内侧前额叶与伏隔核亚区拓扑投射环路在吗啡成瘾记忆及复吸中的作用

Drug addiction, characterized mainly by compulsive drug-seeking and relapse, is an aberrant learning and memory. Previous studies and our recent findings show that both the prelimbic sub-regoin of the medial prefrontal cortex (mPFC)-the nucleus accumbens core (NAc core) and the infralimbic mPFC-NAc shell glutamatergic projection circuitries play differential roles in drug addiction memory and relapse, however, most of these results are derived from studies of cocaine addiction, it is unclear whether these phenomena will occur in opioid addiction. Therefore, in this study, we will first investigate whether an asymmetrical disconnection of brain areas of each of these two projection circuitries influences morphine addiction memory and its relapse by using morphine-induced conditioned place preference as an animal model in rats. Specifically, as oscillatory synchronization is an important index to probe information communication between different brain areas, we will use the multiple-unit ensemble recording technique to record and analyze dynamics of oscillatory synchronization in different phases of morphine addiction memory. Ultimately, these anticipated findings could disclose differentially functional roles of these two projection circuitries in morphine addiction memory and its relapse, and its underlying mechanisms, and could also potentially provide new therapeutic implications for the treatment of drug addiction and craving in addicts.

药物成瘾是一种病理性学习记忆,其核心特征是强迫觅药与复吸。已有的研究和我们最近的研究表明内侧前额叶背侧-伏隔核核部和内侧前额叶腹侧-伏隔核壳部两条谷氨酸能纤维投射环路在药物成瘾记忆及复吸中扮演不同的角色，但这些结果大都基于可卡因药物成瘾研究,是否在阿片类物质成瘾中也具有类似的现象还不清楚。因此，本项目计划用大鼠吗啡条件化位置偏好为动物模型，首先通过交叉干扰这两条投射环路脑区，研究其是否对吗啡成瘾记忆及复吸产生不同的影响。特别地，振荡同步化是研究脑区之间信息交流的重要方法，我们将采用多通道神经元集群记录技术记录并分析这两条环路中脑区内及其之间振荡同步化活动在吗啡成瘾记忆中动态变化。本项目的研究结果将揭示这两条投射环路在吗啡成瘾记忆中的功能性作用的异同及其内在机制，以及可为治疗药物成瘾及复吸提供新的思路和依据。

本项目利用电生理、行为学及药理学等多种技术手段，分别研究了腹侧海马脑区谷氨酸受体在恐惧记忆消退过程中的作用、长期酒精暴露对前额叶-伏隔核突触传递及其可塑性的影响以及帕金森病大鼠不同脑区核团电活动变化。结果发现：1，通过MK-801阻断大鼠腹侧海马脑区谷氨酸NMDA型受体，线索恐惧消退记忆的提取被破坏，进而降低了恐惧记忆的消退；2，在长期（14天）间隔性酒精暴露后，大鼠的前额叶-伏隔核突触传递长时程抑制被降低，但基础突触传递未被改变；3，在背侧纹状体及丘脑束旁核内，帕金森病大鼠表现出异常的局部场电位活动以及2脑区之间局部场电位同步化活动的增强，而且这些变化是动物活动状态依赖的。本项目研究结果表明： 1，腹侧海马NMDA型受体除了在场景恐惧记忆中扮演重要角色外，在线索恐惧记忆消退过程中也具有重要作用；2，酒精暴露引起前额叶-伏隔核突触传递突触可塑性改变，是导致酒精依赖及复饮的重要内在机制之一；3，丘脑-纹状体环路异常改变在帕金森疾病的病理生理机制中扮演重要角色。