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Cellular origin and function of brain 2-arachidonoylglycerol

脑 2-花生四烯酰甘油的细胞起源和功能

基本信息

批准号：
324087152
负责人：
Professor Dr. Andreas Zimmer
金额：
--
依托单位：
Institut für Molekulare Psychiatrie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/324087152?language=en
关键词：
Cellular origin function brain arachidonoylglycerol

项目摘要

The endocannabinoid system (ECS) is a lipid signalling system that modulates a wide range of physiological functions, many of which are important in the context of homeostatic regulation. At the core of this feedback mechanism are presynaptic G-protein-coupled cannabinoid receptors CB1 (CB1), which are also the target of the primary psychoactive component of marijuana (delta9-tetrahydrocannabinol, THC). A second cannabinoid receptor, CB2, is also weakly expressed by neurons, but mostly present on peripheral tissues and immune cells. The full CB1 and CB2 agonist 2-arachidonoyl glycerol (2-AG), one of the main endocannabinoids, is generated by the diacylglycerol lipase (DAGL) enzymes. The two isoforms DAGL-alpha and DAGL-beta have been described, which are encoded by the Dagla and Daglb genes, respectively. The second well-known endocannabinoid is arachidonoylethanolamide (AEA, anandamide). The brain level AEA is lower compared to 2-AG, and AEA also has a lower efficacy and functions as a partial agonist at CB1 and CB2 receptors.To date, all models of endocannabinoid signalling in the brain are based on the assumption that the postsynapse is the main source of 2-AG. However, our preliminary results with neuron-specific Dagla knockout (KO) mice show that this assumption is probably wrong, because we did not find any changes in 2-AG levels in these conditional KO mice - although Dagla expression was substantial reduced. However, constitutive Dagla KO animals show an 80% reduction of brain 2-AG levels with a concomitant phenotype of increased emotional or stress-related behaviours. This phenotype is entirely consistent with the notion that endocannabinoid signalling regulates affective behaviours and stress responses, and is involved in the pathology of depression. It is further known that besides neurons, astrocytes and microglia also express CB1 receptors and produce endocannabinoids in the brain. For microglia, the in vitro production of endocannabinoids is actually about 20-fold higher compared to neurons. Yet, the function of these endocannabinoids and their role in modulating behaviour is completely unclear. Hence, we aim to investigate the production of 2-AG by different brain cells (neurons, astrocytes and microglia) and their role in animal behaviours. Our focus will be on the modulation of anxiety-related behaviours and its influence on the affective states of animals, which is a documented function of the ECS in animals and humans. For this purpose we are planning to use conditional Dagla KO mice that we have recently described. The elucidation of the main cellular source of brain 2-AG will be of fundamental importance to the entire field of cannabinoid research. It will provide a basis for future studies, outside the scope of this proposal, involving physiology, cell and molecular biology.

内源性大麻素系统（ECS）是一种脂质信号传导系统，可调节广泛的生理功能，其中许多功能在体内平衡调节中很重要。这种反馈机制的核心是突触前G蛋白偶联大麻素受体CB 1（CB 1），它也是大麻主要精神活性成分（δ 9-四氢大麻酚，THC）的靶点。第二种大麻素受体CB 2也在神经元中弱表达，但主要存在于外周组织和免疫细胞中。完整的CB 1和CB 2激动剂2-花生四烯酸甘油（2-AG）是主要的内源性大麻素之一，由二酰基甘油脂肪酶（DAGL）酶产生。已经描述了两种同种型DAGL-α和DAGL-β，其分别由Dagla和Daglb基因编码。第二种已知的内源性大麻素是花生四烯酸乙醇酰胺（AEA，anandamide）。与2-AG相比，AEA的脑水平较低，并且AEA也具有较低的功效，并且在CB 1和CB 2受体上起部分激动剂的作用。然而，我们对神经元特异性Dagla敲除（KO）小鼠的初步结果表明，这种假设可能是错误的，因为我们没有发现这些条件性KO小鼠中2-AG水平的任何变化-尽管Dagla表达显著降低。然而，组成性Dagla KO动物显示脑2-AG水平降低80%，伴随情绪或压力相关行为增加的表型。这种表型与内源性大麻素信号调节情感行为和应激反应的概念完全一致，并参与抑郁症的病理学。进一步已知，除了神经元，星形胶质细胞和小胶质细胞也表达CB 1受体并在脑中产生内源性大麻素。对于小胶质细胞，与神经元相比，内源性大麻素的体外生产实际上高出约20倍。然而，这些内源性大麻素的功能及其在调节行为中的作用完全不清楚。因此，我们的目标是研究不同脑细胞（神经元，星形胶质细胞和小胶质细胞）的2-AG的产生及其在动物行为中的作用。我们的重点将是焦虑相关行为的调制及其对动物情感状态的影响，这是ECS在动物和人类中的记录功能。为此，我们计划使用我们最近描述的条件性Dagla KO小鼠。阐明大脑2-AG的主要细胞来源对整个大麻素研究领域具有根本重要性。它将为本提案范围之外的未来研究提供基础，涉及生理学，细胞和分子生物学。