Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy.
Neurobiology of Behavior Laboratory, Santa Lucia Foundation, 00143 Rome, Italy.
Int J Mol Sci. 2020 Oct 3;21(19):7316. doi: 10.3390/ijms21197316.
Cannabinoids induce biphasic effects on memory depending on stress levels. We previously demonstrated that different stress intensities, experienced soon after encoding, impaired rat short-term recognition memory in a time-of-day-dependent manner, and that boosting endocannabinoid anandamide (AEA) levels restored memory performance. Here, we examined if two different stress intensities and time-of-day alter hippocampal endocannabinoid tone, and whether these changes modulate short-term memory.
Male Sprague-Dawley rats were subjected to an object recognition task and exposed, at two different times of the day (i.e., morning or afternoon), to low or high stress conditions, immediately after encoding. Memory retention was assessed 1 hr later. Hippocampal AEA and 2-arachidonoyl glycerol (2-AG) content and the activity of their primary degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), were measured soon after testing.
Consistent with our previous findings, low stress impaired 1-hr memory performance only in the morning, whereas exposure to high stress impaired memory independently of testing time. Stress exposure decreased AEA levels independently of memory alterations. Interestingly, exposure to high stress decreased 2-AG content and, accordingly, increased MAGL activity, selectively in the afternoon. Thus, to further evaluate 2-AG's role in the modulation of short-term recognition memory, rats were given bilateral intra-hippocampal injections of the 2-AG hydrolysis inhibitor KML29 immediately after training, then subjected to low or high stress conditions and tested 1 hr later.
KML29 abolished the time-of-day-dependent impairing effects of stress on short-term memory, ameliorating short-term recognition memory performance.
大麻素对记忆的影响呈双相，这取决于压力水平。我们之前的研究表明，不同强度的应激，在编码后不久经历，会以时间依赖的方式损害大鼠的短期识别记忆，而提高内源性大麻素大麻酰胺（AEA）水平则可以恢复记忆表现。在这里，我们研究了两种不同的应激强度和时间是否会改变海马内源性大麻素的基调，以及这些变化是否会调节短期记忆。
雄性 Sprague-Dawley 大鼠接受物体识别任务，并在一天中的两个不同时间（即上午或下午）暴露于低或高应激条件下，在编码后立即进行。1 小时后评估记忆保留。记忆测试后立即测量海马 AE 和 2-花生四烯酰甘油（2-AG）的含量及其主要降解酶，脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）的活性。
与我们之前的发现一致，低应激仅在上午损害 1 小时的记忆表现，而高应激暴露则独立于测试时间损害记忆。应激暴露降低了 AE 水平，而不改变记忆。有趣的是，高应激暴露降低了 2-AG 含量，并相应地增加了 MAGL 活性，仅在下午。因此，为了进一步评估 2-AG 在调节短期识别记忆中的作用，大鼠在训练后立即给予双侧海马内注射 2-AG 水解抑制剂 KML29，然后暴露于低或高应激条件下，1 小时后进行测试。
KML29 消除了应激对短期记忆的时间依赖性损害作用，改善了短期识别记忆表现。
