The changes of oligodendrocytes induced by anesthesia during brain development

With the advent of modern techniques, drugs, and monitoring, general anesthesia has come to be considered an unlikely cause of harm, particularly for healthy patients. While this is largely true, newly emerging clinical and laboratory studies have sug- gested that exposure to anesthetic agents during early childhood may have long-lasting adverse effects on cognitive function. This concern has been the focus of intense study in the field of anesthesia research. A recent high-profile review by Rappaport et al. （2015） concluded that while many questions remain un- answered, there is strong evidence from laboratory studies that commonly used anesthetics interfere with brain development and that clinical studies suggest a correlation between early childhood exposure to these agents and subsequent effects on learning and cognition. The issue is of sufficient public health importance that a public-private partnership known as Smar- Tots （Strategies for Mitigating Anesthesia-Related Neurotoxicity in Tots） was developed by the FDA to study pediatric anesthetic neurotoxicity. The mechanism of injury underlying this phe- nomenon has yet to be fully elucidated, and there is evidence to suggest that anesthetics may have direct cytotoxic effects on neurons leading to cell death or suppressed neurogenesis （Strat- mann et al., 2010） and that they may interfere with key pro- cesses in neuronal growth and development that underlie brain circuit development （Wagner et al., 2014）.

Impact of SARS-CoV-2 infection during pregnancy on postnatal brain development:The potential role of glial cells

Glial cells are crucial for maintaining central nervous system(CNS)homeostasis.They actively participate in immune responses,as well as form functional barriers,such as blood-brain barrier(BBB),which restrict the entry of pathogens and inflammatory mediators into the CNS.In general,viral infections during the gestational period can alter the embryonic and fetal environment,and the related inflammatory response may affect neurodevelopment and lead to behavioral dysfunction during later stage of life,as highlighted by our group for Zika virus infection.Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)induces a cytokine storm and,during pregnancy,may be related to a more severe form of the coronavirus disease-19(COVID-19)and also to higher preterm birth rates.SARS-CoV-2 can also affect the CNS by inducing neurochemical remodeling in neural cells,which can compromise neuronal plasticity and synaptic function.However,the impact of SARS-CoV-2 infection during pregnancy on postnatal CNS,including brain development during childhood and adulthood,remains undetermined.Our group has recently highlighted the impact of COVID-19 on the expression of molecular markers associated with neuropsychiatric disorders,which are strongly related to the inflammatory response.Thus,based on these relationships,we discussed the impact of SARS-CoV-2 infection either during pregnancy or in critical periods of neurodevelopment as a risk factor for neurological consequences in the offspring later in life,focusing on the potential role of glial cells.Thus,it is important to consider future and long-term public health concerns associated with SARS-CoV-2 infection during pregnancy.

Omega-6 for Body,Omega-3 for Brain:Balance for Brain Development in Children

Food must supply a balance of nutrients to support both brain and body.The human brain makes us uniquely human.Essential fatty acids are part of the metabolic pathways that define tissue structure and function.Omega-6(O6)linoleic acid(LA6)has long been known to be required for skin structure,and as a precursor for inflammatory,thrombotic,immune,and other signaling molecules.Omega-3(O3)alpha-linolenic acid(ALA3)and particularly its long chain product docosahexaenoic acid(DHA3)has a key structural role in the brain,retina,and related neural tissue.In the 20 th century western world,inexpensive,high quality oils primarily from LA6-rich/O3-poor vegetable seed oils became dominant fats produced by the food industry.Provision of LA6-rich/O3-poor oils as the sole source of fat in the diets of pregnant animals causes O3 deficiency and poor brain development,primarily because high LA6 antagonizes metabolism of all O3,creating an artificial metabolic demand for O3.Data developed over the last 2~3 decades show that provision of low LA6 combined with preformed DHA3 optimizes brain function.Recent studies emphasize the importance of nutrition to support brain development,with newer findings showing particular importance of fatty acid balance in malnourished children.The World Health Organization(WHO)through the Codex Alimentarius(“Code for Food”)is increasingly recognizing the primacy of brain health and in part on that basis recently acted to recommend balanced fat for Ready-to-Use-Therapeutic Foods used to treat children with severe acute malnutrition.Similar principles are likely to be important in older persons.Industry now has the tools to adjust the composition of oils to support brain health throughout the life cycle.

Microglial dynamics during brain development

Microglia are the resident immune cells of the central nervous system （CNS）, In the normal state, microglia have a ramified shape and con- tinuously survey the conditions of the brain.

Basic Research on Brain Development and Neural Plasticity Kicked Off

A major basic research projectin the field of neurosciencewas launched on November26 last year at the Shanghai-basedInstitute of Neuroscience of the Chi-nese Academy of Sciences(CAS).

Tetrabromobisphenol A exerts thyroid disrupting effects but has little overt impact on postnatal brain development and neurobehaviors in mice

Tetrabromobisphenol A(TBBPA)is a widely used brominated flame retardant.There is evidence showing that TBBPA can exert thyroid disrupting effects in mammals,but different results were also reported,along with inconsistent reports regarding its neurotoxicity.Here,we investigated thyroid disrupting effects and neurotoxicity of TBBPA(5,50,500μg/(kg·day))to male mice following maternal and direct exposure through drinking water,with the antithyroid drug propylthiouracil(PTU)as the positive control.On postnatal day(PND)15,we expectedly observed severe thyroid compensatory hyperplasia and cerebellar developmental retardation in PTU-treated pups.The highest dose of TBBPA also caused thyroid histological alteration but had no effects on cerebellar development in terms of Purkinje cell morphology and the thickness of the internal granular layer and the molecular layer of the cerebellum.During puberty and adulthood,the thyroid morphological alterations became more pronounced in the TBBPA-treated animals,accompanied by decreased serum thyroid hormone levels.Furthermore,the 50 and 500μg/(kg·day)TBBPA groups showed a significant decrease in the serum level of serotonin,a neurotransmitter associated with anxiety behaviors.Correspondingly,the highest dose group displayed anxiety-like behaviors in the elevated plus-maze test on PND 35,but this neurobehavioral alteration disappeared on PND 56.Moreover,no changes in neurobehavioral parameters tested were found in TBBPAtreated animals at puberty and adulthood.Altogether,all observations show that TBBPA can exert thyroid disrupting effects but has little overt impact on brain development and neurobehaviors in mice,suggesting that thyroid disruption does not necessarily cause overtly adverse neurodevelopmental outcomes.

Dynamic changes in DNA demethylation in the tree shrew (Tupaia belangeri chinensis) brain during postnatal development and aging

Brain development and aging are associated with alterations in multiple epigenetic systems, including DNA methylation and demethylation patterns. Here, we observed that the levels of the 5- hydroxymethylcytosine （5hmC） ten-eleven transtocation （TET） enzyme-mediated active DNA demethylation products were dynamically changed and involved in postnatal brain development and aging in tree shrews （Tupaia belangeri chinensis）. The levels of 5hmC in multiple anatomic structures showed a gradual increase throughout postnatal development, whereas a significant decrease in 5hmC was found in several brain regions in aged tree shrews, including in the prefrontal cortex and hippocampus, but not the cerebellum. Active changes in Tet mRNA levels indicated that TET2 and TET3 predominantly contributed to the changes in 5hmC levels. Our findings provide new insight into the dynamic changes in 5hmC levels in tree shrew brains during postnatal development and aging processes.

Developmental changes of glutamate acid decarboxylase 67 in mouse brain after hypoxia ischemia

Objective To study the developmental changes of glutamic acid decarboxylase-67 （ GAD-67, a GABA synthetic enzyme） in normal and hypoxic ischemic （HI） brain. Methods C57/BL6 mice on postnatal day （P） 5, 9, 21 and 60, corresponding developmentally to premature, term, juvenile and adult human brain were investigated by using both Western blot and immunohistochemistry methods either in normal condition or after hypoxic ischemic insult. Results The immunoreactivity of GAD67 was up regulated with brain development and significant difference was seen between mature （P21, P60） and immature （P5, P9） brain. GAD67 immunoreactivity decreased in the ipsilateral hemisphere in all the ages after hypoxia ischemia （HI） insult, but, significant decrease was only seen in the immature brain. Double labeling of GAD67 and cell death marker, TUNEL, in the cortex at 8h post-HI in the P9 mice showed that （15.6±7.0）% TUNEL positive cells were GAD67 positive which was higher than that of P60 mice. Conclusion These data suggest that GABAergic neurons in immature brain were more vulnerable to HI insult than that of mature brain.

Regulation of neural stem cell by bone morphogenetic protein (BMP) signaling during brain development

Neurogenesis is the process in which neurons are generated from neural stem/progenitor cells(NSCs/NPCs).It involves the proliferation and neuronal fate specification/differentiation of NSCs,as well as migration,maturation and functional integration of the neuronal progeny into neuronal network.NSCs exhibit the two essential properties of stem cells:self-renewal and multi-potency.Contrary to previous dogma that neurogenesis happens only during development,it is generally accepted now that neurogenesis can take place throughout life in mammalian brains.This raises a new therapeutic potential of applying stem cell therapy for stroke,neurodegenerative diseases and other diseases.However,the maintenance and differentiation of NSCs/NPCs are tightly controlled by the extremely intricate molecular networks.Uncovering the underlying mechanisms that drive the differentiation,migration and maturation of specific neuronal lineages for use in regenerative medicine is,therefore,crucial for the application of stem cell for clinical therapy as well as for providing insight into the mechanisms of human neurogenesis.Here,we focus on the role of bone morphogenetic protein(BMP)signaling in NSCs during mammalian brain development.

The effects of a 20-week exercise program on blood-circulating biomarkers related to brain health in overweight or obese children:The ActiveBrains project

Background:Emerging research supports the idea that exercise positively affects neurodevelopment.However,the mechanisms linking exercise with brain health are largely unknown.We aimed to investigate the effect of exercise on(a)blood biomarkers selected based on previous evidence(brainderived neurotrophic factor,β-hydroxybutyrate(BHB),cathepsin B(CTSB),kynurenine,fibroblast growth factor 21(FGF21),soluble vascular cell adhesion molecule-1(sVCAM-1));and(b)a panel of 92 neurology-related proteins(discovery analysis).We also investigated whether changes in these biomarkers mediate the effects of exercise on brain health(hippocampal structure and function,cognitive performance,and mental health).Methods:We randomized 81 overweight/obese children(10.1±1.1 years,41%girls)into 2 groups:either 20 weeks of aerobic plus resistance exercise or control.Candidate biomarkers were assessed using enzyme-linked immunosorbent assay(ELISA)for kynurenine,FGF21,and CTSB;colorimetry forβ-hydroxybutyrate;and XMap for brain-derived neurotrophic factor and soluble vascular cell adhesion molecule-1.The92 neurology-related proteins were analyzed by an antibody-based proteomic analysis.Results:Our intervention had no significant effect on candidate biomarkers(all p>0.05).In the discovery analysis,a reduction in circulating macrophage scavenger receptor type-I was observed(standardized differences between groups=-0.3,p=0.001).This effect was validated using ELISA methods(standardized difference=-0.3,p=0.01).None of the biomarkers mediated the effects of exercise on brain health.Conclusions:Our study does not support a chronic effect of exercise on candidate biomarkers.We observed that while chronic exercise reduced the levels of macrophage scavenger receptor type-Ⅰ,it did not mediate the effects of exercise on brain health.Future studies should explore the implications of this novel biomarker for overall health.

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches.Molecular neuro-oncologyhas now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targetedtherapy.Activity of the phosphoinositide 3;kinase(PI3K)/Akt pathway is often upregulated in brain tumors due to excessive stimu-lation by growth factor receptors and Ras.Loss of function of the tumor suppressor gene PTEN also frequently contributesto

Physiological and pathological functions of circular RNAs in the nervous system

Circular RNAs(circRNAs)are a class of covalently closed single-stranded RNAs that are expressed during the development of specific cells and tissues.CircRNAs play crucial roles in physiological and pathological processes by sponging microRNAs,modulating gene transcription,controlling the activity of certain RNA-binding proteins,and producing functional peptides.A key focus of research at present is the functionality of circRNAs in the nervous system and several advances have emerged over the last 2 years.However,the precise role of circRNAs in the nervous system has yet to be comprehensively reviewed.In this review,we first summarize the recently described roles of circRNAs in brain development,maturity,and aging.Then,we focus on the involvement of circRNAs in various diseases of the central nervous system,such as brain cancer,chronic neurodegenerative diseases,acute injuries of the nervous system,and neuropathic pain.A better understanding of the functionality of circRNAs will help us to develop potential diagnostic,prognostic,and therapeutic strategies to treat diseases of the nervous system.

Temporal and spatial distribution of metabotropic glutamate receptor 5 during development in the rat cortex and hippocampus

Metabotropic glutamate receptor 5 （mGluR5） is expressed by neurons in zones of active neurogenesis and is involved in the development of neural stem cells in vivo and in vitro. We examined the expression of mGluR5 in the cortex and hippocampus of rats during various prenatal and postnatal periods using immunohistochemistry. During prenatal development, mGluR5 was pdmadly localized to neuronal somas in the forebrain. During early postnatal periods, the receptor was mainly present on somas in the cortex, mGluR5 immunostaining was visible in apical dendrites and in the neuropil of neurons and persisted throughout postnatal development. During this period, pyramidal neurons were strongly labeled for the receptor. In the hippocampal CA1 region, mGluR5 immunoreactivity was more intense in the stratum oriens, stratum radiatum, and lacunosum moleculare at P0, P5 and P10 relative to P60. mGluR5 expression increased significantly in the molecular layer and decreased significantly in the granule cell layer of the dentate gyrus at P5, P10 and P60 in comparison with P0. Furthermore, some mGluR5-positive cells were also bromodeoxyuridine- or NeuroD-positive in the dentate gyrus at P14. These results demonstrate that mGluR5 has a differential expression pattern in the cortex and hippocampus during early growth, suggesting a role for this receptor in the control of domain specific brain developmental events.

推拿联合Bobath疗法在小儿运动发育迟缓康复治疗中的应用效果

目的观察推拿联合Bobath疗法在小儿运动发育迟缓康复治疗中的应用效果。方法选取2022年1月至2023年7月肇庆市第二人民医院儿童保健科收治的30例运动发育迟缓小儿为研究组,采用推拿联合Bobath疗法,选取2019年1月至2021年12月的30例患儿为对照组,单纯采用Bobath疗法。比较两组患儿治疗前后的五大区发育商和治疗效果。结果两组治疗后的五大区发育商(大运动、精细运动、语言、适应能力及社交能力)高于治疗前,且研究组精细运动、语言、适应能力及社交能力评分高于对照组,差异有统计学意义(P<0.05);两组患儿的治疗总有效率比较,差异无统计学意义(P>0.05);但研究组的治疗效果整体优于对照组,差异有统计学意义(P<0.05)。结论推拿联合Bobath疗法在运动发育迟缓小儿的语言、适应能力及社交能力康复治疗中较单纯Bobath疗法更具有优势,值得临床应用和基层技术推广。

发展性阅读障碍相关基因KIAA0319对脑发育的影响——从动物到人

发展性阅读障碍是一种常见的学习障碍,KIAA0319是发展性阅读障碍相关基因,可能通过影响脑发育进而影响阅读能力。本文就发展性阅读障碍相关基因KIAA0319对鱼类、非灵长类哺乳动物、灵长类哺乳动物和人类大脑发育的影响进行了综述,发现该基因会对大脑语言及阅读相关脑结构如听觉通路、视觉通路和颞叶等的发育产生影响。听觉通路方面,KIAA0319基因可能会损伤内侧膝状体核从而影响听皮层的信息传入。视觉通路方面,KIAA0319基因可能影响外侧膝状体核内的大细胞,使得视觉信息无法正常传递到视皮层,影响背侧视觉通路。颞叶方面,KIAA0319基因的缺陷可能损害颞叶的灰质和白质,并影响颞叶的半球不对称以及颞叶和其他脑区的连接。不过阅读障碍机制复杂,不同阅读障碍相关基因之间、基因与环境之间存在相互影响,仍需进一步探讨。

Human umbilical cord-derived mesenchymal stem cells promote repair of neonatal brain injury caused by hypoxia/ischemia in rats

Administration of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)is believed to be an effective method for treating neurodevelopmental disorde rs.In this study,we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism.We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy.Rat offspring were intranasally administe red hUC-MSCs on postnatal day 14.We found that polypyrimidine tract-binding protein-1(PTBP-1)participated in the regulation of lipopolysaccharide-induced maternal immune activation,which led to neonatal hypoxic/ischemic brain injury.Intranasal delive ry of hUC-MSCs inhibited PTBP-1 expression,alleviated neonatal brain injury-related inflammation,and regulated the number and function of glial fibrillary acidic protein-positive astrocytes,there by promoting plastic regeneration of neurons and im p roving brain function.These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation.

N-methyl-D-aspartate receptor subtype 3A promotes apoptosis in developing mouse brain exposed to hyperoxia

In the present study, 7 day postnatal C57/BL6 wild-type mice （hyperoxia group） and 7 day postnatal N-methyI-D-aspartate receptor subtype 3A knockout mice （NR3A KO group） were exposed to 75% oxygen and 15% nitrogen in a closed container for 5 days. Wild-type mice raised in normoxia served as controls. TdT-mediated dUTP nick end labeling （TUNEL）/neuron-specific nuclear protein （NeuN） and 5-bromo-2＇-deoxyuridine （BrdU）/NeuN immunofluorescence staining showed that the number of apoptotic cells and the number of proliferative cells in the dentate subgranular zone significantly increased in the hyperoxia group compared with the control group. However, in the same hyperoxia environment, the number of apoptotic cells and the number of proliferative cells significantly decreased in the NR3A KO group compared with hyperoxia group. TUNEL＋/NeuN＋ and BrdU＋/NeuN~ cells were observed in the NR3A KO and the hyperoxia groups. These results demonstrated that the NR3A gene can promote cell apoptosis and mediate the potential damage in the developing brain induced by exposure to non-physiologically high concentrations of oxygen.

Anesthesia-induced neurotoxicity in an animal model of the developing brain:mechanism and therapies

Children are being exposed to an increasingly greater variety of anesthetics with advances in pediatric and obstetric surgery. Recent animal and retrospective human data suggest that the general anes- thetics commonly used in pediatric medicine could he damaging to the developing brain when used at clinical concentrations. In viw~ primate and rodent models have shown that neonatal exposure to clinical concentrations of anesthetics causes neural apoptosis and long-term cognitive impairment. Many general anesthetics.

The Eight Stages of Psychosocial Protective Development: Developmental Psychology

The proposed universal psychological mechanism for developmental psychology is the mental protective system whose different parts emerge and mature in the eight different stages of psychosocial protective development under different social interactions. The proposed eight stages of psychosocial protective development are childhood (infancy, toddlerhood, pre-juvenile age, and juvenile age), adolescence, early young adulthood, late young adulthood, early middle adulthood, late middle adulthood, early late adulthood, and late late adulthood. The mental protection system consists of four socialities (collectivistic, individualistic, interdependent, and generativity), three worldviews (territorial, competitive, and cooperative), and the mental immune system for four regulated and unregulated countermeasures (hyperactivity, phobia, comforter, and rationality) against adversities. During childhood, dependent children have collectivistic sociality under the protection of committed parents and territorial worldview with the boundary of family. Children start with the unregulated mental immune system without delayed gratification due to mental immaturity, and gradually acquire the regulated mental immune system with delayed gratification through mental maturity. Adolescents transit to adulthood. Independent adults have the regulated metal immune system, individualistic sociality with reciprocity, and competitive-cooperative worldviews without boundary. After the age of 50, older people as elder leaders-mentors develop generativity sociality to protect next generation. The paper shows that the mental protective system as the universal psychological mechanism for developmental psychology explains clearly psychosocial protective development, the human evolution, the Piaget’s cognitive development, the Erikson’s psychosocial (ego-social) development, the Confucius’ (educated person’s) six milestones of life, and parent-child relation in the Abrahamic religions (Judaism, Christianity, and Islam) and Confucianism.

Developing the Potential of Children's Brains

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