Effects of Lipopolysaccharide and Progesterone Exposures on Embryonic Cerebral Cortex Development in Mice

Abstract

Our objective was to determine if progesterone pretreatment could ameliorate the detrimental effects of lipopolysaccharide (LPS)-induced inflammation on cortical neurogenesis. Timed pregnant mouse dams (n = 8) were given intraperitoneal injections of progesterone (42 mg/kg) or vehicle on embryonic day 17.5. Two hours later, mice were given intraperitoneal LPS (140 μg/kg) or vehicle. Mice were sacrificed 16 hours later on embryonic day 18. Two-color immunofluorescence was performed with primary antibodies T-box transcription factor 2 (Tbr2), ionized calcium binding adapter molecule 1 (Iba1), cleaved caspase 3 (CC3), and 5-bromo-2'-deoxyuridine (BrdU). Cells were counted, and statistical analysis was determined using analysis of variance and Tukey-Kramer method. The Tbr2 intermediate neural progenitor cell density decreased after LPS exposure (P = .0022). Pre-exposure to progesterone statistically increased Tbr2 intermediate neural progenitors compared to LPS treatment alone and was similar to controls (P = .0022). After LPS exposure, microglia displayed an activated phenotype, and cell density was increased (P < .001). Cell death rates were low among study groups but was increased in LPS exposure groups compared to progesterone alone (P = .0015). Lipopolysaccharide-induced systemic inflammation reduces prenatal neurogenesis in mice. Pre-exposure with progesterone is associated with increased neurogenesis. Progesterone may protect the preterm brain from defects of neurogenesis induced by inflammation.

An integrative microfluidically supported in vitro model of an endothelial barrier combined with cortical spheroids simulates effects of neuroinflammation in neocortex development

“…Our results are in agreement with the findings from studies in mice that analysed the development of the neocortex under inflammatory conditions. Similar to the in vivo model, we also observed a reduced expression of the neocortex development regulators Tbr1, 36 Tbr2, 37 and Pax6 38 in response to inflammation and pro-inflammatory cytokines. The data thus show that our in vitro model of an endothelial barrier co-cultured with neural tissue spheroids is able to reflect crucial aspects of neuroinflammation during neocortex formation.…”

Microglia in steady state

“…Microglia activation by LPS or microglia inactivation by doxycycline or progesterone modulates neural precursor cell number (53,54). Overactivation of microglia leads to a decreased number of precursors and a thinning of the SVZ, whereas a decrease in microglial activity results in an increased number of neural precursors (54). However, it should be mentioned here that the treatments used in these studies were not specific to microglia.…”

“…The expansion binding to low-affinity neuronal growth factor receptor p75 (52 (53). Microglia activation by LPS or microglia inactivation by doxycycline or progesterone modulates neural precursor cell number (53,54). Overactivation of microglia leads to a decreased number of precursors and a thinning of the SVZ, whereas a decrease in microglial activity results in an increased number of neural precursors (54).…”

Clonal analysis reveals laminar fate multipotency and daughter cell apoptosis of mouse cortical intermediate progenitors

“…However, it is presently unclear why proliferation or differentiation of one IP daughter cell should be linked to death of the other daughter cell. Observations of microglia in the VZ/SVZ of embryonic neocortex, including microglia that have ingested Tbr2 + nuclei, denote the likely involvement of microglia in this process (Cunningham et al, 2013;Tronnes et al, 2016).…”