Developmental and Neurobehavioural Effects of Prenatal Exposure to a Ketogenic Diet

Abstract

Inappropriate gestational nutrition can have detrimental effects on the developing fetus. With the in- creasing popularity and therapeutic applications of the ketogenic diet (KD), it is important to investigate whether it can be consumed during gestation. Previous studies on gestational ketosis have primarily investigated ketosis resulting from starvation or diabetes. However, these ketotic conditions do not pro- vide adequate energy and nutrients to the mother or the fetus, and cannot properly imitate the stable ketosis resulting from KD consumption. This thesis aims to elucidate some of the developmental, neurological, and behavioural effects of gestational consumption of a KD on the offspring. To identify such effects, young adult CD-1 mice were fed the KD prior to and during gestation. Their offspring were compared with those from a control group fed a Standard Diet (SD). Comparison was conducted at fetal, neonatal, and early adulthood periods. Regardless of prenatal diet, all mice were adopted by lactating SD foster dams at postnatal-day (P) 2.5 and were weaned to the SD at P21.5. Optical projection tomography was used to image the embryos at embryonic-day (E) 13.5, Magnetic Resonance Imaging was used to image the E17.5 embryos, the neonatal brains at P11.5 and P21.5, and the young-adult brains at P90. Physical activity and susceptibility to anxiety and depression were assessed in adult offspring via standardized neurobehavioural tests. Several morphological differences were noted between the KD and SD offspring at each time-period. Compared with the SD counterpart, the KD embryo was significantly larger at E13.5, but significantly smaller at E17.5. The relative volumes of its brain and heart were also altered. The average KD pup gained weight slower and its brain morphology at P21.5 was significantly altered. For example, the hippocampus and corpus callosum were relatively smaller, while the hypothalamus and cerebellum were relatively enlarged. Neuroanatomical changes also existed in adulthood, and were accompanied by altered susceptibility to anxiety, depression, and hyperactivity. Taken together, prenatal exposure to a KD during programs the offspring anatomy and behaviour, despite exposure to the same diet in postnatal life.