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前边缘皮层投射到丘脑室旁核神经元的NMDA受体参与吗啡戒断记忆提取

储辰珊^1,2, 文雅娴¹, 沈倩如¹, 来滨¹, 陈明¹, 郑平^1,*

¹复旦大学脑科学研究院，脑功能和脑疾病全国重点实验室，教育部脑科学前沿中心，上海 200032；²上海交通大学医学院附属第九人民医院神经内科，上海 200023

摘要

目前治疗药物成瘾的难题主要在于戒毒者的复吸率居高不下。成瘾性药物会给使用者带来极强的欣快感，促进对药物的寻求。形成药物依赖后一旦停止用药，将会出现强烈的负性情绪和不适的躯体反应等戒断症状，场景诱发戒毒者戒断记忆重现是产生复吸的首要原因。我们前期研究表明场景提取吗啡戒断记忆时前边缘皮层(prelimbic cortex, PrL)投射到丘脑室旁核(paraventricular nucleus of the thalamus, PVT)神经元(PrL^-PVT)的c-Fos 表达升高，但是PrL^-PVT投射神经元是否参与戒断记忆提取以及其分子机制仍然未知。本研究使用条件位置厌恶(conditioned place aversion, CPA)模型结合在体钙信号记录、化学遗传学以及核团定点给药的方法研究了PrL-PVT投射神经元在场景提取吗啡戒断记忆中的作用及分子机制。结果发现：戒断相关场景引起PrL^-PVT投射神经元钙信号显著增强；抑制PrL^-PVT投射神经元影响戒断记忆提取；激活PrL^-PVT投射神经元导致动物逃避相应场景；抑制PrL 脑区NMDA受体后，戒断相关场景无法增强PrL^-PVT投射神经元的c-Fos 及Arc 蛋白表达。以上结果表明，PrL^-PVT投射神经元的NMDA受体参与场景提取吗啡戒断记忆。本研究对深入认识戒断记忆提取的神经环路机制及干预和防治药物复吸具有重要意义。

关键词： 戒断记忆; 丘脑室旁核; 前边缘皮层; NMDA受体

NMDA receptors in prelimbic cortex neurons projecting to paraventricular nucleus of the thalamus are associated with morphine withdrawal memory retrieval

CHU Chen-Shan^1,2, WEN Ya-Xian¹, SHEN Qian-Ru¹, LAI Bin¹, CHEN Ming¹, ZHENG Ping^1,*

¹State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China；²Department of Neurology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200023, China

Abstract

At present, the problem of drug addiction treatment mainly lies in the high relapse rate of drug addicts. Addictive drugs will bring users a strong sense of euphoria and promote drug seeking. Once the drug is withdrawn, there will be withdrawal symptoms such as strong negative emotions and uncomfortable physical reactions. The recurrence of context-induced withdrawal memory is an important reason for drug relapse. Our previous study has shown increased c-Fos expression in prelimbic cortex (PrL) neurons projecting to paraventricular nucleus of the thalamus (PVT) (PrL^-PVT) during conditioned context-induced retrieval of morphine withdrawal memory. However, whether PrL^-PVT neurons are involved in withdrawal memory retrieval and the underlying molecular mechanisms remain unknown. In this study, we used conditioned place aversion (CPA) model combined with in vivo calcium signal recording, chemogenetics and nucleus drug injection methods to investigate the role and molecular mechanism of PrL^-PVT neurons in retrieval of morphine withdrawal memory. The results showed that the calcium signals of PrL^-PVT neurons were significantly enhanced by withdrawal-related context; Inhibition of PrL^-PVT neurons blocked the conditioned context-induced morphine withdrawal memory retrieval; Activation of PrL^-PVT neurons caused animals to escape from the context; After the inhibition of NMDA receptors in the PrL, withdrawal-related context failed to increase c-Fos and Arc expressions in PrL^-PVT neurons. The above results suggest that NMDA receptors in PrL^-PVT neurons are associated with retrieval of morphine withdrawal memory. This study is of great significance for further understanding the neural circuit mechanism of withdrawal memory retrieval as well as the intervention and prevention of drug relapse.

Key words: withdrawal memory; paraventricular nucleus of the thalamus; prelimbic cortex; NMDA receptor

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通讯作者：郑平　　E-mail:

引用本文：

储辰珊, 文雅娴, 沈倩如, 来滨, 陈明, 郑平. 前边缘皮层投射到丘脑室旁核神经元的NMDA受体参与吗啡戒断记忆提取[J]. 生理学报 2024; 76 (6): 917-926.

CHU Chen-Shan, WEN Ya-Xian, SHEN Qian-Ru, LAI Bin, CHEN Ming, ZHENG Ping. NMDA receptors in prelimbic cortex neurons projecting to paraventricular nucleus of the thalamus are associated with morphine withdrawal memory retrieval. Acta Physiol Sin 2024; 76 (6): 917-926 (in Chinese with English abstract).