Role of cannabinoid system in systemic and brain ageing

我们提出的研究旨在阐明大麻素信号如何影响衰老过程。我们还假设CB1受体活性的降低以脑区域特异性的方式加速了大脑和全身的衰老。为了验证这一点，我们将首先删除海马体中的Cnr1，并测试这种位点特异性删除对大脑衰老的影响，如上所述。大麻素信号在衰老过程中最严重的下降发生在下丘脑，这是一个影响全身衰老的大脑区域。因此，我们将额外监测下丘脑特异性Cnr1缺失小鼠外周器官的衰老迹象。为了进一步测试CB1受体活性对衰老的脑区特异性，我们将在Cnr1零突变体STOP-CB1小鼠品系中恢复CB1受体在海马或下丘脑的表达，并测试其是否能预防早期衰老症状。最后，我们询问四氢大麻酚（THC）是否以特定的脑区方式发挥其抗衰老作用。为此，我们将测试慢性低剂量四氢大麻酚对18月龄海马特异性CB1受体缺失或恢复小鼠认知能力、脑组织组织学和基因表达的影响。

Our proposed studies aim to clarify how cannabinoid signalling influences the process of ageing. We hypothesize also that the decreased CB1 receptor activity accelerates brain and systemic aging on in a brain area- specific manner. To test this, possibility we will delete Cnr1 first in the hippocampus and test the effect of this site-specific deletion on brain ageing as described above. The most sever decline in cannabinoid signalling in ageing takes place in the hypothalamus, a brain area influencing systemic ageing. Thus, we will additionally monitor signs of ageing in peripheral organs of mice with a hypothalamus-specific deletion of Cnr1. To further test further the brain area specificity of CB1 receptor activity on ageing we will rescue CB1 receptor expression in the hippocampus or in the hypothalamus and test whether it prevents symptoms of early ageing in the Cnr1 null mutant STOP-CB1 mouse strain. Lastly, we ask whether tetrahydrocannabinol (THC) exerts its anti-ageing effect on a brain-area specific manner. For that we will test the effect of chronic low dose THC on the cognitive abilities, brain histology and gene expression of 18-month-old mice with hippocampus specific deletion or restoration of CB1 receptors.