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 (CB ₁ R) 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 CB ₁ R activity is required for obesogenic diet-induced impairment of long-term memory performance. This impairment was prevented by post-training systemic blockade of CB ₁ R, which also normalized training-induced hippocampal cellular and synaptic overactivation. Consistently, obesogenic diet potentiated the increase of hippocampal endocannabinoid levels and enhanced CB ₁ R expression induced by ORM, and genetic CB ₁ R deletion from hippocampal glutamatergic neurons abolished diet-induced memory deficits. Strikingly, obesogenic diet enhanced the hippocampal mTOR pathway in a CB ₁ R-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 of 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 to novel therapeutic strategies.