异丙酚通过调控海马BDNF/TrkB通路实现遗忘效应的机制研究

Anterograde amnesia caused by propofol is one of the core desirable endpoints of general anesthesia. However, some patients might suffer from unintended intraoperative awareness and delayed recovery of cognition during and after propofol anesthesia. A better understanding of how amnesia was produced by propofol might be helpful for daily anesthesia practice...It is widely accepted that suppression of memory consolidation-related protein synthesis likely underlies propofol-induced amnesia for episodic memories. Nevertheless, the related signaling mechanisms are far from clear. ..Our previous work has identified a role of hippocampal cAMP/CREB signaling in propofol induced amnesia. Furthermore, we found that (1) propofol rapidly decreased hippocampal BDNF protein contents; (2) propofol attenuated BDNF-dependent TBS (theta burst stimulation)-LTP in synaptic responses from Schaffer collateral-commissural (SC) pathway to hippocampal CA1 pyramidal cells; (3) propofol inhibited downstreaming CaMKIIα and CREB phosphorylation of BDNF/TrkB signaling but had no effect on ERK1/2 and AKT activity. ..Considering that BDNF/TrkB signaling plays an essential role in LTP-dependent memory consolidation, we propose a fundamental or regulatory role of BDNF/TrkB activation induced cAMP/CREB changes in amnesia caused by propofol. ..This project deals with the following topics: (1) regulation of BDNF release by propofol; (2) roles of transcription and translation control of BDNF expression by propofol; (3) BDNF/TrkB signaling in TBS-LTP inhibited by propofol and its role in propofol-induced amnesia during Morris water maze training. Electrophysiological recording of LTP in cultured hippocampal slices and Morris water maze training with intrahippocampal infusion of selected drugs in rats will be used to fulfill this study. Moreover, cellular and molecular studies of protein expression and signaling transduction via pharmacological manipulations are needed. ..The goal is to elucidate the functions and mechanisms of hippocampal BDNF/TrkB signaling in propofol-induced amnesia. This experimental design might be helpful in seeking an efficient way to prevent amnesia-related intraoperative awareness and postoperative cognitive dysfunctions.

异丙酚等全麻药的遗忘效应既为全身麻醉必需，又与术中知晓、术后认知功能延迟恢复等相关。目前认为，异丙酚通过抑制记忆巩固相关蛋白表达实现遗忘，但机制不清。课题组在确定“海马cAMP/CREB通路参与异丙酚遗忘效应”的基础上，进一步发现异丙酚①下调BDNF表达；②抑制海马CA1区BDNF依赖的TBS-LTP；③抑制BDNF/TrkB下游CaMKIIα活化，但不影响ERK1/2和AKT活性。鉴于海马BDNF/TrkB通路在记忆巩固中的关键作用，我们设想异丙酚通过调控海马BDNF/TrkB信使实现遗忘效应。拟在离体和在体水平，采用脑片电生理、行为学实验和分子生物学技术，从BDNF释放、表达和下游信号活化三方面，研究异丙酚对海马BDNF/TrkB通路的调控机制；并探索反向干预BDNF/TrkB通路状态能否对抗异丙酚的遗忘效应。本研究有助于解释全麻药的遗忘机制，并为防治术中知晓等提供思路。

全麻药异丙酚的遗忘效应既为全身麻醉必需，又与术中知晓、术后认知功能延迟恢复等相关。异丙酚主要通过抑制记忆巩固相关蛋白表达实现遗忘，但机制不清。本课题组在前期研究中已发现海马cAMP/CREB通路参与了异丙酚遗忘效应，在此基础上，我们利用脑片电生理、行为学实验和分子生物学技术，从BDNF释放、表达和下游信号活化三方面，研究异丙酚对BDNF/TrkB的调控机制；并探索反向干预BDNF/TrkB状态能否对抗异丙酚的遗忘效应。研究发现异丙酚能够抑制大鼠海马CA1区TBS诱导的长时程增强（LTP）和BDNF释放、抑制大鼠BDNF/TrkB/PLCγ信号系统活化；BDNF孵育则可逆转异丙酚对TBS-LTP的抑制，双侧海马注射外源性BDNF可部分逆转异丙酚的遗忘效应；预先抑制BDNF/TrkB/PLCγ信号转导后，异丙酚对TBS-LTP的抑制作用消失且异丙酚不能进一步加重遗忘效应。通过该研究，我们证实了异丙酚可通过抑制海马BDNF/TrkB信号系统实现遗忘效应，为进一步研究特异性干预措施提供了理论依据，相关研究发表受资助SCI论文3篇，核心期刊论文2篇，协助培养研究生2名。