Maternal infection during pregnancy is an environmental risk factor for the development of severe brain disorders in offspring, including schizophrenia and autism. However, little is known about the neurodevelopmental mechanisms underlying the association between prenatal exposure to infection and the emergence of cognitive and behavioral dysfunctions in later life. By injecting viral mimetic polyriboinosinic-polyribocytidylic acid (Poly I:C) into mice, we investigated the influence of maternal immune challenge during pregnancy on the development of the cerebral cortex of offspring. Our previous study showed that stimulation of the maternal immune system compromised the expression properties of transcription factors and the synaptogenesis of cortical neurons in upper layers but not those in deeper layers. The objective of the current study was to examine further whether maternal immune challenge has an influence on the cellular-biological features of the cortical progenitors that generate distinct cortical neuronal subtypes. We found the following abnormalities in the cortex of mice given the prenatal Poly I:C injection during later stages of cortical neurogenesis. First, proliferative activity and the expression of Pax6, which is a master regulator of the gene expression of transcription factors, were significantly decreased in the cortical progenitors. Second, the laminar allocation and gene expression were significantly altered in the daughter neurons generated at the same birth dates. These results demonstrate that specific abnormalities in the cortical progenitors preceded deficits in neuronal phenotypes. These changes may underlie the emergence of psychiatric brain and behavioral dysfunctions after in utero exposure to an infection.

Symptoms of depression and anxiety appeared in mice after they had been subjected to a combination of forced swimming for 15 min followed by being kept in cages that were sequentially subjected to leaning, drenching, and rotation within 1-2 days for a total of 3 weeks. The animals were then evaluated by the tail-suspension test, elevated plus-maze test, and open-field test at 1 day after the end of stress exposure. Using these experimental systems, we found that 10-hydroxy-trans-2-decenoic acid (HDEA), an unsaturated fatty acid unique to royal jelly (RJ), protected against the depression and anxiety when intraperitoneally administered once a day for 3 weeks simultaneously with the stress loading. Intraperitoneally administered RJ, a rich source of HDEA, was also protective against the depression, but RJ given by the oral route was less effective. Our present results demonstrate that HDEA and RJ, a natural source of it, were effective in ameliorating the stress-inducible symptoms of depression and anxiety.

Maternal infection during pregnancy is an environmental risk factor for the offspring to develop severe brain disorders, including schizophrenia. However, little is known about the neurodevelopmental mechanisms underlying the association between prenatal exposure to infection and emergence of cognitive and behavioral dysfunctions later in life. By injecting the viral mimetic polyriboinosinic-polyribocytidylic acid (Poly I:C) into mice, we investigated the influence of maternal immune challenge during pregnancy on the development of the cerebral cortex, a responsive organ for cognition. Stimulation of the maternal immune system did not influence the cell number or density of the cortical neurons of postnatal 10-day-old and 8-week-old offspring, whereas gene expressions of upper-layer-specific transcription factors were significantly reduced, without affecting those of the deeper-layer ones. Moreover, the prenatal Poly I:C injection impaired synaptic development of the upper-layer neurons at a later stage, and there was a decrease in the synaptophysin- and glutamic acid decarboxylase-67-positive puncta surrounding the neuronal cell bodies and an increase in the dendritic spine density in postnatal 8-week-old offspring. Considering their importance for cognitive function, the specific abnormalities in the development of upper-layer neuronal phenotypes may underlie the development of psychiatric brain and behavioral dysfunctions emerging after in utero exposure to an infection.

We presently found that medium-chain fatty acids (MCFAs) with 8-12 carbons and their esters facilitated activation (phosphorylation) of mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK) 1/2 of cultured embryonic cortical/hippocampal neurons. In particular, trans-2-decenoic acid ethyl ester (DAEE) had the most potent activity. Additionally, DAEE activated phosphatidylinositol 3-kinase and cAMP-response element binding protein (CREB), suggesting that DAEE generates similar intracellular signal as neurotrophins. Therefore, details of the signal elicited by DAEE were examined in comparison with those of a neurotrophin, brain-derived neurotrophic factor (BDNF). We found that 1) DAEE phosphorylated MAPK/ERK1/2 via MEK activation without the involvement of tyrosine kinases of neurotrophin Trk receptors; 2) DAEE activated CREB predominantly through MAPK/ERK1/2 activation, not through other pathways such as cAMP/protein kinase A; and 3) DAEE increased the expression of mRNAs of BDNF and neurotrophin-3 and the protein content of synapse-specific proteins such as synaptophysin, synapsin-1, and syntaxin. Based on these observations we propose that DAEE and some other derivatives of MCFAs having neurotrophin-like neurotrophic activities may become therapeutic tools for certain neurological or psychiatric disorders.

Abnormalities in tactile perception, such as sensory defensiveness, are common features in autism spectrum disorder (ASD). While not a diagnostic criterion for ASD, deficits in tactile perception contribute to the observed lack of social communication skills. However, the influence of tactile perception deficits on the development of social behaviors remains uncertain, as do the effects on neuronal circuits related to the emotional regulation of social interactions. In neonatal rodents, whiskers are the most important tactile apparatus, so bilateral whisker trimming is used as a model of early tactile deprivation. To address the influence of tactile deprivation on adult behavior, we performed bilateral whisker trimming in mice for 10 days after birth (BWT10 mice) and examined social behaviors, tactile discrimination, and c-Fos expression, a marker of neural activation, in adults after full whisker regrowth. Adult BWT10 mice exhibited significantly shorter crossable distances in the gap-crossing test than age-matched controls, indicating persistent deficits in whisker-dependent tactile perception. In contrast to controls, BWT10 mice exhibited no preference for the social compartment containing a conspecific in the three-chamber test. Furthermore, the development of amygdala circuitry was severely affected in BWT10 mice. Based on the c-Fos expression pattern, hyperactivity was found in BWT10 amygdala circuits for processing fear/anxiety-related responses to height stress but not in circuits for processing reward stimuli during whisker-dependent cued learning. These results demonstrate that neonatal whisker trimming and concomitant whisker-dependent tactile discrimination impairment severely disturbs the development of amygdala-dependent emotional regulation.