Hippocampal endocannabinoid signaling regulates short-term recognition memory in rats: Influence of stress and circadian rhythm

Introduction and objectives: The endocannabinoid system plays a key role in the control of emotional responses to environmental challenges (Morena and Campolongo, 2014). We previously demonstrated that different stress intensities, experienced soon after encoding, impaired rat short-term recognition memory in a circadian-dependent manner, and that boosting endocannabinoid anandamide (AEA) levels restored memory performance (Santori et al., 2019). The effects of stress on the endocannabinoid system are complex, regionally specific and dependent on time (Morena et al., 2016). Here, we examined if two different stress intensities and circadian rhythm alter endocannabinoid system components within the hippocampus, and whether these changes modulate short-term memory. Thus, 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-arachidonoylglycerol (2-AG) content and the activity of their degrading enzymes, FAAH and MAGL (respectively), were measured soon after testing. Results: Independently of the time of the day, stress exposure induced an overall decrease of hippocampal AEA levels not linked to cognitive alterations. Interestingly, exposure to high stress decreased hippocampal 2-AG content and, accordingly, increased MAGL activity, selectively in the afternoon. Therefore, to further investigate hippocampal 2-AG modulation of short-term recognition memory, rats were given bilateral intra-hippocampal administration of the 2-AG hydrolysis inhibitor KML29 immediately after training, then subjected to low or high stress conditions and tested 1-hr later. Consistent with our previous findings (Santori et al., 2019), low stress impaired 1-hr memory performance only in the morning, where exposure to high stress impaired memory performance independently of the testing time. Conclusions: KML29 counteracted stress detrimental effects on short-term recognition memory, both in the morning and the afternoon. Research area: Cognition and behavior