BDNF-Narp介导的神经微环路γ振荡在氯胺酮调控恐惧消退中的作用及机制

Posttraumatic stress disorder (PTSD) is prevalent in patients with intraoperative awareness, which seriously endangers the physical and mental health of patients. Our preliminary study found that ketamine could increase the expression of BDNF, thus prevent the relapse of fear memory effectively. However, the underlying mechanism remains to be elucidated. Given that: 1) BDNF upregulates Narp expression, which can selectively recruit excitatory synaptic drive onto PV interneurons by promoting accumulation of AMPARs and regulate the excitation of PV interneuron. 2) PV interneuron and its specific γ oscillation are involved in the function of learning and memory, whereas their dysfunctions are closely associated with many neuropsychiatric diseases. Based on our results, phenotype loss of parvalbumin (PV) interneurons was involved in PTSD. Therefore, we hypothesize that ketamine can active BDNF-Narp signaling, subsequently facilitate the excitatory synaptic inputs to PV and then up-regulate the power of neural microcircuit γ oscillation, which can extinct the fear memory of PTSD. In our project, we will establish the animal model of PTSD and apply multiple techniques including molecular biology, electrophysiology, and behavior tests to reveal the new mechanisms underlying the fear extinction effects of ketamine in terms of molecules - synapses - cells - neural microcircuit - overall behaviors. This work will provide the theoretical basis for the treatment of sequela of intraoperative awareness.

创伤后应激障碍（PTSD）在术中知晓患者中普遍存在，严重危害患者的身心健康。我们前期研究发现：氯胺酮可通过上调BDNF水平，从而有效消除条件性恐惧记忆，但机制有待进一步阐述。鉴于：1）BDNF上调Narp的表达，其可特异性募集微清蛋白（PV）中间神经元上的AMPA受体，从而调控PV中间神经元兴奋性；2）PV中间神经元特异性产生的神经环路γ振荡参与学习记忆功能，其异常与多种精神疾病的发生密切相关。结合我们的研究结果：PV中间神经元 “表型缺失”参与PTSD的发生。故我们推测：氯胺酮通过活化BDNF-Narp信号通路，增加PV中间神经元接受的兴奋性突触传递及神经微环路γ振荡活动，从而消除PTSD的恐惧记忆。本课题通过建立PTSD动物模型，采用分子生物学、电生理、行为学等技术，从分子—突触—细胞—神经微环路—整体行为多层次揭示氯胺酮消除恐惧记忆的机制，有望为术中知晓后遗症的治疗提供新的理论依据。

术中知晓相关创伤后应激障碍（post-traumatic stress disorder，PTSD）是指在全身麻醉手术过程中，由于麻醉深度过浅导致患者术中知晓，立即或延迟出现并持续存在的一种心理精神障碍，表现为创伤性再体验症状，高度警觉症状及回避反应等三联征，并且持续时间≥1个月。尽管随着脑电监测的广泛应用，全身麻醉下发生术中知晓的几率已显著减少，然而术中知晓患者中PTSD的发病率仍高达71%，严重影响患者的康复和生活质量。因此，寻找安全有效的抗PTSD药物成为目前亟待解决的问题。本课题采用不可逃避足底电刺激小鼠模型，揭示氯胺酮治疗PTSD的机制。.通过前期研究，我们得出一些关键结果：.（1）PTSD模型小鼠表现出明显的焦虑抑郁样行为和恐惧记忆的再现；（2）PTSD模型小鼠AMPA受体亚基 GluA1和GluA2表达减少，脑源性神经营养因子（Brain-derived neurotrophic factor，BDNF）和正五聚蛋白 2（pentraxin 2， Narp）表达下降，BDNF-Narp信号失调；（3）高尔基染色表明PTSD模型小鼠海马树突棘数量减少；（4）氯胺酮可通过上调BDNF水平，有效消除条件性恐惧记忆。本课题揭示了BDNF-Narp信号是氯胺酮治疗PTSD发生的重要机制，为术中知晓后遗症的治疗提供了新视角和实验依据。