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Ketogenic diet (KD) is a high-fat and low-carbohydrate therapy for medically intractable epilepsy, and its applications in other neurological conditions, including those occurring in children, have been increasingly tested. However, how KD affects childhood neurodevelopment, a highly sensitive and plastic process, is not clear. In this study, we explored structural, metabolic, and functional consequences of a brief treatment of a strict KD (weight ratio of fat to carbohydrate plus protein is approximately 6.3:1) in naive juvenile mice of different inbred strains, using a multidisciplinary approach. Systemic measurements using magnetic resonance imaging revealed that unexpectedly, the volumes of most brain structures in KD-fed mice were about 90% of those in mice of the same strain but fed a standard diet. The reductions in volumes were nonselective, including different regions throughout the brain, the ventricles, and the white matter. The relative volumes of different brain structures were unaltered. Additionally, as KD is a metabolism-based treatment, we performed untargeted metabolomic profiling to explore potential means by which KD affected brain growth and to identify metabolic changes in the brain. We found that brain metabolomic profile was significantly impacted by KD, through both distinct and common pathways in different mouse strains. To explore whether the volumetric and metabolic changes induced by this KD treatment were associated with functional consequences, we recorded spontaneous EEG to measure brain network activity. Results demonstrated limited alterations in EEG patterns in KD-fed animals. In addition, we observed that cortical levels of brain-derived neurotrophic factor (BDNF), a critical molecule in neurodevelopment, did not change in KD-fed animals. Together, these findings indicate that a strict KD could affect volumetric development and metabolic profile of the brain in inbred juvenile mice, while global network activities and BDNF signaling in the brain were mostly preserved. Whether the volumetric and metabolic changes are related to any core functional consequences during neurodevelopment and whether they are also observed in humans need to be further investigated. In addition, our results indicate that certain outcomes of KD are specific to the individual mouse strains tested, suggesting that the physiological profiles of individuals may need to be examined to maximize the clinical benefit of KD.

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