Function of the endocannabinoid system in normal and pathological ageing processes of the brain

我们以前已经表明，在GABA能神经元上缺乏CB 1受体的动物的大脑中，神经炎症增加。这一非常出乎意料的结果使我们提出了以下假设：（1）CB 1受体活性对于GABA能神经元和神经胶质细胞之间的通讯很重要;（2）GABA能神经元上的CB 1受体活性对年龄相关的神经炎症变化具有保护作用。因此，我们问，如何调制CB 1受体活性影响神经胶质细胞的串扰。我们以前的研究结果也表明，CB 1受体活性影响神经元的存活和凋亡。为了确定的机制，慢性增加或CB 1受体活性的停止影响神经元的命运，我们将研究如何AKT和ERK信号通路改变后，慢性阻断或CB 1受体活性升高的大脑。最后，我们报道了CB 1受体活性的缺乏导致海马中细胞应激和神经炎症加剧，伴随着认知缺陷的早期发作。我们现在要问的是，通过内源性大麻素降解酶单酰基甘油脂肪酶（MAGL）或脂肪酸酰胺水解酶（FAAH）的遗传或药理学阻断诱导的CB 1受体活性增强是否有利于对抗大脑中与年龄相关的变化。然而，作为一种代偿机制，内源性大麻素水平的慢性升高可能导致CB 1受体密度的降低。因此，我们将首先确定导致CB 1受体活性持续升高的药物治疗方案。

We have shown previously that there is an increased neuroinflammation in the brain of animals lacking CB1 receptors on GABAergic neurons. This highly unexpected result led us to the hypotheses that (1) CB1 receptor activity is important for the communication between GABAergic neurons and glial cells and (2) CB1 receptor activity on GABAergic neurons is protective against age-related neuroinflammatory changes. Therefore we ask, how modulation of CB1 receptor activity influences neuron-glia cross talk. Our previous results also suggested that CB1 receptor activity influences neuronal survival and apoptosis. In order to identify the mechanisms, by which chronic increase or cessation of CB1 receptor activity influences neuronal fate, we will investigate how the AKT and ERK signaling pathway is altered in the brain after chronic blockade or elevation of CB1 receptor activity. Finally, we reported that a lack of CB1 receptor activity leads to exacerbated cellular stress and neuroinflammation in the hippocampus, accompanied by early onset of cognitive deficits. We now ask whether an enhanced CB1 receptor activity induced by genetic or pharmacological blockade of the endocannabinoid degrading enzyme monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) is beneficial against age-related changes in the brain. As a compensatory mechanism, however, the chronic elevation of endocannabinoid levels may lead to a decrease in CB1 receptor density. Therefore, we will first identify a pharmacological treatment regime leading to a sustained elevation in CB1 receptor activity.