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1.
J Mol Biol ; 434(3): 167243, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1851574

ABSTRACT

Brain organoids are self-organized three-dimensional aggregates generated from pluripotent stem cells. They exhibit complex cell diversities and organized architectures that resemble human brain development ranging from neural tube formation, neuroepithelium differentiation, neurogenesis and gliogenesis, to neural circuit formation. Rapid advancements in brain organoid culture technologies have allowed researchers to generate more accurate models of human brain development and neurological diseases. These models also allow for direct investigation of pathological processes associated with infectious diseases affecting the nervous system. In this review, we first briefly summarize recent advancements in brain organoid methodologies and neurodevelopmental processes that can be effectively modeled by brain organoids. We then focus on applications of brain organoids to investigate the pathogenesis of neurotropic viral infection. Finally, we discuss limitations of the current brain organoid methodologies as well as applications of other organ specific organoids in the infectious disease research.


Subject(s)
Brain , Central Nervous System Viral Diseases , Organoids , Brain/growth & development , Brain/virology , Central Nervous System Viral Diseases/virology , Humans , Neurogenesis , Organoids/virology
2.
Nature ; 604(7905): 230-231, 2022 04.
Article in English | MEDLINE | ID: covidwho-1795827
4.
Cell ; 185(1): 42-61, 2022 01 06.
Article in English | MEDLINE | ID: covidwho-1509638

ABSTRACT

The construction of the human nervous system is a distinctly complex although highly regulated process. Human tissue inaccessibility has impeded a molecular understanding of the developmental specializations from which our unique cognitive capacities arise. A confluence of recent technological advances in genomics and stem cell-based tissue modeling is laying the foundation for a new understanding of human neural development and dysfunction in neuropsychiatric disease. Here, we review recent progress on uncovering the cellular and molecular principles of human brain organogenesis in vivo as well as using organoids and assembloids in vitro to model features of human evolution and disease.


Subject(s)
Autism Spectrum Disorder/metabolism , Brain/embryology , Brain/growth & development , Epilepsy/metabolism , Neurogenesis/physiology , Schizophrenia/metabolism , Animals , Autism Spectrum Disorder/genetics , Brain/metabolism , Epilepsy/genetics , Humans , Mutation , Neurons/cytology , Neurons/metabolism , Organoids/embryology , Organoids/growth & development , Schizophrenia/genetics
5.
Neurobiol Dis ; 156: 105422, 2021 08.
Article in English | MEDLINE | ID: covidwho-1267874

ABSTRACT

Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1-5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.


Subject(s)
Cerebellum/drug effects , Cerebral Cortex/drug effects , Glucocorticoids , Lung/drug effects , Pregnenediones/pharmacology , Prodrugs/pharmacology , Signal Transduction/drug effects , Animals , Animals, Newborn , Anti-Inflammatory Agents/pharmacology , Body Weight/drug effects , Brain/drug effects , Brain/growth & development , COVID-19/drug therapy , Dexamethasone/pharmacology , Female , Mice , Mice, Inbred C57BL , Myelin Basic Protein/biosynthesis , Organ Size/drug effects , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/drug effects
6.
Adm Policy Ment Health ; 48(3): 379-387, 2021 05.
Article in English | MEDLINE | ID: covidwho-1144365

ABSTRACT

The COVID-19 pandemic exacerbates the mental, emotional, and behavioral (MEB) health problems of children and adolescents in the United States (U.S.). A collective and coordinated national economic and social reconstruction effort aimed at shoring up services to promote children's MEB, like the Marshall Plan that helped rebuild Europe post-World War II, has been proposed to buttress against the expected retrenchment. The plan prioritizes children's well-being as a social objective. We propose strategically reconstructing the public safety-net systems serving youth, including early education, maternal and child health, child welfare, corrections, and mental health. That plan called for a concentrated focus on coalition-building and contracting by state mental health systems to establish a foundation for an improved health system. This paper offers a complementary set of suggestions for the four non-mental health systems mentioned above by recommending actionable steps based on scientific evidence to support improved services for children at risk for MEB problems. For each system we describe examples of evidence-informed services, policies or programs that (1) prevent disabilities and promote health, (2) protect and preserve families and neighborhoods, and (3) provide quality care. Prioritizing the promotion of children's MEB health by all state systems can shape U.S. children's health and well-being for generations to come.


Subject(s)
COVID-19/epidemiology , Health Promotion/organization & administration , Mental Health Services/organization & administration , Mental Health , Neurodevelopmental Disorders/prevention & control , Adolescent , Adolescent Development , Brain/growth & development , Child , Child Development , Emotions , Humans , Law Enforcement/methods , Maternal-Child Health Services/organization & administration , Pandemics , Parent-Child Relations , Premature Birth , SARS-CoV-2 , United States/epidemiology
7.
Transl Psychiatry ; 11(1): 179, 2021 03 19.
Article in English | MEDLINE | ID: covidwho-1142427

ABSTRACT

Microglia, the resident brain immune cells, play a critical role in normal brain development, and are impacted by the intrauterine environment, including maternal immune activation and inflammatory exposures. The COVID-19 pandemic presents a potential developmental immune challenge to the fetal brain, in the setting of maternal SARS-CoV-2 infection with its attendant potential for cytokine production and, in severe cases, cytokine storming. There is currently no biomarker or model for in utero microglial priming and function that might aid in identifying the neonates and children most vulnerable to neurodevelopmental morbidity, as microglia remain inaccessible in fetal life and after birth. This study aimed to generate patient-derived microglial-like cell models unique to each neonate from reprogrammed umbilical cord blood mononuclear cells, adapting and extending a novel methodology previously validated for adult peripheral blood mononuclear cells. We demonstrate that umbilical cord blood mononuclear cells can be used to create microglial-like cell models morphologically and functionally similar to microglia observed in vivo. We illustrate the application of this approach by generating microglia from cells exposed and unexposed to maternal SARS-CoV-2 infection. Our ability to create personalized neonatal models of fetal brain immune programming enables non-invasive insights into fetal brain development and potential childhood neurodevelopmental vulnerabilities for a range of maternal exposures, including COVID-19.


Subject(s)
Brain/growth & development , Brain/immunology , COVID-19/immunology , Cellular Reprogramming , Fetal Blood/immunology , Induced Pluripotent Stem Cells , Leukocytes, Mononuclear/immunology , Microglia/immunology , Pregnancy Complications, Infectious/immunology , Adult , Female , Humans , Infant, Newborn , Pregnancy
9.
BMJ Open ; 11(1): e044491, 2021 01 31.
Article in English | MEDLINE | ID: covidwho-1060011

ABSTRACT

INTRODUCTION: Children born moderate to late preterm (MLP, 32-36 weeks' gestation) account for approximately 85% of all preterm births globally. Compared with children born at term, children born MLP are at increased risk of poor neurodevelopmental outcomes. Despite making up the largest group of preterm children, developmental outcomes of children born MLP are less well studied than in other preterm groups. This study aimed to (1) compare neurodevelopmental, respiratory health and brain magnetic resonance imaging (MRI) outcomes between children born MLP and term at 9 years of age; (2) examine the differences in brain growth trajectory from infancy to 9 years between children born MLP and term; and in children born MLP; (3) examine the relationship between brain development and neurodevelopment at 9 years; and (4) identify risk factors for poorer outcomes at 9 years. METHODS AND ANALYSIS: The "LaPrem" (Late Preterm MRI Study) study is a longitudinal cohort study of children born MLP and term controls, born at the Royal Women's Hospital in Melbourne, Australia, between 2010 and 2013. Participants were recruited in the neonatal period and were previously followed up at 2 and 5 years. This 9-year school-age follow-up includes neuropsychology, motor and physical activities, and lung function assessments, as well as brain MRI. Outcomes at 9 years will be compared between birth groups using linear and logistic regressions. Trajectories of brain development will be compared between birth groups using mixed effects models. The relationships between MRI and neurodevelopmental outcomes, as well as other early predictors of poor 9-year outcomes, will be explored using linear and logistic regression. ETHICS AND DISSEMINATION: This study was approved by the human research ethics committee at the Royal Children's Hospital, Melbourne, Australia. Study outcomes will be disseminated through peer-reviewed publications, conference presentations and social media.


Subject(s)
Brain , Lung Diseases , Premature Birth , Australia/epidemiology , Brain/diagnostic imaging , Brain/growth & development , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant, Newborn , Longitudinal Studies , Lung Diseases/etiology , Pregnancy , Premature Birth/epidemiology , Prospective Studies , Schools
10.
Neuroimmunomodulation ; 28(1): 22-28, 2021.
Article in English | MEDLINE | ID: covidwho-1059821

ABSTRACT

COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) betacoronavirus, affects children in a different way than it does in adults, with milder symptoms. However, several cases of neurological symptoms with neuroinflammatory syndromes, such as the multisystem inflammatory syndrome (MIS-C), following mild cases, have been reported. As with other viral infections, such as rubella, influenza, and cytomegalovirus, SARS-CoV-2 induces a surge of proinflammatory cytokines that affect microglial function, which can be harmful to brain development. Along with the viral induction of neuroinflammation, other noninfectious conditions may interact to produce additional inflammation, such as the nutritional imbalance of fatty acids and polyunsaturated fatty acids and alcohol consumption during pregnancy. Additionally, transient thyrotoxicosis induced by SARS-CoV-2 with secondary autoimmune hypothyroidism has been reported, which could go undetected during pregnancy. Together, those factors may pose additional risk factors for SARS-CoV-2 infection impacting mechanisms of neural development such as synaptic pruning and neural circuitry formation. The present review discusses those conditions in the perspective of the understanding of risk factors that should be considered and the possible emergence of neurodevelopmental disorders in COVID-19-infected children.


Subject(s)
Brain/growth & development , COVID-19/immunology , Inflammation/immunology , Microglia/immunology , Neurodevelopmental Disorders/immunology , Brain/immunology , Brain/physiopathology , COVID-19/physiopathology , Diet , Dietary Fats, Unsaturated , Fatty Acids, Unsaturated , Fetal Alcohol Spectrum Disorders/immunology , Fetal Alcohol Spectrum Disorders/physiopathology , Humans , Inflammation/physiopathology , Neurodevelopmental Disorders/physiopathology , Neuronal Plasticity , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Systemic Inflammatory Response Syndrome
13.
J Psychiatr Res ; 128: 1-4, 2020 09.
Article in English | MEDLINE | ID: covidwho-478074

ABSTRACT

Prenatal COVID-19 infection is anticipated by the U.S. Centers for Disease Control to affect fetal development similarly to other common respiratory coronaviruses through effects of the maternal inflammatory response on the fetus and placenta. Plasma choline levels were measured at 16 weeks gestation in 43 mothers who had contracted common respiratory viruses during the first 6-16 weeks of pregnancy and 53 mothers who had not. When their infants reached 3 months of age, mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), which assesses their infants' level of activity (Surgency), their fearfulness and sadness (Negativity), and their ability to maintain attention and bond to their parents and caretakers (Regulation). Infants of mothers who had contracted a moderately severe respiratory virus infection and had higher gestational choline serum levels (≥7.5 mM consistent with U.S. Food and Drug Administration dietary recommendations) had significantly increased development of their ability to maintain attention and to bond with their parents (Regulation), compared to infants whose mothers had contracted an infection but had lower choline levels (<7.5 mM). For infants of mothers with choline levels ≥7.5 µM, there was no effect of viral infection on infant IBQ-R Regulation, compared to infants of mothers who were not infected. Higher choline levels obtained through diet or supplements may protect fetal development and support infant early behavioral development even if the mother contracts a viral infection in early gestation when the brain is first being formed.


Subject(s)
Betacoronavirus/pathogenicity , Brain , Child Development , Choline , Fetal Development , Infant Behavior , Pregnancy Complications, Infectious , Adult , Attention , Brain/drug effects , Brain/growth & development , COVID-19 , Child Development/drug effects , Child Development/physiology , Choline/administration & dosage , Choline/blood , Coronavirus Infections/blood , Coronavirus Infections/complications , Coronavirus Infections/virology , Dietary Supplements , Female , Fetal Development/drug effects , Fetal Development/physiology , Gestational Age , Humans , Infant , Infant Behavior/physiology , Infant Behavior/psychology , Male , Nootropic Agents/administration & dosage , Nootropic Agents/blood , Object Attachment , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/complications , Pneumonia, Viral/virology , Pregnancy , Pregnancy Complications, Infectious/blood , Pregnancy Complications, Infectious/virology , Prenatal Care/methods , SARS-CoV-2
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