The role of the endocannabinoid system in brain and systemic ageing

Abstract

Previous research from our laboratory has demonstrated that genetic manipulations leading to reduced CB1 receptor signaling in mice accelerated the ageing process. Specifically, the constitutive deletion of the CB1 receptor in mice resulted in advanced ageing characterized by neuroinflammatory changes, neuronal loss, diminished neurogenesis, lipofuscin accumulation, and cognitive decline. These age-related alterations, primarily observed in the hippocampus, were concomitant with histological changes in peripheral organs such as skin and testis atrophy, along with osteoporosis. Hence, the purpose of the present study was to elucidate whether the observed effects in CB1 receptor constitutive knockouts were attributed to a general deletion of the CB1 receptor or resulted from its region-specific activity. By employing stereotaxic viral injections in young male mice, we aimed to investigate whether the site-specific deletion of the CB1 receptor in the hippocampus accelerated brain ageing and if its absence in the mediobasal hypothalamus contributed to peripheral ageing. Furthermore, we aimed to assess whether rescuing the receptor in the hippocampus and hypothalamus could ameliorate these effects. <br /> Our findings revealed that adult hippocampal CB1 receptor knockouts exhibited pro-inflammatory glial activity, decreased cell proliferation in SGZ of the hippocampal DG, and impaired social recognition memory. This suggests that an intact hippocampal CB1 receptor is crucial in mitigating brain ageing. Contrary to our initial hypotheses, adult and middle-aged hippocampal CB1 receptor rescue animals showed compromised social memory at 6 months and diminished learning flexibility and spatial memory at 12 months. These cognitive declines were correlated with higher pro-inflammatory glial activity, neuronal loss, and lipofuscin accumulation, primarily localized within the CA1 hippocampal subfield. Remarkably, the viral injection predominantly affected glutamatergic cells in the CA1 pyramidal layer but not GABAergic positive neurons, indicating the restoration of the CB1 receptor mostly in excitatory cells. This may contribute to the detrimental effects observed in the hippocampus, potentially elucidating the mechanisms underpinning age-related changes evident in the CB1 receptor conditional rescue group. <br /> Deleting the CB1 receptor in the VMH exacerbated pro-inflammatory alterations and elevated hypothalamic relative <em>Igf1r</em> mRNA expression in old conditional knockout animals. On the other hand, GnRH levels as well as peripheral organ histology remained unchanged. Surprisingly, their frailty scores exhibited notable improvement at 17 months of age, accompanied by reduced body temperature and decreased locomotion in comparison to their age-matched counterparts. Strikingly, the rescue of the CB1 receptor within the same brain region mitigated pro-inflammatory glial activation and diminished <em>Igf1r</em> mRNA expression without affecting GnRH release and organs morphology. Additionally, animals with the conditional rescue of CB1 receptors demonstrated better frailty scores compared to their CB1 receptor-deficient controls at 13 and 14 months, along with hypolocomotion at 14 months. <br /> Overall, these findings underscored the pivotal role of CB1 receptor signaling within the VMH in mitigating localized age-related inflammatory changes and influencing the GH/IGF-1 axis. <br /> In conclusion, our data furnished compelling evidence regarding the brain-region-specific activity of the CB1 receptor and its anti-ageing effects. However, clarification about the precise role of hypothalamic CB1 receptor in the neurohormone regulation and in alleviating systemic ageing necessitates further investigation.