蓝斑-背侧海马或内侧前额叶皮层的神经环路在记忆晚期巩固介导的海洛因潜伏心理渴求中的作用及机制

Drug addiction is a chronic relapsing disorder, characterized by drug craving after prolonged abstinence and high relapse rate. The nature of drug craving is a kind of pathological memory basing on the modification of neuronal synaptic plasticity whcih existed after long-term withdrawal. Previous study showed the late consolidation of pathological memory, which contributes to its persistence. However, still unknown is the relationship between memory late consolidation and drug incubation. Locus coeruleus sends extensively adrenergic efferent projections to dorsal hippocampus and prefrontal cortex, which plays an important role in the encoding, consolidation and expression of emotional memory. In the present research, we intend to adopt self administration model, utilize optogenetics, retrograde tracing, electrophysiology, molecular biology, behavioral pharmacology and TH-Cre transgenic mice, to expolore the time window of the involvement of the tyrosine hydroxylase-expressing (TH+) neurons in locus coeruleus in memory late conslidation, and its role in heroin incubation. We further investigate the role of the adrenergic projections from locus coeruleus to dorsal hippocampus or prefrontal cortex in memory late consolidation windown in heroin incubation and the underlying molecular mechanisms. This research will provide new ideas and theoretical basis for the mechanism investigations of drug craving and the treatment of relapse.

药物成瘾是一种慢性复发性脑疾病，它的核心特征是成瘾者对药物强烈而持久的心理渴求和由此导致的高复吸率。心理渴求的本质是一种以突触可塑性改变为基础的病理性记忆，这种记忆在长期戒断后仍持续存在。最新研究表明病理性记忆存在晚期巩固阶段，它介导了病理性记忆的维持，但记忆晚期巩固与潜伏心理渴求的关系目前尚不清楚。蓝斑与背侧海马和前额叶皮层等脑区存在广泛的去甲肾上腺素(NE)能纤维联系，在情感记忆的编码、巩固和表达中起着重要的作用。本项目拟采用自身给药模型，利用光遗传学、逆向突触示踪、电生理技术、分子生物学、行为药理学和TH-Cre转基因鼠等手段，探索蓝斑NE能神经元参与成瘾记忆晚期巩固的时间窗及其在海洛因潜伏心理渴求中的作用，并进一步研究蓝斑-背侧海马或内侧前额叶皮层的NE能神经环路在晚期巩固介导的海洛因潜伏心理渴求中的作用及分子机制，以期为药物成瘾心理渴求的机制研究和防复吸治疗提供新思路和理论依据。

药物成瘾是困扰全球的严重医疗、社会和公共卫生问题，其核心问题是持续存在的心理渴求和高的复吸率。本项目基于药物成瘾是一种病理性情感记忆的理论，按照申请书中的研究目标开展了工作，取得了重要进展，在Mol Psychiatry、iScience、Transl Psychiatry、Neurosci Bull 等重要期刊发表SCI论文7篇。主要研究成果包括：1）发现蓝斑-前扣带回皮层的去甲肾上腺素能投射在病理性情感记忆的维持中发挥着非常重要的作用；2）发现基底外侧杏仁核中Pi4KIIα调控非条件性刺激诱导的病理性记忆再稳定过程，并在人体研究中明确非条件性刺激唤起-普萘洛尔范式可破坏与多个条件性线索相关联的病理性记忆；3）开发了基于脂肽的甲基苯丙胺疫苗合成，并通过免疫学和行为学实验证明了其有效性；4）提出了靶向中枢神经系统相关抗原治疗情感障碍性疾病的新的免疫疗法。这些成果探索了病理性情感记忆唤起和维持的神经机制和干预策略，为治疗药物成瘾等病理性记忆相关精神疾病提供了理论基础。