Meal scheduling corrects obesogenic diet induced-uncoupling of cortico-hippocampal activities supporting memory.

BACKGROUND: Highly caloric food consumed around the clock perturbs the metabolism and cognitive functioning. We hypothesised that obesogenic food could alter neuronal representations of memory depending on the feeding-fasting cycle. METHODS: We tracked memory performance, dendritic spine dynamics and neuronal representations of memory in C57Bl6J mice fed obesogenic food ad libitum from peri-adolescence. We aimed to correct energy rich diet-induced plasticity deficits and cognitive impairment with time-restricted feeding in males and females. We further used chemogenetics, pharmacology and knock-in mice to investigate functional correlates underlying diet-induced neurocognitive impairments. FINDINGS: We found that changes in the feeding-fasting cycle reverted the effects of ad libitum obesogenic food on memory impairment in both sexes (n = 55, p = 0.003). Concurrently, it also corrected the increased dendritic spine maintenance and neuroactivity in hippocampus and the decreased spine maintenance and activity in parietal cortex (n = 48, p < 0.005). Bi-directional effects in cortex and hippocampus mediated by glucocorticoid signalling are causal to behavioural changes (n = 91, p = 0.0008), and scaling hippocampal with cortical activities restored memory in mice fed obesogenic food (n = 44, p = 0.02). INTERPRETATION: These results indicate that meal scheduling is a promising approach to confront glucocorticoid signalling bias and memory deficits caused by obesogenic food. FUNDING: Agence Nationale de la Recherche (ANR-21-CE14-0086), Fondation pour la Recherche sur le Cerveau (FRC).