SEXUAL DIMORPHISM IN ENDOCANNABINOID-DEPENDENT CIRCUITS MEDIATING MEMORY IMPAIRMENTS INDUCED BY OBESOGENIC DIET CONSUMPTION: INFLUENCE OF OVARIAN HORMONES

In addition to cardiometabolic disorders, obesity is associated with cognitive dysfunction. This is particularly worrisome in the growing population of obese adolescents. In rodents, obesogenic high-fat high-sugar diet (HFD) consumption during adolescence induces memory deficits. We recently demonstrated that alterations of the hippocampal endocannabinoid (eCB) system and its main receptor CB1R participate in HFD-induced memory deficits in male mice. Indeed, systemic blockade of CB1R or decrease of CB1R in hippocampal neurons improved long-term memory of object recognition in HFD-fed males. Here, we investigated whether eCB-CB1R system contributes to HFD-induced memory impairments in females.
As in males, systemic CB1R blockade restored long-term memory in HFD-fed females. However, unlike males, hippocampal CB1R reduction failed to rescue HFD-induced memory deficits in females, while CB1R decrease in the medial prefrontal cortex (mPFC) improved memory in HFD-fed females. Our findings also revealed that memory deficits were mediated by CB1R on glutamatergic neurons in the hippocampus of HFD-fed males but CB1R on GABAergic neurons in the mPFC of HFD-fed females. We then investigated whether ovarian hormones during puberty were responsible for this sexual dimorphism. Ovariectomy per se did not change HFD-induced memory deficits. Interestingly, memory deficits in ovariectomized HFD-fed females were rescued by CB1R decrease in the hippocampus, but not in the mPFC, more specifically on hippocampal GABAergic neurons. Altogether our findings suggest that eCB-CB1R system contributes to the HFD-induced memory deficits in both sexes but that brain structures and cell types involved differ between males and females possibly through modulation by ovarian pubertal hormones.