Development Of Central Nervous System Research Articles

Behavioural impairment and oxidative stress by acute exposure of zebrafish to a commercial formulation of tebuconazole

Tebuconazole is a systemic follicular fungicide known to cause diverse problems in non-target organisms namely associated to the pure active ingredient. As such, the objective of this work was to evaluate developmental changes induced by a tebuconazole commercial formulation to a non-target animal model. Zebrafish embryos at ± 2 h post-fertilization were exposed to tebuconazole wettable powder concentrations (0.05, 0.5 and 5 mg L-1) for 96 h with developmental toxicity assessed throughout the exposure period and biochemical parameters evaluated at the end of the exposure. Behavioural assessment (spatial exploration and response to stimuli) was conducted 24 h after the end of the exposure. While no developmental and physiological alterations were observed, exposure to tebuconazole resulted in an increased generation of reactive oxidative species at the 0.05 and 0.5 mg L-1 concentrations and a decreased GPx activity at the 0.5 mg L-1 concentration suggesting a potential protection mechanism. There was also a change in the avoidance-escape behaviour supporting an anxiolytic effect suggesting possible alterations in the central nervous system development demanding further studies.

Mechanism of peptide allosteric modulator binding to CXCR4 chemokine receptor revealed from accelerated molecular simulations

Chemokine receptors are key GPCRs that control cell migration during immune system responses and development of cardiovascular and central nervous systems, and in numerous diseases In particular, the CXCR4 chemokine receptor promotes metastasis, tumor growth and survival and angiogenesis, and is associated with several types of cancers. Moreover, CXCR4 is used as one of the two co-receptors for T-tropic HIV-1 entry into host cells. Therefore, the CXCR4 is also an important therapeutic target for treating HIV infection.

Neurospheres obtained from the ciliary margin of the chicken eye possess positional values and retinal ganglion cells differentiated from them respond to EphA/ephrin-A system

In the Central Nervous System (CNS) there are some niches of undifferentiated, neural progenitor/stem cells that produce active neurogenesis originating functionally integrated neurons.In the chicken eye, there is a neurogenic niche in the ciliary margin (CM) which has the ability to originate all the cell types of the neural retina. During retinal development, cells acquire positional values along the radial and tangential axes. These positional values are the necessary base for the formation of neural circuits.In this work, we have analyzed whether neural progenitor cells (NPCs) of CM have positional values regarding the radial and tangential axes, and if they have the potential to differentiate into retinal ganglion cells (RGCs) in vitro. Furthermore, we analyzed whether these RGCs preserve positional values along the tangential axis and respond to the Eph/ephrin axon guidance system. In order to answer these questions, we cultured NPCs obtained from the CM favoring the formation of neurospheres.Our results showed that the expanding neurospheres are polarized structures in which their cells have specific positional values along their radial axis, recapitulating the apical-basal polarity of the CM and the neuroepithelium. We also showed that NPCs obtained from CM possess positional values along the nasal-temporal retinal axis. When the neurospheres were submitted to differentiation conditions, we observed that NPCs can differentiate into RGCs. These RGCs present long axons that express different members of the Eph/ephrin system and they are competent to respond to this axon guidance cue system, recapitulating the axonal behavior during retinotectal neural map development.All these findings contribute to understand the cellular and molecular mechanisms involved in CNS development and regeneration.

The current pediatric perspective on type B and C hepatic encephalopathy

That children present with hepatic encephalopathy (HE) in the setting of acute liver failure (ALF) is accepted and a recognized prognostic factor for survival [1,2]. What is less understood is the impact of chronic liver disease (CLD) on the neuro-cognitive and –psychiatric development and outcomes of children with chronic liver disease early in life. Much is extrapolated from the adult literature or from work in experimental models. But what distinguishes children is that central nervous system development, characterized by massive brain growth, is ongoing at the time of liver disease, arguably exposing them to unique risks, something which cannot be extrapolated from adults. The purpose of this brief review is to summarize what is distinctive about the neurocognition of children with CLD or having presented CLD or portosystemic bypass in childhood.

Variational autoencoding of gene landscapes during mouse CNS development uncovers layered roles of Polycomb Repressor Complex 2.

A prominent aspect of most, if not all, central nervous systems (CNSs) is that anterior regions (brain) are larger than posterior ones (spinal cord). Studies in Drosophila and mouse have revealed that Polycomb Repressor Complex 2 (PRC2), a protein complex responsible for applying key repressive histone modifications, acts by several mechanisms to promote anterior CNS expansion. However, it is unclear what the full spectrum of PRC2 action is during embryonic CNS development and how PRC2 intersects with the epigenetic landscape. We removed PRC2 function from the developing mouse CNS, by mutating the key gene Eed, and generated spatio-temporal transcriptomic data. To decode the role of PRC2, we developed a method that incorporates standard statistical analyses with probabilistic deep learning to integrate the transcriptomic response to PRC2 inactivation with epigenetic data. This multi-variate analysis corroborates the central involvement of PRC2 in anterior CNS expansion, and also identifies several unanticipated cohorts of genes, such as proliferation and immune response genes. Furthermore, the analysis reveals specific profiles of regulation via PRC2 upon these gene cohorts. These findings uncover a differential logic for the role of PRC2 upon functionally distinct gene cohorts that drive CNS anterior expansion. To support the analysis of emerging multi-modal datasets, we provide a novel bioinformatics package that integrates transcriptomic and epigenetic datasets to identify regulatory underpinnings of heterogeneous biological processes.

Neurotrophic tyrosine receptor kinase fusion in pediatric central nervous system tumors

Neurotrophins and their related tyrosine kinase receptors (TRKs), encoded by the neurotrophic tyrosine receptor kinase genes NTRKs, play a crucial role in central nervous system development. Oncogenic NTRK gene fusion events have been identified in several cancer subtypes and cause constitutive activation of the TRK receptor, promoting tumorigenesis. While NTRK fusions are rare in cancers overall, they have been identified in appreciable frequency in certain CNS tumors subtypes recently. In other non-CNS neoplasms, the development of NTRK fusion directed therapies has been developed with TRK inhibitors showing promise in clinical trials. Given the difficulty in treating certain pediatric CNS tumors such as high grade gliomas, understanding NTRK fusions in pediatric CNS tumors may lead to more directed treatment and subsequent therapeutic benefit. This review examines the biology of NTRK fusions, the frequency and clinical significance in pediatric CNS tumors, and methods for detection of NTRK fusion in CNS tumors.

Modulation of retinoid-X-receptors differentially regulates expression of apolipoprotein genes apoc1 and apoeb by zebrafish microglia.

ABSTRACTTranscriptome analyses performed in both human and zebrafish indicate strong expression of Apoe and Apoc1 by microglia. Apoe expression by microglia is well appreciated, but Apoc1 expression has not been well-examined. PPAR/RXR and LXR/RXR receptors appear to regulate expression of the apolipoprotein gene cluster in macrophages, but a similar role in microglia in vivo has not been studied. Here, we characterized microglial expression of apoc1 in the zebrafish central nervous system (CNS) in situ and demonstrate that in the CNS, apoc1 expression is unique to microglia. We then examined the effects of PPAR/RXR and LXR/RXR modulation on microglial expression of apoc1 and apoeb during early CNS development using a pharmacological approach. Changes in apoc1 and apoeb transcripts in response to pharmacological modulation were quantified by RT-qPCR in whole heads, and in individual microglia using hybridization chain reaction (HCR) in situ hybridization. We found that expression of apoc1 and apoeb by microglia were differentially regulated by LXR/RXR and PPAR/RXR modulating compounds, respectively, during development. Our results also suggest RXR receptors could be involved in endogenous induction of apoc1 expression by microglia. Collectively, our work supports the use of zebrafish to better understand regulation and function of these apolipoproteins in the CNS.

Порушення ліквороциркуляції в пацієнтів з мальформацією Кіарі: предиктори розвитку сирингомієлітичних кіст і динаміка післяопераційного регресу

Актуальність. Мальформація Кіарі (МК) — це дефект розвитку центральної нервової системи, що проявляється невідповідністю розмірів задньої черепної ямки і розташованих у цій ділянці структур мозку і, як наслідок, опусканням мигдаликів мозочка (МК типу 1), зазвичай з каудальним зміщенням нижніх відділів стовбура мозку, у великий отвір (МК типу 1.5). Унаслідок порушення ліквороциркуляції в 60–90 % пацієнтів із МК спостерігається сирингомієлія. Матеріали та методи. Проведено ретроспективний аналіз клінічних даних 24 пацієнтів із мальформацією Кіарі типу 1 і 1.5, які перенесли оперативні втручання в Ужгородському обласному клінічному центрі нейрохірургії і неврології в період з грудня 2006 р. по грудень 2017 р., під час яких були виконанi субокципітальна декомпресивна краніектомія, ламінектомія на рівні С1, пластика твердої мозкової оболонки. Середній період спостереження після операції становив 5 років. Результати. У пацієнтів, у яких симптоми тривали понад 3 роки, частота утворення сирингомієлітичних кіст становила 57 %. Динаміка регресу порушень ліквороциркуляції в післяопераційному періоді значно варіює залежно від віку. Висновки. Ризик утворення порожнин, заповнених рідиною, у спинному мозку вищий у пацієнтів із МК типу 1 і 1.5, які хворіють понад 3 роки. Хірургічне лікування є ефективним методом, що використовується для корекції порушень ліквороциркуляції. Пункція кісти не є обов’язковою під час хірургічних втручань.

Sex Differences in Animal Models of Sodium-Valproate-Induced Autism in Postnatal BALB/c Mice: Whole-Brain Histoarchitecture and 5-HT2A Receptor Biomarker Evidence.

Simple SummaryValproic acid (VPA) is a well-known antiepileptic medication and mood stabiliser that is frequently prescribed for the treatment of epilepsy, particularly in children, and has proven human teratogenic activity. VPA inhibits histone deacetylase, which causes teratogenicity and cell toxicity. VPA-induced autism in rodents during the pre- and postnatal periods has shown the development of an autism-like phenotype. In mice, the 14th postnatal day is thought to correspond to the third trimester of human development; it is an important period in which neuronal migration, differentiation, myelination, synaptogenesis and gliogenesis occur in the cerebellum, striatum and hippocampus. Therefore, we exposed postnatal day 14 (PND 14) mice to VPA, which resulted in autistic-like behaviours manifested as reduced social interaction, increased repetitive stereotyped behaviour and anxiety, cognitive dysfunction, lowered sensitivity to pain and neurodevelopmental delay. BALB/c mice were used in this work because they are less reactive to social contact in VPA-induced autism than many other inbred mouse strains, such as C57/129 mice. In humans, two to three times more men are affected by autism spectrum disorder (ASD) than women, and, for this reason, the current study compares the histopathological changes and 5-hydroxy-tryptamine 2A (5-HT2A) receptor protein expression in the brain tissue of male and female animals with VPA-induced autism.Autism spectrum disorder (ASD) is characterised by problems with social interaction, verbal and nonverbal communication and repetitive behaviour. In mice, the 14th postnatal day is believed to correspond to the third trimester of human embryonic development and is considered a vital period for central nervous system development. It has been shown that ASD affects 2 to 3 times more male than female individuals. In the present study, ASD was induced in 14 postnatal day (PND) BALB/c mice using valproic acid (VPA). VPA administration brought about substantial differences in the histoarchitecture of the brain in both male and female mice, linked to behavioural deficits. We observed that both male and female mice showed similar morphological changes in the prefrontal cortex, hippocampus and Purkinje cells. We also observed hair loss from PND 17 to 25, which was again similar between male and female mice. However, there were higher rates of change in the cerebral cortex, frontal cortex and temporal lobe and hippocampus in VPA-treated male animals. With respect to the cerebellum, we did not observe any alterations by haematoxylin and eosin (H&E) staining, but detailed morphological observation using scanning electron microscopy (SEM) showed a higher rate of phenotype changes in VPA-treated male animals. Moreover, 5-HT2A receptor protein levels were upregulated in the cerebral cortex, hippocampus and Purkinje cells in VPA-treated male mice compared with control animals and VPA-treated female mice, as shown by immunohistochemical analysis. Based on all these findings, we conclude that male animals are more susceptible to VPA-induced ASD than females.

Glymphatic system

Glymphatic system - is a recently discovered system for waste clearance and solute balance regulation in the brain. In this article we review the modern views on anatomy and physiology of glymphatic system, the factors known to regulate glymphatic flow, as well as the role of glyphatic dysfunction in the development of central nervous system pathology.

K+/Cl- co-transporter-2 upmodulation: a multi-modal therapy to treat spinal cord injury.

K+/Cl- co-transporter-2 upmodulation: a multi-modal therapy to treat spinal cord injury.

Roles of Ependymal Cells in the Physiology and Pathology of the Central Nervous System.

Ependymal cells are indispensable components of the central nervous system (CNS). They originate from neuroepithelial cells of the neural plate and show heterogeneity, with at least three types that are localized in different locations of the CNS. As glial cells in the CNS, accumulating evidence demonstrates that ependymal cells play key roles in mammalian CNS development and normal physiological processes by controlling the production and flow of cerebrospinal fluid (CSF), brain metabolism, and waste clearance. Ependymal cells have been attached to great importance by neuroscientists because of their potential to participate in CNS disease progression. Recent studies have demonstrated that ependymal cells participate in the development and progression of various neurological diseases, such as spinal cord injury and hydrocephalus, raising the possibility that they may serve as a potential therapeutic target for the disease. This review focuses on the function of ependymal cells in the developmental CNS as well as in the CNS after injury and discusses the underlying mechanisms of controlling the functions of ependymal cells.

Methylmercury exposure during prenatal and postnatal neurodevelopment promotes oxidative stress associated with motor and cognitive damages in rats: an environmental-experimental toxicology study

The environmental contamination by methylmercury (MeHg) is a major concern for public health. The effects of MeHg in the central nervous system (CNS) of adult animals have been extensively investigated; however, little is known about the effects of MeHg exposure during intrauterine and lactation periods on motor and cognitive functions of adolescent rats. Therefore, this study aimed to investigate the effect of MeHg exposure during intrauterine life and lactation on both motor and cognitive functions of offspring rats. Ten female Wistar rats were exposed to 40 μg/kg/day of MeHg through cookie treats from the first day of pregnancy until the last day of breastfeeding. Both motor and cognitive functions of offspring male rats were assessed by open field, rotarod, and step-down inhibitory avoidance tests. Forty-one days after birth, the hippocampus and cerebellum were collected to determine total Hg content, antioxidant capacity against peroxyl radicals (ACAP), reduced glutathione (GSH) levels, lipid peroxidation (LPO), and nitrite levels. MeHg exposure during CNS development increased Hg levels in both hippocampal and cerebellar parenchymas, triggered oxidative stress throughout ACAP and GSH decrease, increased LPO and nitrite levels. These alterations resulted in reduced spontaneous and stimulated locomotion and short- and long-term memory deficits. Therefore, damages triggered by MeHg exposure during intrauterine life and lactation had detrimental effects on oxidative biochemistry and motor and cognitive functions of offspring rats.

ChHDAC11 mRNA Expression During Prenatal and Postnatal Chicken (Gallus gallus) Brain Development

Background: Histone deacetylation plays an essential role in transcriptional regulation of cell cycle progression and other evolutionary processes. Several results confirm the importance of the latest found HDAC11 gene to deacetylate histone core in neurons and their supportive cells in developing the vertebrate Central Nervous System (CNS). Objectives: This study investigates the HDAC11 potential role in early chicken CNS development by studying its mRNA expression profile which may have unique means in studying human subjects. Materials & Methods: Chicken HDAC11 RNAs were reverse transcribed to cDNAs, and the amount of chHDAC11 transcripts was measured by ΔCT mean calculation using the real-time quantitative PCR method. One-way ANOVA and Duncan’s analysis (SigmaStat software version 4.0) were used to test the statistical significance of the results. The levels of significance were set at P≤0.05. Quantitative data are presented as Mean±SD. Results: The amount of HDAC11 mRNAs gradually increases, at least 2-3 times, from as early as day 14 (E14/HH40) of prenatal cortex formation to day P0 (E20=HH45) and continue to increase to day 40 in both cortical and hippocampal regions of the postnatal chicken brain during development (*P≤0.05). HDAC11 mRNA is not only expressed in the postnatal cortex and hippocampi regions but also—for the first time—in the developing brain during the prenatal period. Conclusion: Our results show a possibly important role for the latest found HDAC11 conserved gene in the development of vertebrates’ embryonic brain, which in turn may have a significant impact on understanding human brain development.

The LGI1 protein: molecular structure, physiological functions and disruption-related seizures.

Leucine-rich, glioma inactivated 1 (LGI1) is a secreted glycoprotein, mainly expressed in the brain, and involved in central nervous system development and physiology. Mutations of LGI1 have been linked to autosomal dominant lateral temporal lobe epilepsy (ADLTE). Recently auto-antibodies against LGI1 have been described as the basis for an autoimmune encephalitis, associated with specific motor and limbic epileptic seizures. It is the second most common cause of autoimmune encephalitis. This review presents details on the molecular structure, expression and physiological functions of LGI1, and examines how their disruption underlies human pathologies. Knock-down of LGI1 in rodents reveals that this protein is necessary for normal brain development. In mature brains, LGI1 is associated with Kv1 channels and AMPA receptors, via domain-specific interaction with membrane anchoring proteins and contributes to regulation of the expression and function of these channels. Loss of function, due to mutations or autoantibodies, of this key protein in the control of neuronal activity is a common feature in the genesis of epileptic seizures in ADLTE and anti-LGI1 autoimmune encephalitis.

Arsenic exposure via drinking water during pregnancy and lactation induces autism-like behaviors in male offspring mice

Exposure to arsenic (As), an environmental toxicant, causes damages to the central nervous system (CNS) structure and function. Emerging epidemiological studies support that exposure to As, especially during the critical periods of the CNS development, may act as an environmental risk factor of autism spectrum disorders (ASD), which is characterized by behavioral changes, including abnormal social behaviors, restricted interests and repetitive behaviors. However, direct evidence supporting the cause-effect relationship between As exposure and the risk of ASD is still missing. Thus, we aimed to investigate whether As exposure during pregnancy and lactation led to autism-like behaviors in offspring mice in the present study. We established a mice model of exposure to As via drinking water during pregnancy and lactation and conducted a battery of behavioral tests to evaluate social behaviors, repetitive behaviors, anxiety behaviors and learning and memory ability in offspring mice. We found that perinatal exposure to As caused autism-like behaviors in male offspring, which demonstrated by abnormal social behaviors and repetitive behaviors. Anxiety-like behaviors, and learning and memory impairments, known as concomitant behavioral phenotypes in mice with autism-like behaviors, were also observed. Decreases of synaptic density, especially in cortex, hippocampus and cerebellum, are extensively observed in both ASD patients and animal models of ASD. Thus, immunofluorescence staining and western blotting were used to observe the expression of PSD-95 and SYP, well-known markers for presynaptic and postsynaptic membranes, to assess the synaptic density in offspring cortex, hippocampus and cerebellum. We found perinatal exposure to As decreased the expression of PSD-95 and SYP in these brain regions. This indicated that perinatal exposure to As caused decreases of synaptic density, a typical autism-like cellular alteration in brains, which may contribute to autism-like behaviors in offspring.

Altering Cell-Cell Interaction in Prenatal Alcohol Exposure Models: Insight on Cell-Adhesion Molecules During Brain Development.

Alcohol exposure during pregnancy disrupts the development of the brain and produces long lasting behavioral and cognitive impairments collectively known as Fetal Alcohol Spectrum Disorders (FASDs). FASDs are characterized by alterations in learning, working memory, social behavior and executive function. A large body of literature using preclinical prenatal alcohol exposure models reports alcohol-induced changes in architecture and activity in specific brain regions affecting cognition. While multiple putative mechanisms of alcohol’s long-lasting effects on morphology and behavior have been investigated, an area that has received less attention is the effect of alcohol on cell adhesion molecules (CAMs). The embryo/fetal development represents a crucial period for Central Nervous System (CNS) development during which the cell-cell interaction plays an important role. CAMs play a critical role in neuronal migration and differentiation, synaptic organization and function which may be disrupted by alcohol. In this review, we summarize the physiological structure and role of CAMs involved in brain development, review the current literature on prenatal alcohol exposure effects on CAM function in different experimental models and pinpoint areas needed for future study to better understand how CAMs may mediate the morphological, sensory and behavioral outcomes in FASDs.

Contribution of Smoothened Receptor Signaling in GABAergic Neurotransmission and Chloride Homeostasis in the Developing Rodent Brain.

In the early stages of the central nervous system growth and development, γ-aminobutyric acid (GABA) plays an instructive trophic role for key events including neurogenesis, migration, synaptogenesis, and network formation. These actions are associated with increased concentration of chloride ions in immature neurons [(Cl−)i] that determines the depolarizing strength of ion currents mediated by GABAA receptors, a ligand-gated Cl− permeable ion channel. During neuron maturation the (Cl−)i progressively decreases leading to weakening of GABA induced depolarization and enforcing GABA function as principal inhibitory neurotransmitter. A neuron restricted potassium-chloride co-transporter KCC2 is a key molecule governing Cl− extrusion and determining the resting level of (Cl−)i in developing and mature mammalian neurons. Among factors controlling the functioning of KCC2 and the maturation of inhibitory circuits, is Smoothened (Smo), the transducer in the receptor complex of the developmental protein Sonic Hedgehog (Shh). Too much or too little Shh-Smo action will have mirror effects on KCC2 stability at the neuron membrane, the GABA inhibitory strength, and ultimately on the newborn susceptibility to neurodevelopmental disorders. Both canonical and non-canonical Shh-Smo signal transduction pathways contribute to the regulation of KCC2 and GABAergic synaptic activity. In this review, we discuss the recent findings of the action of Shh-Smo signaling pathways on chloride ions homeostasis through the control of KCC2 membrane trafficking, and consequently on inhibitory neurotransmission and network activity during postnatal development.

Id2 and Id4 are not the major negative regulators of oligodendrocyte differentiation during early central nervous system development.

Myelin sheathes ensure the rapid conduction of neural impulse and provide nutritional support for neurons. Myelin sheathes are formed by differentiated oligodendrocytes (OLs) in the central nervous system. During OL development, the differentiation of oligodendrocyte progenitor cells (OPCs) into mature OLs is controlled by both positive differentiation factors (drivers) and negative regulatory factors (brakes). Previous studies have suggested Id2 and Id4 as the key negative factors for OL differentiation. However, these conclusions were mainly based on in vitro studies and the reported OL phenotype in Id4 mutants appear to be mild. In this study, we systematically investigated the in vivo function of Id2 and Id4 genes in OL differentiation in their genetic mutants and in embryonic chicken spinal cord. Our results showed that disruption of Id4 has no effect on OL differentiation and maturation, whereas Id2 mutants and Id2/Id4 compound mutants display a mild and transient precocity of OL differentiation. In agreement with these loss-of-function studies, Id2, but not Id4, is weakly expressed in OPCs. Despite their minor roles in OL differentiation, forced expression of Id2 and Id4 in embryonic chicken spinal cords strongly inhibit the differentiation of OPCs. Taken together, our detailed functional and expressional studies strongly suggest that Id2 and Id4 are not the major in vivo repressors of OPC differentiation during animal development, shedding new light on the molecular regulation of early OL development.

Heterogeneity of white matter astrocytes in the human brain.

Astrocytes regulate central nervous system development, maintain its homeostasis and orchestrate repair upon injury. Emerging evidence support functional specialization of astroglia, both between and within brain regions. Different subtypes of gray matter astrocytes have been identified, yet molecular and functional diversity of white matter astrocytes remains largely unexplored. Nonetheless, their important and diverse roles in maintaining white matter integrity and function are well recognized. Compelling evidence indicate that impairment of normal astrocytic function and their response to injury contribute to a wide variety of diseases, including white matter disorders. In this review, we highlight our current understanding of astrocyte heterogeneity in the white matter of the mammalian brain and how an interplay between developmental origins and local environmental cues contribute to astroglial diversification. In addition, we discuss whether, and if so, how, heterogeneous astrocytes could contribute to white matter function in health and disease and focus on the sparse human research data available. We highlight four leukodystrophies primarily due to astrocytic dysfunction, the so-called astrocytopathies. Insight into the role of astroglial heterogeneity in both healthy and diseased white matter may provide new avenues for therapies aimed at promoting repair and restoring normal white matter function.