Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity
Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity
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DOI：
10.1038/s41386-018-0135-4
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发表时间：
2018-09-01
影响因子：
7.6
通讯作者：
Akirav, Irit
中科院分区：
文献类型：
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作者：
Segev, Amir;Korem, Nachshon;Akirav, Irit
创伤后应激障碍（PTSD）的特征是重新经历创伤事件，并与恐惧反应的缓慢消退有关。与创伤相关线索的恐惧关联的消退受损可能会干扰治疗反应，消退缺陷可能是PTSD发展的发病前风险因素。我们研究了暴露于严重的足电击，然后是情景提醒（SR）对海马CA 1区和基底外侧杏仁核（BLA）的消退，可塑性和内源性大麻素（eCB）含量和活性的影响。我们还研究了在灭绝前使用脂肪酸酰胺水解酶（FAAH）抑制剂URB 597增强eCB信号传导是否可以防止休克/SR诱导的对恐惧反应和可塑性的影响。在消退前全身（0.3 mg/kg）或局部给予CA 1或BLA（0.1 μ g/侧）URB 597降低了恐惧再现，并且这种效果在整个消退训练中持续存在，并且在自发恢复期间不恢复。低剂量的CB 1受体拮抗剂AM 251（0.3 mg/kg i. p.或0.01 μ g/0.5 μ l CA 1内或BLA内）阻断了这些作用，表明URB 597的作用是CB 1受体依赖性的。暴露于休克和提醒诱导行为的后可塑性与海马（损害）和BLA（增强）的长时程增强（LTP）的相反的影响。URB 597被发现可以防止海马和BLA-LTP中的相反电击/SR诱导的后可塑性。暴露于电击和提醒可能会导致内源性大麻素水平的变化，这可能会影响恐惧电路功能。事实上，暴露于休克和SR影响eCB含量：增加2-花生四烯酸甘油（2-AG）和N-花生四烯酸乙醇胺（AEA）水平在CA 1，降低血清和BLA AEA水平，而休克暴露增加FAAH活性在CA 1和BLA。在灭绝前FAAH抑制消除恐惧和调制LTP在海马和杏仁核，大脑区域相关的情绪记忆。研究结果表明，在灭绝之前靶向eCB系统可能有利于恐惧记忆衰减，这些作用可能涉及CA 1和BLA的后可塑性。
Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA). We also examined whether enhancing eCB signaling before extinction, using the fatty acid amide hydrolase (FAAH) inhibitor URB597, could prevent the shock/SRs-induced effects on fear response and plasticity. URB597 administered systemically (0.3 mg/kg) or locally into the CA1 or BLA (0.1 mu g/side) prior to extinction decreased fear retrieval and this effect persisted throughout extinction training and did not recuperate during spontaneous recovery. A low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg i.p. or 0.01 mu g/0.5 mu l intra-CA1 or intra-BLA) blocked these effects suggesting that the effects of URB597 were CB1 receptor-dependent. Exposure to shock and reminders induced behavioral metaplasticity with opposite effects on long-term potentiation (LTP) in the hippocampus (impairment) and the BLA (enhancement). URB597 was found to prevent the opposite shock/SR-induced metaplasticity in hippocampal and BLA-LTP. Exposure to shock and reminders might cause variation in endogenous cannabinoid levels that could affect fear-circuit function. Indeed, exposure to shock and SRs affected eCB content: increased 2-arachidonoyl-glycerol (2-AG) and N-arachidonylethanolamine (AEA) levels in the CA1, decreased serum and BLA AEA levels while shock exposure increased FAAH activity in the CA1 and BLA. FAAH inhibition before extinction abolished fear and modulated LTP in the hippocampus and amygdala, brain regions pertinent to emotional memory. The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.