LPB—CeA胆碱能投射在METH复吸中的调控作用及机制研究

甲基苯丙胺（methamphetamine，METH）是我国常见滥用毒品。高复吸率是临床戒毒难题，应激是诱发复吸的原因之一。外侧臂旁核（lateral parabrachial nucleus，LPB）与中央杏仁核（central amygdala，CeA）是编码应激事件的重要脑区，是毒品作用靶点。课题组研究发现：LPB至CeA（LPB—CeA）存在胆碱能投射；调控LPB胆碱能神经元活动，可干预小鼠METH复吸行为。本项目采用应激诱导小鼠METH复吸模型，结合病毒示踪、光/化学遗传、光纤记录、膜片钳、微透析、液质联用、形态学和分子生物学等方法，探究：①LPB—CeA胆碱能投射的结构和功能图谱；②LPB—CeA胆碱能投射在METH复吸行为中的运行机制；③调控LPB—CeA胆碱能投射活动对METH复吸行为的干预作用及关键靶标。本项目通过阐释毒品复吸的神经环路机制，为临床戒毒提供新的靶点和策略。

Methamphetamine (METH) is one of the most common abused drugs in China. In clinic, the high rate of relapse to drugs is the biggest challenge for the treatment of addiction. Stress is one of the main inducers for the relapse to drugs. Till now, there is lack of effective therapeutic approaches for the treatment of addiction and relapse, partially due to less understanding of the etiology caused by abused drugs. Lateral parabrachial nucleus (LPB) and the central amygdala (CeA) encode the information about stress-related events, and are main neurotoxic targets for the abused drugs. In our preliminary study, we found: ①Choline acetyltransferase (CHAT)-positive neurons are detected in the LPB, which means there are cholinergic neurons in the LPB; ②There exist cholinergic fibers projecting from LPB to the CeA, which forming LPB(CHAT)—CeA neural circuit; ③Local knockdown the activities of CHAT-positive neurons in LPB using CHAT-cre mice can block METH-related reinstatement behaviors in conditioned place preference (CPP) tests. Based on these findings, by establishing stress-induced reinstatement mice models of METH-SA (self-administration) and METH-CPP, combined with techs including virus neurol tracing, photo- / chemico-genetics, fiber photometry, patch clamp, micro-dialysis, liquid chromatography-mass spectrometry, immunofluorescence imaging, RNAscope, electron microscopy and molecular biochemical methods, the current proposal aims to explore: ①The structural and functional maps of the LPB(CHAT)—CeA neural circuit; ②Encoding mechanisms of LPB(CHAT)—CeA circuit underlying stress-induced reinstatement of METH; ③Potential therapeutic effects of regulating activities of LPB(CHAT)—CeA neural circuit on stress-induced relapse to METH abuse, and the key intervention targets within the circuit for the treatment of METH relapse. The results of the current study will put new insight into the neural circuit mechanisms underlying addiction, and provide novel therapeutic targets and strategies for the treatment of drugs addiction.