Feeding-fasting cycle of obesogenic food determines glucocorticoid neuromodulation of cortico-hippocampal activities sustaining long-term memory

BackgroundHighly caloric food consumed around the clock perturbs the metabolism and cognitive functioning. We hypothesized that obesogenic food could alter neuronal representations of memory depending on the feeding-fasting cycle. MethodsWe 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. ResultsWe find 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). ConclusionThese results indicate that meal scheduling is a promising approach to confront glucocorticoid signalling bias and memory deficits caused by obesogenic food. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWhat and when we eat contributes to our health. This is particularly worrisome for kids and adolescents because of the lifelong effects that unrestricted snacking on highly caloric food could cause on brain maturation. A variety of school policies and nutritional programs have emerged to prevent poor nutritional habits. But obesity is on the rise and a major cause of neurological disabilities difficult to detect and treat. Human studies are limited by the size and duration of sampling with low resolution metrics to prove causality between nutritional habits and cognitive health trajectory. Animal studies showed that all-day snacking on highly caloric food disrupts innate biological rhythms that influence hormonal secretions, neuronal structure and function in brain regions that encode, store and retrieve memories. It isnt known if, like adipocytes and hepatocytes, the brain in obesity can develop glucocorticoid resistance -a state that would prevent the robust but complex effects of this hormone on memory- to the point that researchers still question whether glucocorticoids are a cause or solution to obesity related-brain comorbidities. Added value of this studyLongitudinal sampling of several metrics at multiple timepoints in mice fed highly caloric food since peri-adolescence up to adulthood showed that the trajectory of obesity-related brain comorbidities is corrected when reinstating the feeding/fasting cycle, albeit consuming highly caloric food. Glucocorticoid resistance -manifesting as receptor phosphorylation deficits impeding coincidence detection between glucocorticoid and neuronal activities -was reversible when reinstating the feeding/fasting cycle, albeit consuming highly caloric food. Studies in receptor mutant mice lacking a phosphorylation site-independent of glucocorticoids showed it is required to reinstate neuroplasticity to changes of feeding/fasting cycle, albeit consuming highly caloric food. Fos-trapping experiments showed less engagement of pyramidal neurons in the cortex when activity-dependent phosphorylation of glucocorticoid receptor was low, and more in the hippocampus of mice fed obesogenic diet, which reinstating the feeding/fasting cycle reverted, albeit consuming highly caloric food. Finally, chemogenetic experiments confirmed the requirement for the co-engagement of cortical and hippocampal pyramidal neurons to fully remember, despite poor nutritional habits. Implications of all the available evidenceThe cortico-hippocampal activities necessary for remembering are uncoupled by obesogenic food consumed ad libitum but not on meal scheduling, extending neuroimaging correlation studies in obese adolescents. Poor nutritional habits cause glucocorticoid resistance in the brain as previously suggested, with altered neuronal representation of memory that meal scheduling corrected. This result should transform school policies and familial nutritional habits to promote cognitive health. Future research will develop allosteric ligands targeting phosphorylation motifs in the glucocorticoid receptor as more specific alternative to orthosteric ligands for the treatment of obesity-related brain comorbidities.