FKBP5在创伤后恐惧记忆中的作用及机制

Stress response can be elicited by traumatic events, which is physical and/or psychological in nature, the response involve the neuroendocrine system, by which achieve homeostasis via cortisol negative feedback loop. It is reported that traumatic events are commonly plagued by recurrent frightening thoughts and memories of the aversive experience and suffer from a host of persistent physiological and behavioral sequelae, all these symptoms must be severe enough to impair social, occupational or interpersonal function, then, GR related signaling might be sufficient to regulate fear conditioning and consolidation and would thus be in a prime position to mediate mood and anxiety disorder. In our previous observation, several immune system relevant genes were identified, FKBP5 in particular was demonstrated to implicate in the modulation of Fyn tyrosine kinase activation and neuroendocrine circuit during traumatic stress. Based on these finding, in the present study, traumatic mice was established and exposed to a cat urine predator scent stressor, the role of FKBP5 in the fear conditioning and consolidation following traumatic events, could be manifested by the examination of the presence of single nucleotide polymorphisms (SNPs), FKBP5-GR complex in the dendrite spine in prefrontal cortex and limbic system, as well as SNPs of FKBP5 in the traumatic stress mediated exploratory and learned task performance, object recognition/location memory, social defeat and avoidance test. The result will help to elucidate the mechanism underlying posttraumatic stress disorder, especially psychiatric disorder, and guide the development of early and more effective clinical intervention.

创伤应激会诱导一系列生理和行为反应，神经内分泌系统、尤其是HPA轴在维持机体内环境稳态中起着重要的作用。研究表明创伤后常伴随出现焦虑性心理障碍，即被恐惧思想和负性经历的记忆所困扰，这些症状足以损毁人的社会、职业和交流功能，因此，探讨HPA轴相关信号通路在恐惧记忆的形成和强化中的作用及机制对于阐明创伤后心理障碍的发生至关重要。我们的前期工作提示酪氨酸蛋白激酶参与对糖皮质激素受体负性调节因子FKBP5及创伤应激过程中神经内分泌环路的调节。鉴于此，本研究应用创伤应激小鼠模型，给予恐惧样刺激，通过检测前额叶皮质和边缘系统FKBP5基因多态性，及其对糖皮质激素受体，树突棘结构及脑血流，小鼠的探索、目标识别及定位记忆、和社交行为的调节，证明FKBP5在创伤后恐惧记忆形成及强化中的作用。证实上述实验假设有助于了解创伤后应激反应尤其是心理障碍的发生机制，为相关的临床预防和治疗提供药物作用的靶点。

急慢性应激会诱导一系列生理和行为反应，神经内分泌系统、尤其是HPA轴在维持机体内环境稳态中起着重要的作用。研究表明FKBP5在应激反应，及应激后恐惧记忆形成及强化中的作用。首先，我们建立了包括创伤，电击在内的多种急慢性应激模型，并通过c-fos的表达，发现HPA轴以及前额叶皮质等情绪调节神经环路在多种急慢性应激中被激活；在探讨应激后反应的研究中，我们发现焦虑性心理障碍会诱导而发生或增强，如小鼠在应激后出现对吗啡成瘾的易化和对酒精摄取的增强，前额叶皮质及下丘脑的炎症因子及CRF信号系统参与其中；FKBP5通过对糖皮质激素受体的调节而抑制HPA轴的激活，进而调节树突棘结构及脑血流、和小鼠的探索、记忆等社交行为；在成功建立的恐惧记忆模型，我们发现FKBP5能通过调节前额叶皮质与下丘脑的神经环路，及部位特异性的PKC相关基因网络，而调节恐惧记忆的形成和强化。基于以上研究结果，提示FKBP5是应激过程中神经内分泌环路的重要调节因素之一，作为糖皮质激素受体负性调节因子，它能减弱恐惧思想和负性经历的记忆，并参与解除恐惧记忆对人的社会、职业和交流功能的破坏。上述实验结果有助于了解应激反应后心理障碍的发生机制，为相关的临床预防和治疗提供药物作用的靶点。