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

我们以前已经证明，在GABA能神经元上缺乏CB1受体的动物的大脑中有增加的神经炎症。这一非常出人意料的结果使我们提出假设：(1)CB1受体活性对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CB1受体活性对年龄相关的神经炎性变化具有保护作用。因此，我们问，CB1受体活性的调节如何影响神经元-神经胶质细胞的串扰。我们以前的结果也表明，CB1受体的活性影响神经元的存活和凋亡。为了明确CB1受体活性慢性增强或停止影响神经元命运的机制，我们将研究慢性阻断或提高CB1受体活性后AKT和ERK信号通路在脑内的变化。最后，我们报告说，CB1受体活性的缺乏会导致海马区细胞应激和神经炎症的加剧，并伴随着认知障碍的早期发作。我们现在的问题是，通过遗传或药物阻断内源性大麻素降解酶单酰甘油脂肪酶(MAGL)或脂肪酸酰胺水解酶(FAAH)而引起的CB1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CB1受体密度的下降。因此，我们将首先确定导致CB1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.