Obesogenic diet impairs memory consolidation via the hippocampal endocannabinoid system

Although obesogenic high-fat/high-sugar diets impair memory function in humans and rodents, the underlying mechanisms remain elusive. Given that the brain endocannabinoid system and type-1 cannabinoid receptors (CB₁Rs) control memory processes and are overactive under obesogenic conditions, we studied whether the effects of obesogenic diet consumption on memory function are dependent on this system. Using an object recognition memory (ORM) task in male mice, we showed that CB₁R activity is required for obesogenic-diet-induced impairment of long-term memory performance. This impairment was prevented by post-training systemic blockade of CB₁R, which also normalized training-induced hippocampal cellular and synaptic overactivation. Consistently, the obesogenic diet potentiated the increase in hippocampal endocannabinoid levels and enhanced CB₁R expression induced by ORM, and genetic CB₁R deletion from hippocampal glutamatergic neurons abolished diet-induced memory deficits. Strikingly, the obesogenic diet enhanced the hippocampal mechanistic target of rapamycin (mTOR) pathway in a CB₁R-dependent manner, and pharmacological mTOR inhibition after training rescued diet-induced ORM consolidation deficits. Together, these results establish how an obesogenic environment can lead to hippocampal overactivation of the endocannabinoid system and the mTOR pathway to eventually impair memory consolidation. Thus, these results shed light on the mechanisms of diet-induced cognitive alterations and may pave the way for novel therapeutic strategies.