Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal pathology

Children with neurofibromatosis type 1 (NF1) develop low-grade brain tumors throughout the optic pathway. Nearly 50% of children with optic pathway gliomas (OPGs) experience visual impairment, and few regain their vision after chemotherapy. Recent studies have revealed that girls with optic nerve gliomas are five times more likely to lose vision and require treatment than boys. To determine the mechanism underlying this sexually dimorphic difference in clinical outcome, we leveraged Nf1 optic glioma (Nf1-OPG) mice. We demonstrate that female Nf1-OPG mice exhibit greater retinal ganglion cell (RGC) loss and only females have retinal nerve fiber layer (RNFL) thinning, despite mice of both sexes harboring tumors of identical volumes and proliferation. Female gonadal sex hormones are responsible for this sexual dimorphism, as ovariectomy, but not castration, of Nf1-OPG mice normalizes RGC survival and RNFL thickness. In addition, female Nf1-OPG mice have threefold more microglia than their male counterparts, and minocycline inhibition of microglia corrects the retinal pathology. Moreover, pharmacologic inhibition of microglial estrogen receptor-β (ERβ) function corrects the retinal abnormalities in female Nf1-OPG mice. Collectively, these studies establish that female gonadal sex hormones underlie the sexual dimorphic differences in Nf1 optic glioma–induced retinal dysfunction by operating at the level of tumor-associated microglial activation

PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis

Abstract Sepsis‐associated acute kidney injury (AKI) is a significant problem in critically ill children and adults resulting in increased morbidity and mortality. Fundamental mechanisms contributing to sepsis‐associated AKI are poorly understood. Previous research has demonstrated that peroxisome proliferator‐activated receptor α (PPARα) expression is associated with reduced organ system failure in sepsis. Using an experimental model of polymicrobial sepsis, we demonstrate that mice deficient in PPARα have worse kidney function, which is likely related to reduced fatty acid oxidation and increased inflammation. Ultrastructural evaluation with electron microscopy reveals that the proximal convoluted tubule is specifically injured in septic PPARα deficient mice. In this experimental group, serum metabolomic analysis reveals unanticipated metabolic derangements in tryptophan‐kynurenine‐NAD+ and pantothenate pathways. We also show that a subgroup of children with sepsis whose genome‐wide expression profiles are characterized by repression of the PPARα signaling pathway has increased incidence of severe AKI. These findings point toward interesting associations between sepsis‐associated AKI and PPARα‐driven fatty acid metabolism that merit further investigation

Effects of Chronic Variable Stress Across Developmental Stages in Mice

Posttraumatic Stress Disorder (PTSD) is a response to trauma exposure that involves a number of symptoms that can be highly impairing to affected individuals. Only a subset of those exposed to traumatic events will develop the disorder, which is conceptualized as developing via conditional fear. Research into factors predisposing for PTSD is needed. Furthermore, little work has been done to investigate predisposing factors in children more specifically. This research tests the effects of stress exposure on subsequent fear learning, across developmental stages in mice, as a model for PTSD. Juvenile and adult male mice were exposed to chronic variable stress (CVS) for a period of 7d and their behavior was examined immediately thereafter. Both juvenile and adult mice exposed to CVS showed exaggerated anxiety behavior, as indicated by decreased exploratory behavior on the elevated plus-maze. While adult mice exposed to CVS displayed enhancements in long-term context fear learning, juvenile mice failed to display this pattern. Findings suggest differences in stress effects across developmental stages and provide further evidence supporting dissociation of the anxiety and fear pathways in the rodent brain. While PTSD does occur in childhood, onset is more common in adulthood, which may be reflective of differential developmental schedules in the fear and anxiety pathways

Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition

Undernutrition in children is a pressing global health problem, manifested in part by impaired linear growth (stunting). Current nutritional interventions have been largely ineffective in overcoming stunting, emphasizing the need to obtain better understanding of its underlying causes. Treating Bangladeshi children with severe acute malnutrition with therapeutic foods reduced plasma levels of a biomarker of osteoclastic activity without affecting biomarkers of osteoblastic activity or improving their severe stunting. To characterize interactions among the gut microbiota, human milk oligosaccharides (HMOs), and osteoclast and osteoblast biology, young germ-free mice were colonized with cultured bacterial strains from a 6-mo-old stunted infant and fed a diet mimicking that consumed by the donor population. Adding purified bovine sialylated milk oligosaccharides (S-BMO) with structures similar to those in human milk to this diet increased femoral trabecular bone volume and cortical thickness, reduced osteoclasts and their bone marrow progenitors, and altered regulators of osteoclastogenesis and mediators of Th2 responses. Comparisons of germ-free and colonized mice revealed S-BMO-dependent and microbiota-dependent increases in cecal levels of succinate, increased numbers of small intestinal tuft cells, and evidence for activation of a succinate-induced tuft cell signaling pathway linked to Th2 immune responses. A prominent fucosylated HMO, 2'-fucosyllactose, failed to elicit these changes in bone biology, highlighting the structural specificity of the S-BMO effects. These results underscore the need to further characterize the balance between, and determinants of, osteoclastic and osteoblastic activity in stunted infants/children, and suggest that certain milk oligosaccharides may have therapeutic utility in this setting

Gut-derived metabolites mediating cognitive development in 5-year-old children: Early-life transplant in mice has lasting effects throughout adulthood

The gut microbiota has been causally linked to cognitive development. We aimed to identify metabolites mediating its effect on cognitive development, and foods or nutrients related to most promising metabolites. Faeces from 5-year-old children (DORIAN-PISAC cohort, including 90 general population families with infants, 42/48 females/males, born in 2011-2014) were transplanted (FMT) into C57BL/6 germ-free mice. Children and recipient mice were stratified by cognitive phenotype, or based on protective metabolites. Food frequency questionnaires were obtained in children. Cognitive measurements in mice included five Y-maze tests until 23 weeks post-FMT, and (at 23 weeks) PET-CT for brain metabolism and radiodensity, and ultrasound-based carotid vascular indices. Children (faeces, urine) and mice (faeces, plasma) metabolome was measured by 1H NMR spectroscopy, and the faecal microbiota was profiled in mice by 16S rRNA amplicon sequencing. Cognitive scores of children and recipient mice were correlated. FMT-dependent modifications of brain metabolism were observed. Mice receiving FMT from high-cognitive or protective metabolite-enriched children developed superior cognitive-behavioural performance. A panel of metabolites, namely xanthine, hypoxanthine, formate, mannose, tyrosine, phenylalanine, glutamine, was found to mediate the gut-cognitive axis in donor children and recipient mice. Vascular indices partially explained the metabolite-to-phenotype relationships. Children's consumption of legumes, whole-milk yogurt and eggs, and intake of iron, zinc and vitamin D appeared to support protective gut metabolites. Overall, metabolites involved in inflammation, purine metabolism and neurotransmitter synthesis mediate the gut-cognitive axis, and holds promise for screening. The related dietary and nutritional findings offer leads to microbiota-targeted interventions for cognitive protection, with long-lasting effects

Lyme Disease and the Workplace

{Excerpt] Lyme disease, an infection by the bacterium Borrelia burgdorferi, was named after a Connecticut town where a group of arthritis cases in children appeared in the early 1970s. These bacteria are carried by infected blacklegged ticks and are transmitted to humans through tick bites. While deer feed ticks and spread them around — actually mice infect the majority of ticks carrying Lyme in the Northeast. A mouse might have dozens of ticks covering its ears and face and can infect up to 95% of those ticks. Climate change is part of the surge in Lyme disease cases, but a big factor has been the history of land use in the Northeast. When the area was first settled, early farmers clear-cut nearly all of the forests to plant crops and raise livestock, as well as cutting down trees for commercial use and for firewood. While a lot of forest has come back, today it\u27s broken up by roads, farms, and housing developments. Mice tend to thrive in these fragmented landscapes because their predators -- foxes, hawks, owls -- need big forests to survive

Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.

Autism spectrum disorders (ASDs) are complex and heterogeneous developmental disabilities affecting an ever-increasing number of children worldwide. The diverse manifestations and complex, largely genetic aetiology of ASDs pose a major challenge to the identification of unifying neuropathological features. Here we describe the neurodevelopmental defects in mice that carry deleterious alleles of the Wdfy3 gene, recently recognized as causative in ASDs. Loss of Wdfy3 leads to a regionally enlarged cerebral cortex resembling early brain overgrowth described in many children on the autism spectrum. In addition, affected mouse mutants display migration defects of cortical projection neurons, a recognized cause of epilepsy, which is significantly comorbid with autism. Our analysis of affected mouse mutants defines an important role for Wdfy3 in regulating neural progenitor divisions and neural migration in the developing brain. Furthermore, Wdfy3 is essential for cerebral expansion and functional organization while its loss-of-function results in pathological changes characteristic of ASDs

Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease

Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with lifethreatening cerebral oedema and dysmyelination in affected individuals. Treatment requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain injury. Despite careful management, children commonly suffer metabolic decompensation in the context of catabolic stress associated with non-specific illness. The mechanisms underlying this decompensation and brain injury are poorly understood. Using recently developed mouse models of classic and intermediate maple syrup urine disease, we assessed biochemical, behavioural and neuropathological changes that occurred during encephalopathy in these mice. Here, we show that rapid brain leucine accumulation displaces other essential amino acids resulting in neurotransmitter depletion and disruption of normal brain growth and development. A novel approach of administering norleucine to heterozygous mothers of classic maple syrup urine disease pups reduced branched-chain amino acid accumulation in milk as well as blood and brain of these pups to enhance survival. Similarly, norleucine substantially delayed encephalopathy in intermediate maple syrup urine disease mice placed on a high protein diet that mimics the catabolic stress shown to cause encephalopathy in human maple syrup urine disease. Current findings suggest two converging mechanisms of brain injury in maple syrup urine disease including: (i) neurotransmitter deficiencies and growth restriction associated with branchedchain amino acid accumulation and (ii) energy deprivation through Krebs cycle disruption associated with branched-chain ketoacid accumulation. Both classic and intermediate models appear to be useful to study the mechanism of brain injury and potential treatment strategies for maple syrup urine disease. Norleucine should be further tested as a potential treatment to prevent encephalopathy in children with maple syrup urine disease during catabolic stress

Interleukin-17A Mediates Acquired Immunity to Pneumococcal Colonization

Although anticapsular antibodies confer serotype-specific immunity to pneumococci, children increase their ability to clear colonization before these antibodies appear, suggesting involvement of other mechanisms. We previously reported that intranasal immunization of mice with pneumococci confers CD4+ T cell–dependent, antibody- and serotype-independent protection against colonization. Here we show that this immunity, rather than preventing initiation of carriage, accelerates clearance over several days, accompanied by neutrophilic infiltration of the nasopharyngeal mucosa. Adoptive transfer of immune CD4+ T cells was sufficient to confer immunity to naïve RAG1−/− mice. A critical role of interleukin (IL)-17A was demonstrated: mice lacking interferon-γ or IL-4 were protected, but not mice lacking IL-17A receptor or mice with neutrophil depletion. In vitro expression of IL-17A in response to pneumococci was assayed: lymphoid tissue from vaccinated mice expressed significantly more IL-17A than controls, and IL-17A expression from peripheral blood samples from immunized mice predicted protection in vivo. IL-17A was elicited by pneumococcal stimulation of tonsillar cells of children or adult blood but not cord blood. IL-17A increased pneumococcal killing by human neutrophils both in the absence and in the presence of antibodies and complement. We conclude that IL-17A mediates pneumococcal immunity in mice and probably in humans; its elicitation in vitro could help in the development of candidate pneumococcal vaccines