Intrauterine inflammation reduces postnatal neurogenesis in the hippocampal subgranular zone and leads to accumulation of hilar ectopic granule cells

Abstract

Prenatal inflammation is associated with poor neurobehavioral outcomes in exposed offspring. A common route of exposure for the fetus is intrauterine infection, which is often associated with preterm birth. Hippocampal development may be particularly vulnerable to an inflammatory insult during pregnancy as this region remains highly neurogenic both prenatally and postnatally. These studies sought to determine if intrauterine inflammation specifically altered hippocampal neurogenesis and migration of newly produced granule neurons during the early postnatal period. Microglial and astroglial cell populations known to play a role in the regulation of postnatal neurogenesis were also examined. We show that intrauterine inflammation significantly reduced hippocampal neurogenesis between postnatal days 7 (P7) and P14 as well as decreased granule cell density at P28. Ectopic migration of granule cells was observed in LPS-exposed mice at P14, but not at P28. Intrauterine inflammation had no effect on hippocampal astrocyte or microglia density or on apoptosis rate at the postnatal time points examined. Thus, exposure to intrauterine inflammation disrupts early postnatal neurogenesis and leads to aberrant migration of newly born granule cells.

Intrauterine Inflammation Alters the Transcriptome and Metabolome in Placenta

“…Using a model of intrauterine inflammation that is similar to human pregnancies complicated by acute chorioamnionitis ( Elovitz and Mrinalini, 2005 ; Elovitz et al, 2011 ; Hester et al, 2018 ; Brown et al, 2019 ), we demonstrated that intrauterine LPS injection alters the placenta metabolome and is associated with marked changes in expression of genes involved in key pathways including vascular function and reactivity, mitochondria function and nutrient sensing, glucose and lipid metabolism, and ceramide and sphingosine-1-phosphate signaling.…”

“…The University of Pennsylvania Institutional Animal Care and Use Committee approved all experiments in this study. Details of the intrauterine inflammation model have been previously published ( Elovitz and Mrinalini, 2005 ; Elovitz et al, 2011 ; Hester et al, 2018 ; Brown et al, 2019 ). CD-1 out-bred, timed pregnant mice were purchased from Charles River Laboratories (Wilmington, MA).…”

The role of maternal T cell and macrophage activation in preterm birth: Cause or consequence?

“…Such responses could stop at damage to the placenta or cross into the amniotic fluid (e.g. cytokines) or the fetus to cause damage to internal organs, including the brain [104,105] possibly leading to the processes that force medically indicated PTB or increasing morbidity in prematurely born infants. This later issue and the fetal defense against this is beyond the scope of this review and an extensive literature is elsewhere (e.g.…”

The Role of Innate Immune System in the Human Amniotic Membrane and Human Amniotic Fluid in Protection Against Intra-Amniotic Infections and Inflammation

“…Importantly, various pathogens and the inflammatory response that follows the infection, affect the fetal development (especially the developing fetal lung and brain), and may also impact the long-term health of the infant (70). IAI can affect different neurological developmental processes, inducing neuroinflammation, cerebral palsy, and periventricular white matter injury in the fetus, and even neuropsychiatric diseases have been linked to IAI (71)(72)(73)(74)(75)(76). Chronically damaged lungs in the form of bronchopulmonary dysplasia are also highly associated with IAI (77)(78)(79).…”