基底外侧杏仁核多巴胺D1受体介导环境线索提取药物戒断记忆的神经环路

Memory includes the encoding, storing and retrieval of information in the brain. This project will study the environmental cues-induced retrieval of the drug withdraw memory in animals that already forget the withdrawal symptoms. Our previous work found that chronic morphine treatment could significantly increase the expression of dopamine D1 receptors in the glutamatergic presynaptic terminals in the pyramidal cells of the basolateral amygdala (BLA) and the blockade of the D1 receptors in BLA could significantly inhibit the retrieval of the drug withdraw memory in the animal model. In this project, we will select some important neural nucleus, such as the ventral tegmental area, medial prefrontal cortex, anterior cingulate cortex, hippocampus, thalamus, and study their role, position and relationship in the circuit underlying environmental cues-induced retrieval of drug withdraw memory mediated by dopamine D1 receptors in BLA. We will also study whether some abnormal neural circuits induced by the chronic morphine treatment play roles in the environmental cues-induced retrieval of drug withdraw memory mediated by dopamine D1 receptors in BLA. This study is of important significance for revealing the neural circuit underlying environmental cues-induced retrieval of drug withdraw memory, for proposing how to selectively interfere the “bad” memory and for understanding the neuronal mechanism of the store and retrieval of memory.

记忆涉及信息的编码、存储和提取。本项目拟在形成药物戒断记忆的动物模型上，研究成瘾药物戒断后，已“遗忘”戒断症状的动物，在遇到环境线索时，药物戒断记忆被提取的神经机制。我们前期工作发现慢性吗啡处理可明显增加基底外侧杏仁核(BLA)锥体细胞兴奋性突触前末梢多巴胺D1受体的表达，BLA局部阻断D1受体可以显著抑制环境线索对吗啡成瘾鼠药物戒断记忆的提取。在此基础上，本项目拟选择一些重要核团如腹侧被盖区、前额叶皮层内侧区、扣带皮层前部、海马、丘脑等，研究它们在BLA兴奋性突触前神经末梢D1受体介导环境线索提取药物戒断记忆中的位置和相互关系，揭示哪些核团反映了戒断记忆的激活，哪些核团是戒断记忆激活的上游环节，并探索在吗啡作用下是否有新形成的异常神经环路介导了环境线索对戒断记忆的提取。本研究不仅对揭示环境线索提取戒断记忆的神经环路，也对理解更广意义的记忆存储和提取的神经机制具有重要意义。

记忆涉及信息的编码、存储和提取。本项目拟在形成药物戒断记忆的动物模型上，研究成瘾药物戒断后，已“遗忘”戒断症状的动物，在遇到环境线索时，药物戒断记忆被提取的神经机制。通过研究我们发现DAMGO可抑制BLA突触前谷氨酸释放，其机制是通过激活PLA2所致。这一作用很可能是DAMGO抗焦虑的主要机制。然而，外源性给予吗啡可取消DAMGO对 BLA突触前谷氨酸释放的抑制作用，并且其机制是由于吗啡对PLA2活性具有抑制作用，这种抑制作用取消了DAMGO对PLA2的激活作用。更为有趣的是，我们发现吗啡处了剥夺DAMGO的作用外，其自身还可通过另一条分子通路即ERK-Synapsin通路引起谷氨酸释放增加。这一作用可能是吗啡使用后受到应激因素易从抗焦虑转变为焦虑样负性情绪状态的原因之一。同时我们还发现mir-105可通过调节mPFC-BLA投射神经元突触前D1受体参与环境相关戒断记忆的再提取，这对于了解D1受体介导环境线索对吗啡成瘾鼠药物戒断记忆提取的机制提供了理论依据。