Role of cannabinoid system in systemic and brain ageing

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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.