High-fat diet consumption increases hippocampal plasticity and affects performance in a spatial learning task in young female mice

High-fat diet (HFD) consumption, a widespread dietary pattern in modern society, has been associated with an increased risk of cognitive impairments and psychiatric diseases. However, the underlying biological mechanisms remain poorly understood. This study aimed to identify early phenotypes of vulnerability to unhealthy dietary challenges emerging during adolescence and to elucidate the mechanisms through which HFD affects brain function.

Spatial learning of female C57/Bl6 mice, fed a HFD enriched in omega-6 polyunsaturated fatty acids (PUFA) for five weeks, were tested in the IntelliCage system. Peripheral levels of adipokines and cytokines were measured by ELISA and LUMINEX, respectively. Electrophysiology and RNA sequencing analyses were used to evaluate hippocampal plasticity and transcriptomic changes.

HFD consumption significantly increased body weight and leptin and reduced adiponectin blood concentrations. Interestingly, HFD enhanced hippocampal neuronal plasticity by increasing LTP amplitude in the CA1 region, and affected performance in a spatial learning task. Furthermore, HFD was associated with hippocampal transcriptional changes involving extracellular matrix remodeling and signaling pathways.

In conclusion, these findings suggest that enhanced neural plasticity associated with preserved cognitive function may represent an early adaptive response to HFD exposure in females, potentially preceding later alterations in brain function. Further studies are needed to establish the temporal dynamics and sex dependence of these responses and to clarify their contribution to the complex effects of HFD on brain function. This work was funded by the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS.

Marianna Samà and Silvia Poggini have contributed equally to this work as first author. Igor Branchi andFrancesca Cirulli have contributed equally to this work as last author. Center for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, viale Regina Elena 299, 00161, Rome, Italy Marianna Samà, Silvia Poggini, Chiara Musillo, Aurelia Viglione, Igor Branchi & Francesca Cirulli National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, viale Regina Elena 299, 00161, Rome, Italy Marianna Samà, Igor Branchi & Francesca Cirulli PhD program in Behavioral Neuroscience, Department of Psychology, Sapienza University of Rome, via dei Marsi 78, 00185, Rome, Italy Department of Physiology and Pharmacology Vittorio Erspamer, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy Department of Physiology and Pharmacology, Laboratory Affiliated to Istituto Pasteur Italia, and to Neurobiology Center-CRiN, Sapienza University, Piazzale Aldo Moro, 5, 00185, Rome, Italy The authors declare no competing interests.

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