β-arrestin偏向性受体信号通路在可卡因奖赏记忆再巩固中的作用研究

β-肾上腺素受体是一类与G蛋白偶联的神经递质受体，在脑内广泛分布并在学习记忆等脑功能中发挥关键作用，是药物研发的重要靶点。过去一直认为该受体通过激活G蛋白信号通路参与记忆再巩固，申请者最近发现物体辨别记忆的再巩固并不依赖于β-肾上腺素受体/G蛋白通路而依赖于β-arrestin，提出β-肾上腺素受体/β-arrestin偏向性信号通路介导记忆再巩固的假说。在此基础上，本研究采用可卡因奖赏记忆模型，β-肾上腺素受体和β-arrestin条件敲除小鼠，结合腺相关病毒建立Cre-loxP重组酶系统和及早基因驱动的四环素调控表达系统，进行脑区条件敲除和神经元选择性敲除，结合β-ARs偏向性工具药，揭示β-arrestin偏向性肾上腺素受体信号通路在药物奖赏记忆再巩固中的作用及机制，以验证我们的假说。本研究有良好前期基础，可行性强和重要的理论创新，为药物成瘾等记忆相关疾病提供药物靶点。

β-adrenergic receptors (β-ARs) as the G protein coupled receptor, widely distribute in central nervous system, playing an important role in learning and memory. Activation of β-AR promotes downstream signals through Gs and β-arrestin. It is mostly accepted that β-AR is involved in memory formation through Gs dependent cAMP activation. However, our recent research shows that blockade of β-adrenergic receptor impaired memory reconsolidation of object recognition through non-G protein dependent pathway and proposes that β-arrestin biased pathway activation regulates memory reconsolidation. Based on the previous study, our question is will β-AR biased pathway be involved in addictive drug memory reconsolidation. The aim of this project is to study the role of β-AR biased signaling pathways in reward memory reconsolidation induced by cocaine. Then combined with Cre-Loxp system carried by AAV and Doxycycline manipulation system driven by immediately early gene, the β-AR and β-arrestin conditional knockout mice will be developed. The biased ligands for β-ARs are also performed in these animal models. The effect of regulation of β-AR function or expression on reward memory reconsolidation of cocaine will be investigated and whether the β-arrestin biased signal pathway regulated by β-ARs is involved in. This novel mechanism of cocaine reward memory reconsolidation will supply a new neurobiological evidence for memory dynamic storage and clues for clinical treatment for drug addiction.