Neuronal and Cellular Signal Transduction, Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Clinical Lipidomics Unit, Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
Cells. 2022 Apr 30;11(9):1517. doi: 10.3390/cells11091517.
Elementary emotional states and memory can be regulated by the homeostasis of the endocannabinoid system (ECS). Links between the ECS and the autophagy receptor p62 have been found at the molecular level and in animal studies. This project aimed to validate the anxiety and memory phenotype of p62 knockout (KO) animals and whether the ECS plays a role in this. We examined the behavior of p62 KO animals and analyzed whether endocannabinoid levels are altered in the responsible brain areas. We discovered in age-dependent obese p62 KO mice decreased anandamide levels in the amygdala, a brain structure important for emotional responses. Against our expectation, p62 KO animals did not exhibit an anxiety phenotype, but showed slightly increased exploratory behavior as evidenced in novel object and further tests. In addition, KO animals exhibited decreased freezing responses in the fear conditioning. Administration of the phytocannabinoid delta-tetrahydrocannabinol (THC) resulted in lesser effects on locomotion but in comparable hypothermic effects in p62 KO compared with WT littermates. Our results do not confirm previously published results, as our mouse line does not exhibit a drastic behavioral phenotype. Moreover, we identified further indications of a connection to the ECS and hence offer new perspectives for future investigations.
基本情绪状态和记忆可以通过内源性大麻素系统 (ECS) 的内稳态来调节。在分子水平和动物研究中都发现了 ECS 与自噬受体 p62 之间的联系。本项目旨在验证 p62 敲除 (KO) 动物的焦虑和记忆表型，以及 ECS 是否在其中发挥作用。我们检查了 p62 KO 动物的行为，并分析了负责大脑区域的内源性大麻素水平是否发生了改变。我们发现，在年龄依赖性肥胖的 p62 KO 小鼠中，杏仁核中的花生四烯酸水平降低，杏仁核是对情绪反应很重要的脑结构。出乎我们的意料，p62 KO 动物没有表现出焦虑表型，但在新物体和进一步的测试中表现出轻微增加的探索行为。此外，KO 动物在恐惧条件反射中表现出较少的冻结反应。植物大麻素 δ-四氢大麻酚 (THC) 的给药对运动的影响较小，但与 WT 同窝仔相比，KO 动物的体温降低效应相当。我们的结果与先前发表的结果不一致，因为我们的小鼠品系没有表现出明显的行为表型。此外，我们还发现了与 ECS 进一步联系的迹象，从而为未来的研究提供了新的视角。
