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.

生酮饮食 (KD) 是一种用于治疗难治性癫痫的高脂肪和低碳水化合物疗法，其在其他神经系统疾病（包括儿童疾病）中的应用已得到越来越多的测试。然而，KD如何影响儿童神经发育，一个高度敏感和可塑性的过程，尚不清楚。在这项研究中，我们使用多学科方法探索了对不同近交系幼年小鼠进行严格 KD（脂肪与碳水化合物加蛋白质的重量比约为 6.3:1）的短暂治疗的结构、代谢和功能后果。使用磁共振成像进行的全身测量显示，出乎意料的是，喂食 KD 的小鼠的大多数大脑结构的体积约为相同品系但喂食标准饮食的小鼠的 90%。体积的减少是非选择性的，包括整个大脑、心室和白质的不同区域。不同大脑结构的相对体积没有改变。此外，由于 KD 是一种基于代谢的治疗，我们进行了非靶向代谢组学分析，以探索 KD 影响大脑生长的潜在方式，并确定大脑中的代谢变化。我们发现，通过不同小鼠品系中不同和共同的途径，KD 显着影响大脑代谢组学特征。为了探索这种 KD 治疗引起的体积和代谢变化是否与功能后果相关，我们记录了自发 EEG 以测量大脑网络活动。结果表明，喂食 KD 的动物的脑电图模式变化有限。此外，我们观察到，脑源性神经营养因子 (BDNF) 的皮质水平是神经发育中的关键分子，在 KD 喂养的动物中没有变化。总之，这些发现表明，严格的 KD 可能会影响近交幼鼠大脑的体积发育和代谢特征，而大脑中的全局网络活动和 BDNF 信号传导大多被保留。体积和代谢变化是否与神经发育过程中的任何核心功能后果有关，以及它们是否也在人类中观察到，需要进一步研究。此外，我们的结果表明，KD 的某些结果是特定于所测试的个体小鼠品系的，这表明可能需要检查个体的生理特征以最大化 KD 的临床益处。