Decline in cognitive performance, an aspect of the normal aging process, is influenced by the endocannabinoid system (ECS). Cannabinoid receptor 1 (CB1) signaling diminishes with advancing age in specific brain regions that regulate learning and memory and abolishing CB1 receptor signaling accelerates cognitive aging in mice. We recently demonstrated that prolonged exposure to low dose (3 mg/kg/day) Δ⁹-tetrahydrocannabinol (THC) improved the cognitive performances in old mice on par with young untreated mice. Here we investigated the potential influence of cannabidiol (CBD) on this THC effect, because preclinical and clinical studies indicate that the combination of THC and CBD often exhibits an enhanced therapeutic effect compared to THC alone. We first tested the effectiveness of a lower dose (1 mg/kg/day) THC, and then the efficacy of the combination of THC and CBD in 1:1 ratio, same as in the clinically approved medicine Sativex^®. Our findings reveal that a 1 mg/kg/day THC dose still effectively improved spatial learning in aged mice. However, a 1:1 combination of THC and CBD failed to do so. The presence of CBD induced temporal changes in THC metabolism ensuing in a transient elevation of blood THC levels. However, as CBD metabolizes, the inhibitory effect on THC metabolism was alleviated, causing a rapid clearance of THC. Thus, the beneficial effects of THC seemed to wane off more swiftly in the presence of CBD, due to these metabolic effects. The findings indicate that THC-treatment alone is more efficient to improve spatial learning in aged mice than the 1:1 combination of THC and CBD.

Endocannabinoid system activity declines with age in the hippocampus, along with the density of the cannabinoid receptor type-1 (CB1). This process might contribute to brain ageing, as previous studies showed that the constitutive deletion of the CB1 receptor in mice leads to early onset of memory deficits and histological signs of ageing in the hippocampus including enhanced pro-inflammatory glial activity and reduced neurogenesis. Here we asked whether the CB1 receptor exerts its activity locally, directly influencing hippocampal ageing or indirectly, accelerating systemic ageing. Thus, we deleted the CB1 receptor site-specifically in the hippocampus of 2-month-old CB1^flox/flox mice using stereotaxic injections of rAAV-Cre-Venus viruses and assessed their social recognition memory four months later. Mice with hippocampus-specific deletion of the CB1 receptor displayed a memory impairment, similarly as observed in constitutive knockouts at the same age. We next analysed neuroinflammatory changes in the hippocampus, neuronal density and cell proliferation. Site-specific mutant mice had enhanced glial cell activity, up-regulated levels of TNFα in the hippocampus and decreased cell proliferation, specifically in the subgranular zone of the dentate gyrus. Our data indicate that a local activity of the CB1 receptor in the hippocampus is required to maintain neurogenesis and to prevent neuroinflammation and cognitive decline.

Neurotrophin brain-derived neurotrophic factor (BDNF) and neurotransmitter serotonin (5-HT) regulate each other and have been implicated in several neuronal mechanisms, including neuroplasticity. We have investigated the effects of BDNF on serotonergic neurons by deleting BDNF receptor TrkB from serotonergic neurons in the adult brain. The transgenic mice show increased 5-HT and Tph2 levels with abnormal behavioral phenotype. In spite of increased food intake, the transgenic mice are significantly leaner than their wildtype littermates, which may be due to increased metabolic activity. Consistent with increased 5-HT, the proliferation of hippocampal progenitors is significantly increased, however, long-term survival of newborn cells is unchanged. Our data indicates that BDNF-TrkB signaling regulates the functional phenotype of 5-HT neurons with long-term behavioral consequences.

Aging is associated with reduced central nervous system endocannabinoid ‎tone. Here we ‎sought to decipher the involvement of hypothalamic cannabinoid receptor type-1 (Cnr1) in ‎driving peripheral tissue aging, with a particular focus on bone and joint structural changes. ‎METHODS: To this end, we generated mice with hypothalamus-specific ablation of Cnr1 (i.e. CB1^hypoKO), or with hypothalamus-specific rescue of the receptor (CB1^STOPhypoRS) using stereotaxic viral injections into the mediobasal hypothalamus at 2-3-‎months of Cnr1^fl/fl or CB1^STOP mice. Animals were aged to 18 or 19 months and assessed for body weight, ‎temperature and frailty. After sacrifice, we examined structural and histological features of hypothalamic tissue, skin, ‎testis, joint, and bone as well as circulating hormone levels. ‎RESULTS: CB1^hypoKO exhibited reduced frailty index vs WT at 17 months of age, with unchanged body weight, temperature and survival vs WT mice. Interestingly, CB1^hypoKO mice displayed a reduction in the lateral meniscal ‎mineral volume of the tibiofemoral joint, associated with less blood vessels and articular cartilage damage. Imunohistochemical analysis revealed that CB1^hypoKO mice displayed enriched tyrosine hydroxylase (TH) intensity surround blood vessels, yet meniscal tissue displayed reduced TH positive cells and ATF4 nuclear coappearence for CB1^hypoKO mice vs WT. These results suggest that a lack of hypothalamic CB1 tone increases meniscal sympathetic tone, impairs ATF4 nuclear localisation and is associated with an increase in meniscal mineralisation. This subsequently hinders OA development with age.