• Neuroinformatics
• The University of Manchester - Inst... close

Abstract Maternal infection during pregnancy, leading to maternal immune activation (mIA) and cytokine release, increases the offspring risk of developing a variety of neurodevelopmental disorders (NDDs), including schizophrenia. Animal models have provided evidence to support these mechanistic links, with placental inflammatory responses and dysregulation of placental function implicated. This leads to changes in fetal brain cytokine balance and altered epigenetic regulation of key neurodevelopmental pathways. The prenatal timing of such mIA-evoked changes, and the accompanying fetal developmental responses to an altered in utero environment, will determine the scope of the impacts on neurodevelopmental processes. Such dysregulation can impart enduring neuropathological changes, which manifest subsequently in the postnatal period as altered neurodevelopmental behaviours in the offspring. Hence, elucidation of the functional changes that occur at the molecular level in the placenta is vital in improving our understanding of the mechanisms that underlie the pathogenesis of NDDs. This has notable relevance to the recent COVID-19 pandemic, where inflammatory responses in the placenta to SARS-CoV-2 infection during pregnancy and NDDs in early childhood have been reported. This review presents an integrated overview of these collective topics and describes the possible contribution of prenatal programming through placental effects as an underlying mechanism that links to NDD risk, underpinned by altered epigenetic regulation of neurodevelopmental pathways.

Near infra-red spectroscopy (NIRS) is a comparatively new method for monitoring the oxygenation in blood and tissue in the brain of the fetus and the neonate. Absorption of light in the wavelength range 700-1000 nm through such tissue is measured, which is then used to calculate changes in the concentration of cerebral oxygenated and de-oxygenated haemoglobin (HbO2 and Hb) and hence cerebral blood volume (CBV). Studies carried out on several groups of newborn babies have shown clear changes in HbO, Hb and CBV with hypoxia and bradycardia. These changes may well have implications in the occurrence of hypoxic/ischaemic brain injury. Intra partum NIR measurements on the fetal brain have demonstrated clear changes in HbO2, Hb and CBVm, coinciding with the onset of contractions. © 1992.

The viral mimetic polyinosinic:polycytidylic acid (poly(I:C)) is increasingly used to induce maternal immune activation (mIA) to model neurodevelopmental disorders (NDDs). Robust and reproducible phenotypes across studies are essential for the generation of models that will enhance our understanding of NDDs and enable the development of improved therapeutic strategies. However, differences in mIA-induced phenotypes using poly(I:C) have been widely observed, and this has prompted the reporting of useful and much needed methodological guidelines. Here, we perform a detailed investigation of molecular weight and endotoxin variations in poly(I:C) procured from two of the most commonly used suppliers, Sigma and InvivoGen. We demonstrate that endotoxin contamination and molecular weight differences in poly(I:C) composition lead to considerable variability in maternal IL-6 response in rats treated on gestational day (GD)15 and impact on fetal outcomes. Specifically, both endotoxin contamination and molecular weight predicted reductions in litter size on GD21. Further, molecular weight predicted a reduction in placental weight at GD21. While fetal body weight at GD21 was not affected by poly(I:C) treatment, male fetal brain weight was significantly reduced by poly(I:C), dependent on supplier. Our data are in agreement with recent reports of the importance of poly(I:C) molecular weight, and extend this work to demonstrate a key role of endotoxin on relevant phenotypic outcomes. We recommend that the source and batch numbers of poly(I:C) used should always be stated and that molecular weight variability and endotoxin contamination should be minimised for more robust mIA modelling.

AbstractPrevious studies have demonstrated the use of functional magnetic resonance imaging (fMRI) to assess fetal brain activity. To extend these studies, a fetal fMRI experiment using a visual stimulus has been performed at 0.5 T. This used a block fMRI paradigm with a bright, constant‐intensity light source being shone at the maternal abdomen for 8 sec followed by 16 sec of darkness. This was repeated typically 40 times on nine subjects all of whom were greater than 36 weeks gestational age. Of these, one could not be analysed due to motion, three did not show significant activation, and five showed significant activation (P < 0.0085). In all cases, activation was localised within the frontal cortex. Exact localisation was difficult but this may correspond to the frontal eye fields and dorsolateral prefontal cortex. In no cases was significant activation present within the occipital region as would have been expected and was observed in 2/8 adult subjects. Hum. Brain Mapping 20:239–245, 2003. © 2003 Wiley‐Liss, Inc.