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The first reports of Zika virus infection in Brazil were in early 2015 (1). Shortly thereafter, Zika virus was associated with microcephaly (2). In February 2016, the World Health Organization [...]

ABSTRACT Background: Pyrrolizidine alkaloids (PAs) are commonly found in many plants including those used in medical therapeutics. The hepatotoxicities of PAs have been demonstrated both in vivo and in vitro; [...]

Purpose There is compelling evidence that interference of various anesthetics with synaptic functions and stress-provoking procedures during critical periods of brain maturation results in increased neuroapoptotic cell death. The hypothesis is that adverse intrauterine environmental conditions leading to intrauterine growth restriction (IUGR) with altered brain development may result in enhanced susceptibility to developmental anesthetic neurotoxicity. Methods This was a prospective, randomized, blinded animal study performed in a university laboratory involving 20 normal-weight (NW) and 19 IUGR newborn piglets. General inhalation anesthesia with isoflurane and nitrous oxide at clinically comparable dosages were administered for about 10 h. Surgical and monitoring procedures were accompanied by appropriate stage of general anesthesia. Resulting effects on developmental anesthetic and stress-induced neurotoxicity were assessed by estimation of apoptotic rates in untreated piglets and piglets after 10-h general anesthesia with MAC 1.0 isoflurane in 70 % nitrous oxide and 30 % oxygen. Results IUGR piglets exposed to different levels of isoflurane inhalation exhibited a significant increased apoptosis rate (TUNEL-positive neuronal cells) compared to NW animals of similar condition (P < 0.05). Cardiovascular and metabolic monitorings revealed similar effects of general anesthesia together with similar effects on brain electrical activity and broadly a similar dose-dependent gradual restriction in brain oxidative metabolism in NW and IUGR piglets. Conclusions There is no indication that the increased rate in neuroapoptosis in IUGR piglets is confounded by additional adverse systemic or organ-specific impairments resulting from administered mixed inhalation anesthesia. Developmental anesthetic and stress-induced neuroapoptosis presumably originated in response to fetal adaptations to adverse conditions during prenatal life and should be considered in clinical interventions on infants having suffered from fetal growth restriction., Author(s): Harald Schubert [sup.1], Michael Eiselt [sup.2], Bernd Walter [sup.3] [sup.4], Harald Fritz [sup.5], Michael Brodhun [sup.6], Reinhard Bauer [sup.3] [sup.7] Author Affiliations: (1) grid.9613.d, 0000000119392794, Institute of Laboratory Animal [...]

Newborn neurons in the dentate gyrus of the adult hippocampus rely upon cAMP response element binding protein (CREB) signaling for their differentiation into mature granule cells and their integration into the dentate network. Among its many targets, the transcription factor CREB activates expression of a gene locus that produces two microRNAs, miR-132 and miR-212. In cultured cortical and hippocampal neurons, miR-132 functions downstream from CREB to mediate activity-dependent dendritic growth and spine formation in response to a variety of signaling pathways. To investigate whether miR-132 and/or miR-212 contribute to the maturation of dendrites in newborn neurons in the adult hippocampus, we inserted LoxP sites surrounding the miR-212/132 locus and specifically targeted its deletion by stereotactically injecting a retrovirus expressing Cre recombinase. Deletion of the miR-212/132 locus caused a dramatic decrease in dendrite length, arborization, and spine density. The miR-212/132 locus may express up to four distinct microRNAs, miR-132 and -212 and their reverse strands miR-[132.sup.*] and [-212.sup.*]. Using ratiometric microRNA sensors, we determined that miR-132 is the predominantly active product in hippocampal neurons. We conclude that miR-132 is required for normal dendrite maturation in newborn neurons in the adult hippocampus and suggest that this microRNA also may participate in other examples of CREB-mediated signaling. microRNA-212 | neurogenesis | plasticity | learning doi/ 10.1073/pnas.1015691107

Gonadotropin-releasing hormone (GnRH) signaling regulates reproductive physiology in mammals. GnRH is released by a subset of hypothalamic neurons and binds to GnRH receptor (GnRHR) on gonadotropes in the anterior pituitary gland to control production and secretion of gonadotropins that in turn regulate the activity of the gonads. Central control of reproduction is well understood in adult animals, but GnRH signaling has also been implicated in the development of the reproductive axis. To investigate the role of GnRH signaling during development, we selectively ablated GnRHR-expressing cells in mice. This genetic strategy permitted us to identify an essential stage in male reproductive axis development, which depends on embryonic GnRH signaling. Our experiments revealed a striking dichotomy in the gonadotrope population of the fetal anterior pituitary gland. We show that luteinizing hormone-expressing gonadotropes, but not follicle-stimulating hormone-expressing gonadotropes, express the GnRHR at embryonic day 16.75. Furthermore, we demonstrate that an embryonic increase in luteinizing hormone secretion is needed to promote development of follicle-stimulating hormone-expressing gonadotropes, which might be mediated by paracrine interactions within the pituitary. Moreover, migration of GnRH neurons into the hypothalamus appeared normal with appropriate axonal connections to the median eminence, providing genetic evidence against autocrine regulation of GnRH neurons. Surprisingly, genetic ablation of GnRHR expressing cells significantly increased the number of GnRH neurons in the anterior hypothalamus, suggesting an unexpected role of GnRH signaling in establishing the size of the GnRH neuronal population. Our experiments define a functional role of embryonic GnRH signaling. gonadotropin-releasing hormone neurons | gonadotropin-releasing hormone receptor | gonadotrope development | diphtheria toxin | Cre recombinase www.pnas.org/cgi/doi/ 10.1073/pnas.1000423107

Neural stem cells have a broad differentiation repertoire during embryonic development and can be reprogrammed to pluripotency comparatively easily. We report that adult neural stem cells can be reprogrammed at very high efficiency to monocytes, a differentiated fate of an unrelated somatic lineage, by ectopic expression of the Ets transcription factor PU.1. The reprogrammed cells display a marker profile and functional characteristics of monocytes and integrate into tissues after transplantation. The failure to reprogram lineage-committed neural cells to monocytes with PU.1 suggests that neural stem cells are uniquely amenable to reprogramming. PU.1 | Ets transcription factor | transdifferentiation | microglia doi/ 10.1073/pnas.1009412107