情感记忆异常。神经退行性疾病(如阿尔茨海默病、帕金森病等)患者或动物大脑H2S含量出现异常。但目前对于H2S与学习记忆和情感记忆的关系尚未有相关的报道。本实验研究气体信号分子H2S在大鼠海马区和杏仁核区介导的记忆行为中的作用及机制。方法条件性恐惧记忆和新事物认知实验观察大鼠的记忆行为;脑片膜片钳和场电位技术记录NMDA受体介导的电流及LTP;Western blotting实验研究突触可塑性相关蛋白的表达水平。结果条件性和线索性恐惧学习训练均可明显增加大鼠海马区H2S的含量。H2S合成酶抑制剂可损伤海马依赖的情景性恐惧记忆,和杏仁核依赖的线索性恐惧记忆。外源性补充H2S可剂量依赖性的增强大鼠的记忆行为。同样,外源性给予H2S也可明显增强杏仁核依赖的条件性味觉厌恶记忆,以及海马依赖的新物体认知功能。电生理实验发现,H2S选择性增强海马区含NR2A亚基的NMDA受体介导的电流和NMDA受体依赖的海马LTP;且NR2A特异性阻断剂可取消H2S对LTP和认知功能的增强作用。但选择性增强丘脑-杏仁核通路含NR2B亚基的NMDA受体所介导的电流及NMDA受体依赖性LTP。H2S增强学习记忆的作用与PKA,PKC,CaMKⅡ和CREB等信号通路激活有关。结论作为一种内源性气体信号分子,H2S在海马和杏仁核依赖的记忆行为中扮演着重要角色,为将H2S释放药物开发成为治疗情感障碍性疾病的药物提供新思路。
Objective Hydrogen sulfide (H2S) is an endogenous gas signaling molecule that exerts a wide range of biological effects in organisms. The central nervous system of H2S as a synaptic regulatory molecules, with neuroprotection. Studies have found that amygdala-dependent affective memory abnormalities may occur in patients with frontotemporal degenerative diseases and Alzheimer’s disease. Patients with neurodegenerative diseases (such as Alzheimer’s disease, Parkinson’s disease, etc.) or animal brain abnormal H2S content. However, there is no relevant report about the relationship between H2S and learning and memory. This study investigated the role of gas signaling molecule H2S in memory-mediated memory behavior in the hippocampus and amygdala of rats. Methods Conditioned fear memory and novelty cognition experiments were used to observe the memory behavior of rats. Brain slices patch clamp and field potentials were used to record NMDA receptor-mediated currents and LTP. Western blotting was used to investigate the expression of synaptic plasticity-related proteins . Results Conditional and clues learning training can significantly increase the content of H2S in hippocampus of rats. H2S synthase inhibitors can damage the hippocampus-dependent contextual fear memory and amygdaloid-dependent clichés. Exogenously supplemented H2S enhances memory behavior in rats in a dose-dependent manner. Similarly, exogenous administration of H2S significantly enhanced amygdalus-dependent conditioned taste aversive memory and cognitive function of new hippocampus-dependent new subjects. Electrophysiological experiments showed that H2S selectively enhanced NMDA receptor-mediated current and NMDA receptor-dependent hippocampal LTP in the hippocampus with NR2A subunit; and NR2A-specific blockade of H2S attenuated LTP and cognitive function effect. But selectively enhances the NMDA receptor-mediated current and NMDA receptor-dependent LTP of the NR2B subunit of the thalamic-amygdala pathway. The role of H2S in enhancing learning and memory is related to the activation of signal pathways such as PKA, PKC, CaMKII and CREB. Conclusions As a kind of endogenous gas signaling molecule, H2S plays an important role in memory behavior dependent on hippocampus and amygdala, which provides a new idea for the development of H2S-releasing drug as drug for the treatment of affective disorder.