Selective Inhibition of Amygdala Neuronal Ensembles Encoding Nicotine-Associated Memories Inhibits Nicotine Preference and Relapse

Abstract

BACKGROUND: Nicotine craving and relapse often occurs after reactivation of nicotine reward memories. We recently developed a memory retrieval–reconsolidation interference procedure in which reactivating nicotine reward memories by acute exposure to nicotine (the unconditioned stimulus [UCS]) and then pharmacologically interfering with memory reconsolidation decreased relapse to nicotine seeking in rats and nicotine craving in smokers. Here, we investigated underlying mechanisms. METHODS: In the first series of experiments, we trained rats for nicotine-induced conditioned place preference (CPP) or nicotine self-administration and ventricularly microinjected them with the protein synthesis inhibitor anisomycin immediately after UCS-induced memory retrieval. In the second series of experiments, we used tyramide-amplified immunohistochemistry–fluorescence in situ hybridization to examine neural ensembles in the basolateral amygdala (BLA) reactivated by nicotine conditioned stimulus– or UCS-induced memory retrieval. We then used the Daun02 chemogenetic inactivation procedure to selectively inhibit the nicotine UCS-reactivated BLA neuronal ensembles. RESULTS: Ventricular injections of the anisomycin immediately after nicotine UCS memory retrieval inhibited sub-sequent nicotine CPP and relapse to operant nicotine seeking after short or prolonged abstinence. More important, within BLA, distinct neuronal ensembles encoded pavlovian CPP and operant self-administration reward memories and nicotine (the UCS) injections in the home cage reactivated both neuronal ensembles. Daun02 chemogenetic inactivation of the nicotine-reactivated ensembles inhibited both nicotine CPP and relapse to nicotine seeking. CONCLUSIONS: Results demonstrate that the nicotine UCS-induced memory retrieval manipulation reactivates multiple nicotine reward memories that are encoded by distinct BLA neuronal ensembles that play a role in nicotine preference and relapse.

Pi4KIIα Regulates Unconditioned Stimulus-Retrieval-Induced Fear Memory Reconsolidation through Endosomal Trafficking of AMPA Receptors

“…This discrepancy may reflect distinct retrieval paradigms. Indeed, US retrieval has been shown to activate more memory traces and stronger protein alterations than CS retrieval (Liu et al, 2014;Xue et al, 2017;Yuan et al, 2019). Furthermore, we found that the pharmacological inhibition of Pi4KIIa in the BLA decreased GluA1 levels 1 h after US retrieval, and the genetic knockdown of Pi4KIIa impaired the enhancement of mEPSC frequency that was induced by US retrieval, suggesting a regulatory role for Pi4KIIa in GluA1 surface expression and synaptic efficacy in the rat BLA.…”

Basolateral amygdala is required for reconsolidation updating of heroin‐associated memory after prolonged withdrawal

“…The training of intravenous heroin self‐administration, extinction training, heroin‐priming‐induced reinstatement, renewal, and spontaneous recovery of heroin‐seeking behaviors are based on previous studies . The heroin operant‐CS retrieval manipulations were identical to the one used in our previous studies . We injected the rats noncontingently with the previously self‐administered drug (UCS) (heroin 0.1 mg/kg, sc) in their homecage .…”

“…We performed the stereotactic surgery and implanted 23‐gauge guide cannulas (Plastics One) 1 mm above BLA . For virus injections, the virus construct was injected bilaterally into the BLA based on previous reports .…”

Research progress and prospect of neural activity-dependent tools

“…这些IEG报告品系被用于绘制特定 刺激相关的全脑活性图谱 [67,83,84] 、研究激活类群的电 生理特性 [43,62] 以及通过在体成像揭示集群的功能动态 编码特征 [58,69] , 此外表达LacZ的工具还被用于活性神 经集群的干预, Koya等人 [85] 利用β-gal能够催化前体药 物Daun02转化成具有抑制神经元兴奋作用的柔毛霉 素(daunorubicin)的特性, 将Daun02给予到刺激后的cfos-LacZ大鼠的感兴趣脑区, 从而实现了刺激活化神 经集群的失活(图1A). 应用LacZ-Daun02失活系统, 一 系列研究成瘾药物引发行为敏化 [85] 、渴求 [86~89] 、复 吸 [39,90,91] 等作用机制的工作发表.…”