5-羟色胺4受体激动剂抑制恐惧记忆消除后重现的生物学机制

Posttraumatic stress disorder (PTSD) is a psychological disease which severely deteriorates psychological and physiological health. The handicap of treatment of PTSD is the trend of relapse of fear memory after extinction training. The applicant have found that 5-HT 4 receptor (5-HT4R) agonist RS 67333 reduced relapse of extincted fear memory and converted the extinction circuitry to a more immature state, which could reduce the relapse of extincted fear memory. Thus, we raise the hypothesis that agonism of 5-HT4R could reduce the relapse of the extincted fear memory. In the project, we plan to explore and clarify the mechanisms of 5-HT4R on the relapse of extincted fear memory using rodent animal fear condition model, Western-blot, encephalic region microinjectin,immunohistochemistry and brain slice patch-clamp techniques. First, we will study the relationship between the 5-HT4R-cAMP-CREB-BDNF pathway and the reduced extincted fear memory relapse as well as immature state convert. Second, we will explore the molecular mechanisms of modulation of 5-HT4R on plasticity of fear extinction circuitry. Third, we will study the electrophysiological mechanisms of modulation effect of 5-HT4R on the extinction circuitry plasticity.The research results of the project would provide the experimental basis and novel target for the effective treatment of PTSD.

创伤后应激障碍（PTSD）是严重影响人民身心健康的心理疾病，其治疗难点是恐惧记忆在消除后易于重现。申请人在前期研究中发现5-羟色胺4受体（5-HT4受体）激动剂RS67333能抑制恐惧记忆消除后重现并能诱导杏仁核神经元幼稚化逆转，文献表明，神经元幼稚化状态有利于抑制恐惧记忆消除后重现。因此，我们提出假设：激动5-HT4受体可抑制恐惧记忆消除后重现。本项目拟在前期研究基础上，采用啮齿类动物条件性恐惧模型、蛋白电泳、免疫组化、脑区微量给药、脑片钳等技术研究5-HT4受体调控恐惧记忆消除后重现的生物机制。首先，从整体水平研究5-HT4受体-cAMP-CREB-BDNF途径与抑制恐惧记忆重现及诱导幼稚化逆转的相关性，其次，从分子水平阐明5-HT4受体调控消除神经环路的可塑性，再次，采用脑片钳研究5-HT4受体对消除神经环路可塑性调控的电生理机制。研究成果将为PTSD治疗提供新的思路和靶标。

创伤后应激障碍（PTSD）是严重影响人民身心健康的心理疾病，其治疗的难点是创伤性恐惧记忆在消除后易于重现。申请人发现激动5-HT4受体能抑制恐惧记忆消除后重现，RS67333能促进神经元的幼稚化逆转。本项目发现5-HT4受体激动剂RS67333能抑制情景因素诱发恐惧记忆消退后恢复， RS67333能促进海马Akt、BDNF、CREB表达及CREB磷酸化，RS67333海马及内侧前额叶局部给药也能抑制情景因素诱发恐惧记忆消退后恢复。但是我们的研究发现用CREB的磷酸化抑制剂HCG 001抑制CREB在海马的磷酸化过程并不能阻断RS67333的药理作用。综上所述，RS67333能抑制恐惧记忆消退后恢复，其机制可能与Akt、BDNF、CREB的信号通路相关，主要作用的脑区为背根海马及内侧前额叶皮层。