Early Influences of Microbiota on White Matter Development in Germ-Free Piglets

Abnormalities in the prefrontal cortex (PFC), as well as the underlying white matter (WM) tracts, lie at the intersection of many neurodevelopmental disorders. The influence of microorganisms on brain development has recently been brought into the clinical and research spotlight as alterations in commensal microbiota are implicated in such disorders, including autism spectrum disorders, schizophrenia, depression, and anxiety via the gut-brain axis. In addition, gut dysbiosis is common in preterm birth patients who often display diffuse WM injury and delayed WM maturation in critical tracts including those within the PFC and corpus callosum. Microbial colonization of the gut aligns with ongoing postnatal processes of oligodendrogenesis and the peak of brain myelination in humans; however, the influence of microbiota on gyral WM development remains elusive. Here, we develop and validate a neonatal germ-free swine model to address these issues, as piglets share key similarities in WM volume, developmental trajectories, and distribution to humans. We find significant region-specific reductions, and sexually dimorphic trends, in WM volume, oligodendrogenesis, and mature oligodendrocyte numbers in germ-free piglets during a key postnatal epoch of myelination. Our findings indicate that microbiota plays a critical role in promoting WM development during early life when the brain is vulnerable to environmental insults that can result in an array of disabilities manifesting later in life.

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CNS Glycosylphosphatidylinositol Deficiency Results in Delayed White Matter Development, Ataxia, and Premature Death in a Novel Mouse Model

10.1101/763490 ◽

2019 ◽

Author(s):

Marshall Lukacs ◽

Rolf W. Stottmann

Keyword(s):

White Matter ◽

Mouse Model ◽

Critical Role ◽

Premature Death ◽

Post Translational Modification ◽

Gpi Anchor ◽

Wide Range ◽

Affected Tissue ◽

White Matter Development ◽

The Central Nervous System

AbstractThe Glycosylphosphatidylinositol (GPI) anchor is a post-translational modification added to approximately 150 different proteins to facilitate proper membrane anchoring and trafficking to lipid rafts. Biosynthesis and remodeling of the GPI anchor requires the activity of over twenty distinct genes. Defects in the biosynthesis of GPI anchors in humans leads to Inherited Glycosylphosphatidylinositol Deficiency (IGD). IGD patients display a wide range of phenotypes though the central nervous system (CNS) appears to be the most commonly affected tissue. A full understanding of the etiology of these phenotypes has been hampered by the lack of animal models due to embryonic lethality of GPI biosynthesis gene null mutants. Here we model IGD by genetically ablating GPI production in the CNS with a conditional mouse allele of phosphatidylinositol glycan anchor biosynthesis, class A (Piga) and Nestin-Cre. We find that the mutants do not have structural brain defects but do not survive past weaning. The mutants show progressive decline with severe ataxia consistent with defects in cerebellar development. We show the mutants have reduced myelination and defective Purkinje cell development. Surprisingly we found Piga was expressed in a fairly restricted pattern in the early postnatal brain consistent with the defects we observed in our model. Thus, we have generated a novel mouse model of the neurological defects of IGD which demonstrates a critical role for GPI biosynthesis in cerebellar and white matter development.

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Identifying neurodevelopmental anomalies of white matter microstructure associated with high risk for psychosis in 22q11.2DS

Translational Psychiatry ◽

10.1038/s41398-020-01090-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Joëlle Bagautdinova ◽

Maria C. Padula ◽

Daniela Zöller ◽

Corrado Sandini ◽

Maude Schneider ◽

...

Keyword(s):

Risk Factors ◽

White Matter ◽

High Risk ◽

Developmental Trajectories ◽

Clinical Risk Factors ◽

White Matter Tracts ◽

Clinical Risk ◽

White Matter Microstructure ◽

White Matter Development ◽

The Impact

AbstractDisruptions of white matter microstructure have been widely reported in schizophrenia. However, the emergence of these alterations during preclinical stages remains poorly understood. 22q11.2 Deletion Syndrome (22q11.2DS) represents a unique model to study the interplay of different risk factors that may impact neurodevelopment in premorbid psychosis. To identify the impact of genetic predisposition for psychosis on white matter development, we acquired longitudinal MRI data in 201 individuals (22q11.2DS = 101; controls = 100) aged 5–35 years with 1–3 time points and reconstructed 18 white matter tracts using TRACULA. Mixed model regression was used to characterize developmental trajectories of four diffusion measures—fractional anisotropy (FA), axial (AD), radial (RD), and mean diffusivity (MD) in each tract. To disentangle the impact of additional environmental and developmental risk factors on white matter maturation, we used a multivariate approach (partial least squares (PLS) correlation) in a subset of 39 individuals with 22q11.2DS. Results revealed no divergent white matter developmental trajectories in patients with 22q11.2DS compared to controls. However, 22q11.2DS showed consistently increased FA and reduced AD, RD, and MD in most white matter tracts. PLS correlation further revealed a significant white matter-clinical risk factors relationship. These results indicate that while age-related changes are preserved in 22q11.2DS, white matter microstructure is widely disrupted, suggesting that genetic high risk for psychosis involves early occurring neurodevelopmental insults. In addition, multivariate modeling showed that clinical risk factors further impact white matter development. Together, these findings suggest that genetic, developmental, and environmental risk factors may play a cumulative role in altering normative white matter development during premorbid stages of psychosis.

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Regional white matter development in children with autism spectrum disorders

Developmental Psychobiology ◽

10.1002/dev.20471 ◽

2010 ◽

Vol 52 (8) ◽

pp. 755-763 ◽

Cited By ~ 24

Author(s):

Dennis P. Carmody ◽

Michael Lewis

Keyword(s):

Autism Spectrum Disorders ◽

White Matter ◽

Children With Autism ◽

Autism Spectrum ◽

White Matter Development ◽

Spectrum Disorders

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Diffusion-weighted imaging evidence of altered white matter development from late childhood to early adulthood in Autism Spectrum Disorder

NeuroImage Clinical ◽

10.1016/j.nicl.2018.06.002 ◽

2018 ◽

Vol 19 ◽

pp. 840-847 ◽

Cited By ~ 10

Author(s):

Fikret Işık Karahanoğlu ◽

Bengi Baran ◽

Quynh Trang Huong Nguyen ◽

Djalel-Eddine Meskaldji ◽

Anastasia Yendiki ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

White Matter ◽

Diffusion Weighted Imaging ◽

Early Adulthood ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Late Childhood ◽

Diffusion Weighted ◽

White Matter Development

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Global and regional white matter development in early childhood

10.1101/524785 ◽

2019 ◽

Cited By ~ 1

Author(s):

Jess E. Reynolds ◽

Melody N. Grohs ◽

Deborah Dewey ◽

Catherine Lebel

Keyword(s):

Early Childhood ◽

White Matter ◽

Brain Injuries ◽

Diffusion Tensor ◽

Developmental Trajectories ◽

Early Adulthood ◽

Mean Diffusivity ◽

Age Related ◽

White Matter Development ◽

Age Range

AbstractWhite matter development continues throughout childhood and into early adulthood, but few studies have examined early childhood, and the specific trajectories and regional variation in this age range remain unclear. The aim of this study was to characterize developmental trajectories and sex differences of white matter in typically developing young children. Three hundred and ninety-six diffusion tensor imaging datasets from 120 children (57 male) aged 2-8 years were analyzed using tractography. Fractional anisotropy (FA) increased and mean diffusivity (MD) decreased in all white matter tracts by 5-15% over the 6-year period, likely reflecting increases in myelination and axonal packing. Males showed steeper slopes in a number of brain areas. Overall, early childhood is associated with substantial development of all white matter and appears to be an important period for the development of occipital and limbic connections, which showed the largest changes. This study provides a detailed characterization of age-related white matter changes in early childhood, offering baseline data that can be used to understand cognitive and behavioural development, as well as to identify deviations from normal development in children with various diseases, disorders, or brain injuries.

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CNS glycosylphosphatidylinositol deficiency results in delayed white matter development, ataxia and premature death in a novel mouse model

Human Molecular Genetics ◽

10.1093/hmg/ddaa046 ◽

2020 ◽

Vol 29 (7) ◽

pp. 1205-1217 ◽

Cited By ~ 3

Author(s):

Marshall Lukacs ◽

Lauren E Blizzard ◽

Rolf W Stottmann

Keyword(s):

White Matter ◽

Mouse Model ◽

Critical Role ◽

Premature Death ◽

Post Translational Modification ◽

Gpi Anchor ◽

Wide Range ◽

Affected Tissue ◽

White Matter Development ◽

The Central Nervous System

Abstract The glycosylphosphatidylinositol (GPI) anchor is a post-translational modification added to approximately 150 different proteins to facilitate proper membrane anchoring and trafficking to lipid rafts. Biosynthesis and remodeling of the GPI anchor requires the activity of over 20 distinct genes. Defects in the biosynthesis of GPI anchors in humans lead to inherited glycosylphosphatidylinositol deficiency (IGD). IGD patients display a wide range of phenotypes though the central nervous system (CNS) appears to be the most commonly affected tissue. A full understanding of the etiology of these phenotypes has been hampered by the lack of animal models due to embryonic lethality of GPI biosynthesis gene null mutants. Here we model IGD by genetically ablating GPI production in the CNS with a conditional mouse allele of phosphatidylinositol glycan anchor biosynthesis, class A (Piga) and Nestin-Cre. We find that the mutants do not have structural brain defects but do not survive past weaning. The mutants show progressive decline with severe ataxia consistent with defects in cerebellar development. We show that the mutants have reduced myelination and defective Purkinje cell development. Surprisingly, we found that Piga was expressed in a fairly restricted pattern in the early postnatal brain consistent with the defects we observed in our model. Thus, we have generated a novel mouse model of the neurological defects of IGD which demonstrates a critical role for GPI biosynthesis in cerebellar and white matter development.

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The Role of the SLP in Autism Spectrum Disorder Screening and Assessment

Perspectives on Language Learning and Education ◽

10.1044/lle15.2.50 ◽

2008 ◽

Vol 15 (2) ◽

pp. 50-59 ◽

Cited By ~ 1

Author(s):

Amy Philofsky

Keyword(s):

Language Development ◽

Critical Role ◽

Children With Autism ◽

Autism Spectrum ◽

Children With Asd ◽

Prevalence Estimates ◽

Notable Increase ◽

Screening Assessment ◽

Critical Components

AbstractRecent prevalence estimates for autism have been alarming as a function of the notable increase. Speech-language pathologists play a critical role in screening, assessment and intervention for children with autism. This article reviews signs that may be indicative of autism at different stages of language development, and discusses the importance of several psychometric properties—sensitivity and specificity—in utilizing screening measures for children with autism. Critical components of assessment for children with autism are reviewed. This article concludes with examples of intervention targets for children with ASD at various levels of language development.

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Aviation and the Microbiome

Aerospace Medicine and Human Performance ◽

10.3357/amhp.5576.2020 ◽

2020 ◽

Vol 91 (8) ◽

pp. 651-661

Author(s):

Joshua T. Davis ◽

Hilary A. Uyhelji

Keyword(s):

Psychological Health ◽

Aviation Safety ◽

Autism Spectrum ◽

Unintended Consequences ◽

Microbial Colonization ◽

Future Research ◽

Aerospace Medicine ◽

Medical Certification ◽

Physical Disorders ◽

The Impact

INTRODUCTION: Although the impact of microorganisms on their hosts has been investigated for decades, recent technological advances have permitted high-throughput studies of the collective microbial genomes colonizing a host or habitat, also known as the microbiome. This literature review presents an overview of microbiome research, with an emphasis on topics that have the potential for future applications to aviation safety. In humans, research is beginning to suggest relationships of the microbiome with physical disorders, including type 1 and type 2 diabetes mellitus, cardiovascular disease, and respiratory disease. The microbiome also has been associated with psychological health, including depression, anxiety, and the social complications that arise in autism spectrum disorders. Pharmaceuticals can alter microbiome diversity, and may lead to unintended consequences both short and long-term. As research strengthens understanding of the connections between the microbiota and human health, several potential applications for aerospace medicine and aviation safety emerge. For example, information derived from tests of the microbiota has potential future relevance for medical certification of pilots, accident investigation, and evaluation of fitness for duty in aerospace operations. Moreover, air travel may impact the microbiome of passengers and crew, including potential impacts on the spread of disease nationally and internationally. Construction, maintenance, and cleaning regimens that consider the potential for microbial colonization in airports and cabin environments may promote the health of travelers. Altogether, the mounting knowledge of microbiome effects on health presents several opportunities for future research into how and whether microbiome-based insights could be used to improve aviation safety.Davis JT, Uyhelji HA. Aviation and the microbiome. Aerosp Med Hum Perform. 2020; 91(8):651–661.

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