记忆痕迹在可卡因渴求孵育中的作用和机制研究

Relapse to drug use in humans or non-human can occur after prolonged abstinence and is often precipitated by exposure to drug-associated cues that provoke drug craving. The phenomenon, termed “incubation of drug craving”, was identified based on observations that time-dependent increases in cue-induced drug seeking occurred after withdrawal from the drug. The interventions of incubation can decrease the probability of relapse for drug. Thus the investigation of the underlying mechanisms of drug craving incubation is of scientific importance and valuable for treatment of addicts. Addiction is also a long-term memory. The re-exposure to the associated environmental cue as memory retrieval will induce drug seeking behavior. Then the persistent memory for drug is the pathological cause for relapse. Some studies showed that engram cells contribute to memory retrieval. In our previous studies, we have labeled engram cells of cocaine reward memory and investigated their neuronal plasticity remodeling. Our preliminary data showed that persistent chemical inhibition of these engram cells suppressed incubation of cocaine reward, suggesting the involvement of engram cells in incubation. In this projection, we will focus our study on basic scientific questions about the role of memory engrams and their molecular and synaptic mechanisms in incubation, then reveal the key role of memory engrams in the regulation of incubation of cocaine craving. This project is critical for understanding the mechanism of incubation and developing the targets for addicts treatment.

精神活性物质作用于脑内奖赏系统导致机体产生用药的心理渴求。在戒断后，机体对药物的渴求逐渐加强，即渴求孵育，这是药物复吸的关键原因。因此，对药物渴求孵育的机制研究具有重要科学意义。药物成瘾是一种长期记忆，相关环境线索的暴露能诱导记忆提取，进而导致药物复吸。该记忆的持续性存在是导致药物复吸的病理性基础。研究发现编码记忆的痕迹神经元对记忆的提取等功能起到关键作用。我们的前期研究标记了编码可卡因奖赏记忆的痕迹神经元，探讨了痕迹神经元的特性。我们的初步研究发现在戒断期内持续性抑制记忆痕迹神经元的活性能抑制药物渴求孵育，表明记忆痕迹神经元对孵育有重要影响。在此，本项目将集中探讨记忆痕迹神经元在可卡因渴求孵育中的作用，系统研究记忆痕迹神经元在孵育过程中所发生的神经元形态和突触功能重塑，解析记忆痕迹神经元在孵育过程中发生功能改变的分子基础，阐述可卡因渴求孵育的细胞和分子机制，为药物成瘾提供潜在治疗靶点。

药物渴求孵育是指药物成瘾患者经历戒断后对药物的心理渴求并没有随着戒断时间的延长而消失，相反在戒断几周后会对药物的渴求会随着戒断时间的延长呈现逐渐上升的趋势，并且维持很长一段时间。对药物渴求的孵育作用是药物戒断后复吸的重要风险因素之一。目前对于药物渴求孵育的发生机制尚不清楚。药物成瘾其本质是一种病理性记忆。本项目在以往工作的基础上，聚焦于伏隔核可卡因记忆痕迹神经元在可卡因渴求孵育中的作用和机制展开研究。我们的研究发现了伏隔核壳核可卡因痕迹神经元活性上调介导了可卡因渴求孵育，进一步研究发现可卡因戒断能诱导伏隔核壳核可卡因痕迹神经元内向整流钾通道Kir2.1下调并升高细胞膜兴奋性，进而介导了可卡因渴求孵育，阐述了可卡因渴求孵育的细胞和分子机制，揭示了腹侧海马至伏隔核记忆痕迹相关神经环路在可卡因奖赏相关记忆存储中的作用，发现伏隔核至苍白球的多巴胺D1受体阳性神经元投射环路介导了负性情感的编码并抑制可卡因奖赏相关记忆的形成。期间共发表本基金标注的高质量论文8篇，其中包括Cell Research (2021), Nature Neuroscience (2019), Science Signaling (2018)。授权国家发明专利和实用新型专利两项。上述研究为药物成瘾提供潜在治疗靶点和干预策略。