Early life stress induces persistent alteration in endocannabinoid system and leads to dysfunc- tional modulation of emotional memory retrieval

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Early life stress (ELS) is one of the best characterised risk factors for later development of stress-related disorders, such as post-traumatic stress disorder (PSTD). A hallmark feature in PTSD is persistent, uninhibited retrieval of emotional memory. Recent evi-dence from this lab indicated that glucocorticoids interact with the endocannabinoid system, particularly 2-arachidonoyglycerol (2-AG), to impair the retrieval of emotional memory under stress. Given that adult rats with ELS history show an inability to upregulate 2-AG signalling in hippocampus after acute stress, we hypothesized that glucocorticoids will not impair emotional memory retrieval in ELS animals, whereas a direct augmentation of hippocampal 2-AG signalling will. We first showed that the well-established limited nesting paradigm resulted in fragmented maternal care and elevated plasma corticosterone levels in pups. At adulthood, we trained male offspring on a contextual fear memory paradigm. One hour before retention testing, 24 hours after training, rats were injected with corticosterone (CORT, 3 mg/kg) systemically or administered the 2-AG hydrolysis (MAGL) inhibitor KML-29 (0.2 μg/0.5 μL) di-rectly into the hippocampus. Unlike control rats, we found that systemic CORT injection did not impair retrieval of contextual fear memory in ELS animals. By contrast, direct hippocampal administration of KML-29 impaired memory retrieval in both ELS and control rats in a CB1 receptor-dependent fashion. Thus, these findings support our hypothesis that the inability of ELS rats to modulate memory retrieval under stress might originate from their inability to mount a 2-AG response. Our findings are highly relevant for informing future studies on the link between ELS and maladaptive stress coping and the increased risk for stress-related psychopa-thologies.
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