Morena Maria, Roozendaal Benno, Trezza Viviana, Ratano Patrizia, Peloso Andrea, Hauer Daniela, Atsak Piray, Trabace Luigia, Cuomo Vincenzo, McGaugh James L, Schelling Gustav, Campolongo Patrizia
Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy;
Department of Cognitive Neuroscience, Radboud University Medical Centre, 6501 HB Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands;
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18333-8. doi: 10.1073/pnas.1420285111. Epub 2014 Dec 8.
Previous studies have provided extensive evidence that administration of cannabinoid drugs after training modulates the consolidation of memory for an aversive experience. The present experiments investigated whether the memory consolidation is regulated by endogenously released cannabinoids. The experiments first examined whether the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are released by aversive training. Inhibitory avoidance training with higher footshock intensity produced increased levels of AEA in the amygdala, hippocampus, and medial prefrontal cortex (mPFC) shortly after training in comparison with levels assessed in rats trained with lower footshock intensity or unshocked controls exposed only to the training apparatus. In contrast, 2-AG levels were not significantly elevated. The additional finding that posttraining infusions of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which selectively increases AEA levels at active synapses, administered into the basolateral complex of the amygdala (BLA), hippocampus, or mPFC enhanced memory strongly suggests that the endogenously released AEA modulates memory consolidation. Moreover, in support of the view that this emotional training-associated increase in endocannabinoid neurotransmission, and its effects on memory enhancement, depends on the integrity of functional interactions between these different brain regions, we found that disruption of BLA activity blocked the training-induced increases in AEA levels as well as the memory enhancement produced by URB597 administered into the hippocampus or mPFC. Thus, the findings provide evidence that emotionally arousing training increases AEA levels within prefrontal-limbic circuits and strongly suggest that this cannabinoid activation regulates emotional arousal effects on memory consolidation.
以往的研究提供了大量证据表明，训练后给予大麻素药物可调节对厌恶经历的记忆巩固。本实验研究了记忆巩固是否受内源性释放的大麻素调节。实验首先检测了厌恶训练是否会释放内源性大麻素花生四烯乙醇胺（AEA）和2-花生四烯酸甘油酯（2-AG）。与接受较低电击强度训练的大鼠或仅暴露于训练装置的未电击对照组相比，在接受较高电击强度的抑制性回避训练后不久，杏仁核、海马体和内侧前额叶皮质（mPFC）中的AEA水平升高。相比之下，2-AG水平没有显著升高。另外一项发现是，训练后向杏仁核基底外侧复合体（BLA）、海马体或mPFC注射脂肪酸酰胺水解酶（FAAH）抑制剂URB597（可选择性提高活跃突触处的AEA水平）能强烈增强记忆，这有力地表明内源性释放的AEA调节记忆巩固。此外，为支持这样一种观点，即这种与情绪训练相关的内源性大麻素神经传递增加及其对记忆增强的作用取决于这些不同脑区之间功能相互作用的完整性，我们发现破坏BLA的活动会阻断训练诱导的AEA水平升高以及向海马体或mPFC注射URB597所产生的记忆增强。因此，这些发现提供了证据，表明情绪唤起训练会增加前额叶-边缘回路中的AEA水平，并有力地表明这种大麻素激活调节情绪唤起对记忆巩固的影响。
