Epidemiological studies suggest that poor nutrition during pregnancy influences offspring predisposition to experience developmental and psychiatric disorders. Animal studies have shown that maternal undernutrition leads to behavioral impairment, which is linked to alterations in monoaminergic systems and inflammation in the brain. In this study, we focused on the ethanolamine plasmalogen of the brain as a possible contributor to behavioral disturbances observed in offspring exposed to maternal undernutrition. Maternal food or protein restriction between gestational day (GD) 5.5 and GD 10.5 resulted in hyperactivity of rat male adult offspring. Genes related to the phospholipid biosynthesis were found to be activated in the PFC, but not in the NAcc or striatum, in the offspring exposed to prenatal undernutrition. Corresponding to these gene activations, increased ethanolamine plasmalogen (18:0p-22:6) was observed in the PFC using mass spectrometry imaging. A high number of crossings and the long time spent in the center area were observed in the offspring exposed to prenatal undernutrition and were mimicked in adult rats via the intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome. Additionally, plasmalogen (18:0p-22:6) increased only in the PFC, and not in the NAcc or striatum. These results suggest that brain plasmalogen is one of the key molecules to control behavior, and its injection using liposome is a potential therapeutic approach for cognitive impairment.SIGNIFICANCE STATEMENTMaternal undernutrition correlates to developmental and psychiatric disorders. Here, we found that maternal undernutrition in early pregnancy led to hyperactivity in rat male offspring and induced gene activation of phospholipid-synthesizing enzyme and elevation of ethanolamine plasmalogen (18:0p-22:6) level in the PFC. Intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome maintained crossing activity and the activity was circumscribed to the center area for a long time period, as in prenatally undernourished offspring with aberrant behavior. Furthermore, the amount of ethanolamine plasmalogen (18:0p-22:6) increased in the PFC of the rat after injection. Our result suggests that brain plasmalogen is one of the key molecules to control behavior and that its injection using liposome is a potential therapeutic approach for cognitive impairment.

Epidemiological studies suggest that exposure to prenatal stressors, including malnutrition, maternal immune activation (MIA), and adverse life events, is associated with increased risks of schizophrenia, autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD). However, the underlying pathophysiological mechanisms are unclear. The first trimester of pregnancy is particularly a vulnerable period. During this period, the self-renewal of neural stem cells and neurogenesis vigorously occur, and synaptic connections are partially formed in the telencephalon. Disturbance of this neuronal proliferation and migration during the first trimester may underlie the increased susceptibility to these disorders. Epigenetic modifications, such as DNA methylation and histone modification, are critical mechanisms for regulating gene expression. They can be affected by stress and are associated with an increase in susceptibility to schizophrenia and developmental disabilities. Injection of polyinosinic-polycytidylic acid or lipopolysaccharide induces MIA, enhances the expression of proinflammatory cytokines, and leads to the activation of microglia and the subsequent epigenetic modification of neurons or glia in the offspring. Furthermore, maternal high-fat diet and obesity similarly induce MIA and therefore may increase the risk of developmental disabilities. In addition, maternal stress reprograms the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the stress response in the offspring. Thus, exposure to prenatal stress may increase the susceptibility to schizophrenia, ASD, or ADHD in the offspring through epigenetic modifications, MIA, and alteration of the HPA axis.

Aims:  Human olfactory epithelium becomes functional at birth, but prenatal development remains unclear. In the present study, we aimed to clarify the development of human olfactory epithelium using scanning electron microscopy (SEM).Methods:  The development of human olfactory epithelium was observed in 24 externally normal fetuses, which were formalin‐fixed and long‐preserved, with a crown‐rump length (CRL) of 102–336 mm (gestational week 14–38). The olfactory mucosa in the superior wall of the nasal septum near the choana were dissected and observed under SEM. We examined the number of olfactory vesicles per unit area, diameter of olfactory vesicles, and number and length of cilia on olfactory vesicles.Results:  At circa (ca) CRL 100 mm (ca 14 weeks), olfactory epithelium displayed several olfactory vesicles with 1–2 short cilia per unit area. At ca CRL 150 mm (ca 18 weeks), olfactory vesicles were present in small clusters, and cilia were longer. At CRL lager than 225 mm (ca 26 weeks), olfactory vesicles became located separately from each other, while length and number of cilia per olfactory vesicle were further increased.Conclusion:  The present findings suggest that fetal olfactory epithelium becomes morphologically almost the same as that in adults in late gestation, much later than previously thought.