miR-138通过增加棕榈酰基转移酶DHHC2活性促进恐惧记忆形成的机制研究

创伤后应激障碍已成为迫切需要解决的社会公共卫生问题，严重危害患者的社会功能和身心健康，造成了巨大的社会负担。然而，目前关于这种病理性恐惧记忆的神经生物学机制尚未完全明确。申请人前期研究发现恐惧训练后小鼠基底杏仁核miR-138表达显著上调，棕榈酰基转移酶DHHC2活性增加；且我们在基底杏仁核注射miR-138沉默病毒后，DHHC2酶活性降低，且恐惧记忆受损。因此，我们推测miR-138可能是通过增加DHHC2酶活性从而介导谷氨酸能突触传递来调控恐惧记忆的形成，然而，其具体机制尚待继续阐明。在前期工作基础上，采用条件恐惧记忆模型、病毒沉默技术、全细胞膜片钳及分子生物学等技术方法，研究miR-138介导的棕榈酰基转移酶DHHC2酶活性变化在恐惧记忆形成中的作用及其机制。从而阐明miR-138在病理性恐惧记忆中的作用提供可靠的理论基础，并为治疗创伤后应激障碍提供新的靶点和新的思路。

Post-traumatic stress disorder (PTSD) has become an urgent public health problem, seriously endangers the social function and physical and mental health of patients, and it also poses an enormous economic burden on society. However, at present, the neurobiological mechanism of pathologic fear memory has not been fully defined. Our previous study found that a significant upregulation of miR-138, as well as the activity of palmitoyl acyl transferases DHHC2. Silencing miR-138 with lentivirus lead to a decrease of DHHC2 activity, as well as an impairment of fear memory. Therefore, we speculate that miR-138 improves the formation of fear memory via increasing the glutamatergic synaptic transmission was mediated by enhancing the activity of DHHC2, but its mechanism remains to be clarified. Hence, based on previous works, our study combines model of fear conditioning, virus silencing technique, whole cell patch clamp as well as molecular biology to observe the effect and mechanism of miR-138 mediated changes of activity of DHHC2 on fear memory formation. Therefore, our study provides a reliable theoretical basis to clarify the role of miR-138 in pathologic fear memory, and affords novel targets and new thinking for treatment of PTSD.