Obesogenic diet impairs memory consolidation via the hippocampal endocannabinoid system

Ducourneau EG(1), Janthakhin Y(1), Oliveira da Cruz JF(2), Artinian J(1), Alfos S(1), Helbling JC(1), Matias I(2), Bakoyiannis I(1), N’Diaye M(1), Bosch-Bouju C(1), Potier M(1), Bellocchio L(2), Busquets-Garcia A(2), Trifilieff P(1), Marsicano G(3), Ferreira G(4).

Author information:
(1)University of Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux 33076, France.
(2)University of Bordeaux, INSERM, NeuroCentre Magendie, U1215, Bordeaux 33077, France.
(3)University of Bordeaux, INSERM, NeuroCentre Magendie, U1215, Bordeaux 33077, France. Electronic address: .
(4)University of Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux
33076, France. Electronic address: .

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.

Copyright © 2025 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cub.2025.10.049
PMID: 41237773

Conflict of interest statement: Declaration of interests The authors declare no
competing interests.

Auteurs Bordeaux Neurocampus