Morena Maria, De Castro Valentina, Gray J Megan, Palmery Maura, Trezza Viviana, Roozendaal Benno, Hill Matthew N, Campolongo Patrizia
Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy, Hotchkiss Brain Institute and Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, Alberta T2N 4N1, Canada,
Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy.
J Neurosci. 2015 Oct 14;35(41):13962-74. doi: 10.1523/JNEUROSCI.1983-15.2015.
Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level. Male adult Sprague Dawley rats were trained on a water maze spatial task at two different water temperatures (19°C and 25°C) to elicit either higher or lower stress levels, respectively. Rats trained under the higher stress condition had better memory and higher corticosterone concentrations than rats trained at the lower stress condition. The cannabinoid receptor agonist WIN55212-2 (10-30 ng/side), the 2-arachidonoyl glycerol (2-AG) hydrolysis inhibitor JZL184 (0.1-1 μg/side), and the anandamide (AEA) hydrolysis inhibitor URB597 (10-30 ng/side) were administered bilaterally into the hippocampus 60 min before probe-trial retention testing. WIN55212-2 or JZL184, but not URB597, impaired probe-trial performances only of rats trained at the higher stressful condition. Furthermore, rats trained under higher stress levels displayed an increase in hippocampal 2-AG, but not AEA, levels at the time of retention testing and a decreased affinity of the main 2-AG-degrading enzyme for its substrate. The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing.
Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial memory recall of stressful experiences. Thus, our findings provide evidence that the endocannabinoid 2-arachidonoylglycerol is a key player in mediating the impact of stress on memory retrieval. These findings can pave the way to new potential therapeutic intervention for the treatment of neuropsychiatric disorders, such as post-traumatic stress disorder, where a previous exposure to traumatic events could alter the response to traumatic memory recall leading to mental illness.
环境厌恶程度的变化会影响大鼠的情绪记忆过程。我们之前已经表明，大麻素对记忆的影响取决于训练时的应激水平以及环境背景的厌恶程度。在此，我们研究了海马内源性大麻素系统是否根据与训练相关的唤醒水平来调节记忆提取。成年雄性Sprague Dawley大鼠在两种不同水温（19°C和25°C）下接受水迷宫空间任务训练，分别引发较高或较低的应激水平。在较高应激条件下训练的大鼠比在较低应激条件下训练的大鼠具有更好的记忆力和更高的皮质酮浓度。在探测试验保留测试前60分钟，将大麻素受体激动剂WIN55212 - 2（10 - 30纳克/侧）、2 - 花生四烯酸甘油（2 - AG）水解抑制剂JZL184（0.1 - 1微克/侧）和花生四烯乙醇胺（AEA）水解抑制剂URB597（10 - 30纳克/侧）双侧注射到海马中。WIN55212 - 2或JZL184，但不是URB597，仅损害了在较高应激条件下训练的大鼠的探测试验表现。此外，在较高应激水平下训练的大鼠在保留测试时海马中2 - AG水平升高，但AEA水平未升高，并且主要的2 - AG降解酶对其底物的亲和力降低。目前的研究结果表明，海马中的内源性大麻素2 - AG在应激经历的空间记忆提取的选择性调节中起关键作用，揭示了应激对记忆加工影响所涉及的神经生物学机制。
内源性大麻素在情绪事件记忆的调节中起核心作用。在此我们证明，海马中的内源性大麻素2 - 花生四烯酸甘油，这是一个在记忆过程调节中至关重要的脑区，选择性地调节应激经历的空间记忆回忆。因此，我们的研究结果提供了证据，表明内源性大麻素2 - 花生四烯酸甘油是介导应激对记忆提取影响的关键因素。这些发现可以为治疗神经精神疾病，如创伤后应激障碍，开辟新的潜在治疗干预途径，在创伤后应激障碍中，先前暴露于创伤事件可能会改变对创伤记忆回忆的反应，导致精神疾病。
