In addition to metabolic and cardiovascular disorders, obesity is associated with cognitive dysfunction in humans. Similarly, an obesogenic high-fat diet (HFD) consumption in animal models, in particular during adolescence, induces relational, spatial and object-based memory deficits. Interestingly, recent results from the laboratory indicate that alterations of the hippocampal endocannabinoid system and its main receptor CB1R, well known to regulate brain plasticity and memory processes, participates in HFD-induced memory deficits in male mice. Indeed, systemic blockade of CB1R or decrease of hippocampal CB1R improved memory in HFD-fed males. This project aims at identifying whether the endocannabinoid-CB1R system contributes to HFD-induced memory deficits in females and whether similar mechanisms (brain structures and cell types) are involved.

First, we showed that systemic injection of a CB1R antagonist rescued deficits of long-term object recognition memory in HFD-fed females, as previously shown in males. This indicates CB1R signaling regulates the impact of HFD on memory function in both sexes. However, contrary to males, decrease of hippocampal CB1R in HFD-fed females did not improve recognition memory deficits despite similar levels of CB1R decrease in both sexes. Interestingly, decrease of CB1R in the medial prefrontal cortex rescued recognition memory deficits in females, but not males. These results show a double dissociation in the hippocampal and prefrontal CB1R regulation of HFD effect on memory in females and males.

Furthermore, whereas hippocampal CB1R on glutamatergic (but not GABAergic) neurons are involved in memory deficits in HFD-fed males, prefrontal CB1R on GABAergic (but not glutamatergic) neurons are involved in HFD-fed females.

We finally wondered whether these sexual differences could be mediated by ovarian hormones during puberty. Ovariectomy by itself did not affect HFD-induced memory deficits in females, but decrease of hippocampal, but not prefrontal, CB1R improves memory deficits in ovariectomized HFD-fed females.

Altogether our results indicate that endocannabinoid-CB1R system is involved in HFD-induced memory deficits in both sexes but that brain structures and cells types involved differ between males and females through a modulation from ovarian hormones.

More information:

• https://www.bordeaux-neurocampus.fr/staff/guillaume-ferreira/