Type I interferon alters invasive extravillous trophoblast function.

Inappropriate type I interferon (IFN) signaling during embryo implantation and placentation is linked to poor pregnancy outcomes. Here, we evaluated the consequence of elevated type I IFN exposure on implantation using a biomimetic model of human implantation in an organ-on-a-chip device. We found that type I IFN reduced extravillous trophoblast (EVT) invasion capacity. Analyzing single-cell transcriptomes, we uncovered that IFN truncated endovascular EVT emergence in the implantation-on-a-chip device by stunting EVT epithelial-to-mesenchymal transition. Disruptions to the epithelial-to-mesenchymal transition is associated with the pathogenesis of preeclampsia, a life-threatening hypertensive disorder of pregnancy. Strikingly, unwarranted IFN stimulation induced genes associated with increased preeclampsia risk and a preeclamptic gene-like signature in EVTs. These dysregulated EVT phenotypes ultimately reduced EVT-mediated endothelial cell vascular remodeling in the implantation-on-a-chip device. Overall, our work indicates IFN signaling can alter EVT epithelial-to-mesenchymal transition progression which results in diminished EVT-mediated spiral artery remodeling and a preeclampsia gene signature upon sustained stimulation. Our work implicates unwarranted type I IFN as a maternal disturbance that can result in abnormal EVT function that could trigger preeclampsia.

Estradiol promotes and progesterone reduces anxiety-like behavior produced by nicotine withdrawal in female rats.

This study assessed sex differences and the role of ovarian hormones in nicotine withdrawal. Study 1 compared physical signs, anxiety-like behavior, and corticosterone levels in male, intact female, and ovariectomized (OVX) female rats during nicotine withdrawal. Estradiol (E2) and progesterone levels were also assessed in intact females that were tested during different phases of the 4-day estrous cycle. Study 2 assessed the role of ovarian hormones in withdrawal by comparing the same measures in OVX rats that received vehicle, E2, or E2+progesterone prior to testing. Briefly, rats received a sham surgery or an ovariectomy procedure. Fifteen days later, rats were prepared with a pump that delivered nicotine for 14 days. On the test day, rats received saline or the nicotinic receptor antagonist, mecamylamine to precipitate withdrawal. Physical signs and anxiety-like behavior were assessed on the elevated plus maze (EPM) and light-dark transfer (LDT) tests. During withdrawal, intact females displayed greater anxiety-like behavior and increases in corticosterone levels as compared to male and OVX rats. Females tested in the estrus phase (when E2 is relatively low) displayed less anxiety-like behavior and had lower corticosterone levels versus all other phases. Anxiety-like behavior and corticosterone levels were positively correlated with E2 and negatively correlated with progesterone levels. Intact females displaying high E2/low progesterone showed greater anxiety-like behavior and corticosterone levels as compared to females displaying low E2/high progesterone. Lastly, OVX-E2 rats displayed greater anxiety-like behavior than OVX-E2+progesterone rats. These data suggest that E2 promotes and progesterone reduces anxiety-like behavior produced by nicotine withdrawal.

Sex differences in cholinergic systems in the interpeduncular nucleus following nicotine exposure and withdrawal.

The medial habenula-interpeduncular nucleus (MHb-IPN) pathway modulates negative affective states produced by nicotine withdrawal. Sex differences in the contribution of acetylcholine (ACh) systems in this pathway have not been explored. Thus, this study assessed ACh levels and gene expression of α- and ß-containing nicotinic acetylcholine receptor (nAChR) subunits in the IPN of female and male rats following nicotine treatment and withdrawal. Rats were prepared with a pump that delivered nicotine for 14 days, and naïve controls received a sham surgery. In Study 1, rats were prepared with a probe in the IPN, and ACh levels were measured following saline and then mecamylamine administration. In Study 2, separate groups of naïve control or nicotine-treated rats received saline or mecamylamine and physical signs and anxiety-like behavior were assessed using elevated plus maze (EPM) procedures. The IPN was then dissected and mRNA levels were assessed using RT-qPCR methods. Nicotine treatment increased ACh levels to a larger extent in females than males. Nicotine withdrawal produced a similar increase in physical signs; however, females displayed greater anxiety-like behavior than males. In females, gene expression of α5 increased following nicotine treatment and withdrawal. In males, α7 increased following nicotine treatment and α2 and α3 increased during nicotine withdrawal. Both females and males displayed an increase in ß3 and ß4 during nicotine withdrawal. In females, anxiety-like behavior was correlated with α4, α5, and ß2 gene expression in the IPN. These results suggest that sex differences in withdrawal are modulated via cholinergic systems in the IPN.