Vertebrate Central Nervous System Research Articles

Glutamate transporters are involved in direct inhibitory synaptic transmission in the vertebrate retina.

In the central nervous system of vertebrates, glutamate serves as the primary excitatory neurotransmitter. However, in the retina, glutamate released from photoreceptors causes hyperpolarization in post-synaptic ON-bipolar cells through a glutamate-gated chloride current, which seems paradoxical. Our research reveals that this current is modulated by two excitatory glutamate transporters, EAAT5b and EAAT7. In the zebrafish retina, these transporters are located at the dendritic tips of ON-bipolar cells and interact with all four types of cone photoreceptors. The absence of these transporters leads to a decrease in ON-bipolar cell responses, with eaat5b mutants being less severely affected than eaat5b/eaat7 double mutants, which also exhibit altered response kinetics. Biophysical investigations establish that EAAT7 is an active glutamate transporter with a predominant anion conductance. Our study is the first to demonstrate the direct involvement of post-synaptic glutamate transporters in inhibitory direct synaptic transmission at a central nervous system synapse.

Differential cellular stiffness across tissues that contribute to Xenopus neural tube closure.

During the formation of the neural tube, the primordium of the vertebrate central nervous system, the actomyosin activity of cells in different regions drives neural plate bending. However, how the stiffness of the neural plate and surrounding tissues is regulated and mechanically influences neural plate bending has not been elucidated. Here, we used atomic force microscopy to reveal the relationship between the stiffness of the neural plate and the mesoderm during Xenopus neural tube formation. Measurements with intact embryos revealed that the stiffness of the neural plate was consistently higher compared with the non-neural ectoderm and that it increased in an actomyosin activity-dependent manner during neural plate bending. Interestingly, measurements of isolated tissue explants also revealed that the relationship between the stiffness of the apical and basal sides of the neural plate was reversed during bending and that the stiffness of the mesoderm was lower than that of the basal side of the neural plate. The experimental elevation of mesoderm stiffness delayed neural plate bending, suggesting that low mesoderm stiffness mechanically supports neural tube closure. This study provides an example of mechanical interactions between tissues during large-scale morphogenetic movements.

M1-type polarized macrophage contributes to brain damage through CXCR3.2/CXCL11 pathways after RGNNV infection in grouper

ABSTRACT The vertebrate central nervous system (CNS) is the most complex system of the body. The CNS, especially the brain, is generally regarded as immune-privileged. However, the specialized immune strategies in the brain and how immune cells, specifically macrophages in the brain, respond to virus invasion remain poorly understood. Therefore, this study aimed to examine the potential immune response of macrophages in the brain of orange-spotted groupers (Epinephelus coioides) following red-spotted grouper nervous necrosis virus (RGNNV) infection. We observed that RGNNV induced macrophages to produce an inflammatory response in the brain of orange-spotted grouper, and the macrophages exhibited M1-type polarization after RGNNV infection. In addition, we found RGNNV-induced macrophage M1 polarization via the CXCR3.2- CXCL11 pathway. Furthermore, we observed that RGNNV triggered M1 polarization in macrophages, resulting in substantial proinflammatory cytokine production and subsequent damage to brain tissue. These findings reveal a unique mechanism for brain macrophage polarization, emphasizing their role in contributing to nervous tissue damage following viral infection in the CNS.

Single-Nucleus Sequencing of Silkworm Larval Brain Reveals the Key Role of Lysozyme in the Antiviral Immune Response in Brain Hemocytes

Introduction: The brain is considered as an immune-privileged organ, yet innate immune reactions can occur in the central nervous system of vertebrates and invertebrates. Silkworm (Bombyx mori) is an economically important insect and a lepidopteran model species. The diversity of cell types in the silkworm brain, and how these cell subsets produce an immune response to virus infection, remains largely unknown. Methods: Single-nucleus RNA sequencing (snRNA-seq), bioinformatics analysis, RNAi, and other methods were mainly used to analyze the cell types and gene functions of the silkworm brain. Results: We used snRNA-seq to identify 19 distinct clusters representing Kenyon cell, glial cell, olfactory projection neuron, optic lobes neuron, hemocyte-like cell, and muscle cell types in the B. mori nucleopolyhedrovirus (BmNPV)-infected and BmNPV-uninfected silkworm larvae brain at the late stage of infection. Further, we found that the cell subset that exerts an antiviral function in the silkworm larvae brain corresponds to hemocytes. Specifically, antimicrobial peptides were significantly induced by BmNPV infection in the hemocytes, especially lysozyme, exerting antiviral effects. Conclusion: Our single-cell dataset reveals the diversity of silkworm larvae brain cells, and the transcriptome analysis provides insights into the immune response following virus infection at the single-cell level.

Phenols and GABAA receptors: from structure and molecular mechanisms action to neuropsychiatric sequelae.

γ-Aminobutyric acid type A receptors (GABAARs) are members of the pentameric ligand-gated ion channel (pLGIC) family, which are widespread throughout the invertebrate and vertebrate central nervous system. GABAARs are engaged in short-term changes of the neuronal concentrations of chloride (Cl-) and bicarbonate (HCO3 -) ions by their passive permeability through the ion channel pore. GABAARs are regulated by various structurally diverse phenolic substances ranging from simple phenols to complex polyphenols. The wide chemical and structural variability of phenols suggest similar and different binding sites on GABAARs, allowing them to manifest themselves as activators, inhibitors, or allosteric ligands of GABAAR function. Interest in phenols is associated with their great potential for GABAAR modulation, but also with their subsequent negative or positive role in neurological and psychiatric disorders. This review focuses on the GABAergic deficit hypotheses during neurological and psychiatric disorders induced by various phenols. We summarize the structure-activity relationship of general phenol groups concerning their differential roles in the manifestation of neuropsychiatric symptoms. We describe and analyze the role of GABAAR subunits in manifesting various neuropathologies and the molecular mechanisms underlying their modulation by phenols. Finally, we discuss how phenol drugs can modulate GABAAR activity via desensitization and resensitization. We also demonstrate a novel pharmacological approach to treat neuropsychiatric disorders via regulation of receptor phosphorylation/dephosphorylation.

Intrinsic circuitry of the rhombicbrain (central nervous system's intermediate sector) in a mammal.

The rhombicbrain (rhombencephalon or intermediate sector) is the vertebrate central nervous system part between the forebrain-midbrain (rostral sector) and spinal cord (caudal sector), and it has three main divisions: pons, cerebellum, and medulla. Using a data-driven approach, here we examine intrinsic rhombicbrain (intrarhombicbrain) network architecture that in rat consists of 52,670 possible axonal connections between 230 gray matter regions (115 bilaterally symmetrical pairs). Our analysis indicates that only 8,089 (15.4%) of these connections exist. Multiresolution consensus cluster analysis yields a nested hierarchy model of rhombicbrain subsystems that at the top level are associated with 1) the cerebellum and vestibular nuclei, 2) orofacial-pharyngeal-visceral integration, and 3) auditory connections; the bottom level has 68 clusters, ranging in size from 2 to 11 regions. The model provides a basis for functional hypothesis development and interrogation. More granular network analyses performed on the intrinsic connectivity of individual and combined main rhombicbrain divisions (pons, cerebellum, medulla, pons + cerebellum, and pons + medulla) demonstrate the mutability of network architecture in response to the addition or subtraction of connections. Clear differences between the structure-function network architecture of the rhombicbrain and forebrain-midbrain are discussed, with a stark comparison provided by the subsystem and small-world organization of the cerebellar cortex and cerebral cortex. Future analysis of the connections within and between the forebrain-midbrain and rhombicbrain will provide a model of brain neural network architecture in a mammal.

CRK and NCK adaptors may functionally overlap in zebrafish neurodevelopment, as indicated by common binding partners and overlapping expression patterns.

CRK adaptor proteins are important for signal transduction mechanisms driving cell proliferation and positioning during vertebrate central nervous system development. Zebrafish lacking both CRK family members exhibit small, disorganized retinas with 50% penetrance. The goal of this study was to determine whether another adaptor protein might functionally compensate for the loss of CRK adaptors. Expression patterns in developing zebrafish, and bioinformatic analyses of the motifs recognized by their SH2 and SH3 domains, suggest NCK adaptors are well-positioned to compensate for loss of CRK adaptors. In support of this hypothesis, proteomic analyses found CRK and NCK adaptors share overlapping interacting partners including known regulators of cell adhesion and migration, suggesting their functional intersection in neurodevelopment.

GluD1 binds GABA and controls inhibitory plasticity.

Fast synaptic neurotransmission in the vertebrate central nervous system relies primarily on ionotropic glutamate receptors (iGluRs), which drive neuronal excitation, and type A γ-aminobutyric acid receptors (GABAARs), which are responsible for neuronal inhibition. However, the GluD1 receptor, an iGluR family member, is present at both excitatory and inhibitory synapses. Whether and how GluD1 activation may affect inhibitory neurotransmission is unknown. In this work, by using a combination of biochemical, structural, and functional analyses, we demonstrate that GluD1 binds GABA, a previously unknown feature of iGluRs. GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring. The identification of GluD1 as a GABA receptor that controls inhibitory synaptic plasticity challenges the classical dichotomy between glutamatergic and GABAergic receptors.

Perinatal exposure to bisphenol A impairs cognitive function via the gamma-aminobutyric acid signaling pathway in male rat offspring.

Bisphenol A (BPA) is a common synthetic endocrine disruptor that can be utilized in the fabrication of materials such as polycarbonates and epoxy resins. Numerous studies have linked BPA to learning and memory problems, although the precise mechanism remains unknown. Gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the vertebrate central nervous system, and it is intimately related to learning and memory. This study aims to evaluate whether altered cognitive behavior involves the GABA signaling pathway in male offspring of rats exposed to BPA during the prenatal and early postnatal periods. Pregnant rats were orally given BPA (0, 0.04, 0.4, and 4 mg/kg body weight (BW)/day) from the first day of pregnancy to the 21st day of breastfeeding. Three-week-old male rat offspring were selected for an open-field experiment and a new object recognition experiment to evaluate the effect of BPA exposure on cognitive behavior. Furthermore, the role of GABA signaling markers in the cognition affected by BPA was investigated at the molecular level using western blotting and real-time polymerase chain reaction (RT-PCR). The research demonstrated that BPA exposure impacted the behavior and memory of male rat offspring and elevated the expression of glutamic acid decarboxylase 67 (GAD67), GABA type A receptors subunit (GABAARα1), and GABA vesicle transporter (VGAT) in the hippocampus while decreasing the expression levels of GABA transaminase (GABA-T) and GABA transporter 1 (GAT-1). These findings indicate that the alteration in the expression of GABA signaling molecules may be one of the molecular mechanisms by which perinatal exposure to BPA leads to decreased learning and memory in male rat offspring.

Study of low-frequency spectroscopic characteristics of γ-aminobutyric acid with THz and low-wavenumber Raman spectroscopy

γ-aminobutyric (GABA) is the most important inhibitory neurotransmitier in vertebrate central nervous systems. The content level of GABA is related to the different degree of malignancy gliomas. Thus, it can be considered a promising glioma biomarker. In this paper, the spectroscopic properties of GABA have been characterized by combining the THz spectroscopy with low-wavenumber Raman spectroscopy. The experimental results showed that, GABA exhibited three absorption peaks and three refractive index peaks in the range of 0.6–2.1 THz. The limit of detection can reach up to 0.428 % based on the absorption coefficient at the peak of 2.04 THz. Moreover, the low-wavenumber Raman spectrum of GABA showed seven characteristic peaks at 41.0, 50.8, 58.8, 77.2, 98.8, 115.6, 141.2 cm−1 in 0–150 cm−1 region. Moreover, the THz and low-wavenumber theoretical spectra of GABA were simulated with solid-state density function theory, respectively. The calculated results were in good agreement with the experimental observations. On the basis of calculated result, the vibrational motions of each THz and Raman characteristic modes were quantitatively decomposed by analytical mode-decoupling method, where the contribution percentages of external translation, external librations and intramolecular vibration of each vibration modes were analyzed Furthermore, the low-frequency characteristics of GABA was analyzed by combining the THz and low-wavenumber Raman spectroscopy. It is beneficial for the structural information analysis and quantitative identification of biomarker GABA in early stage diagnosis of glioma.

Biofilm formation initiating rotifer-specific biopolymer and its predicted components

The rotifer-specific biopolymer, namely Rotimer, is a recently discovered group of the biomolecule family. Rotimer has an active role in the biofilm formation initiated by rotifers (e.g., Euchlanis dilatata or Adineta vaga) or in the female-male sexual interaction of monogononts. To understand the Ca2+- and polarity-dependent formation of this multifunctional viscoelastic material, it is essential to explore its molecular composition. The investigation of the rotifer-enhanced biofilm and Rotimer-inductor conglomerate (RIC) formation yielded several protein candidates to predict the Rotimer-specific main components. The exudate of E. dilatata males was primarily applied from different biopolimer-containing samples (biofilm or RIC). The advantage of males over females lies in their degenerated digestive system and simple anatomy. Thus, their exudate is less contaminated with food and endosymbiont elements. The sequenced and annotated genome and transcriptome of this species opened the way for identifying Rotimer proteins by mass spectrometry. The predicted rotifer-biopolymer forming components are SCO-spondins and 14–3-3 protein. The characteristics of Rotimer are similar to Reissner's fiber, which is found in the central nervous system of vertebrates and is mainly formed from SCO-spondins. This molecular information serves as a starting point for its interdisciplinary investigation and application in biotechnology, biomedicine, or neurodegeneration-related drug development.

Light-Sensitive Open Channel Block of Ionotropic Glutamate Receptors by Quaternary Ammonium Azobenzene Derivatives.

Glutamate ionotropic receptors mediate fast excitation processes in the central nervous system of vertebrates and play an important role in synaptic plasticity, learning, and memory. Here, we describe the action of two azobenene-containing compounds, AAQ (acrylamide-azobenzene-quaternary ammonium) and QAQ (quaternary ammonium-azobenzene-quaternary ammonium), which produced rapid and fully reversible light-dependent inhibition of glutamate ionotropic receptors. The compounds demonstrated voltage-dependent inhibition with only minor voltage-independent allosteric action. Calcium-impermeable AMPA receptors had weaker sensitivity compared to NMDA and calcium-permeable AMPA receptors. We further revealed that the compounds bound to NMDA and calcium-permeable AMPA receptors in different modes. They were able to enter the wide selectivity filter of AMPA receptors, and strong negative voltages caused permeation into the cytoplasm. The narrow selectivity filter of the NMDA receptors did not allow the molecules to bypass them; therefore, QAQ and AAQ bound to the shallow channel site and prevented channel closure by a foot-in-the-door mechanism. Computer simulations employing available AMPA and NMDA receptor structures readily reproduced the experimental findings, allowing for the structure-based design of more potent and selective drugs in the future. Thus, our work creates a framework for the development of light-sensitive blockers of calcium-permeable AMPA receptors, which are desirable tools for neuroscience.

Brain Dopamine-Clock Interactions Regulate Cardiometabolic Physiology: Mechanisms of the Observed Cardioprotective Effects of Circadian-Timed Bromocriptine-QR Therapy in Type 2 Diabetes Subjects.

Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine-a dopamine D2 receptor agonist) therapy of type 2 diabetes subjects improved hyperglycemia, hyperlipidemia, hypertension, immune sterile inflammation, and/or adverse cardiovascular event rate. The present review details the seminal circadian science investigations delineating important roles for CNS circadian peak dopaminergic activity in the regulation of peripheral fuel metabolism and cardiovascular biology and also summarizes the clinical study findings of bromocriptine-QR therapy on cardiometabolic outcomes in type 2 diabetes subjects.

Mechanistic Hypotheses for Proprioceptive Sensing Within the Avian Lumbosacral Spinal Cord.

Animals need to accurately sense changes in their body position to perform complex movements. It is increasingly clear that the vertebrate central nervous system contains a variety of cells capable of detecting body motion, in addition to the comparatively well-understood mechanosensory cells of the vestibular system and the peripheral proprioceptors. One such intriguing system is the lower spinal cord and column in birds, also known as the avian lumbosacral organ (LSO), which is thought to act as a set of balance sensors that allow birds to detect body movements separately from head movements detected by the vestibular system. Here, we take what is known about proprioceptive, mechanosensory spinal neurons in other vertebrates to explore hypotheses for how the LSO might sense mechanical information related to movement. Although the LSO is found only in birds, recent immunohistochemical studies of the avian LSO have hinted at similarities between cells in the LSO and the known spinal proprioceptors in other vertebrates. In addition to describing possible connections between avian spinal anatomy and recent findings on spinal proprioception as well as sensory and sensorimotor spinal networks, we also present some new data that suggest a role for sensory afferent peptides in LSO function. Thus, this perspective articulates a set of testable ideas on mechanisms of LSO function grounded in the emerging spinal proprioception scientific literature.

Ancient multiplicity in cyclic nucleotide-gated (CNG) cation channel repertoire was reduced in the ancestor of Olfactores before re-expansion by whole genome duplications in vertebrates.

Cyclic nucleotide-gated (CNG) cation channels are important heterotetrameric proteins in the retina, with different subunit composition in cone and rod photoreceptor cells: three CNGA3 and one CNGB3 in cones and three CNGA1 and one CNGB1 in rods. CNGA and CNGB subunits form separate subfamilies. We have analyzed the evolution of the CNG gene family in metazoans, with special focus on vertebrates by using sequence-based phylogeny and conservation of chromosomal synteny to deduce paralogons resulting from the early vertebrate whole genome duplications (WGDs). Our analyses show, unexpectedly, that the CNGA subfamily had four sister subfamilies in the ancestor of bilaterians and cnidarians that we named CNGC, CNGD, CNGE and CNGF. Of these, CNGC, CNGE and CNGF were lost in the ancestor of Olfactores while CNGD was lost in the vertebrate ancestor. The remaining CNGA and CNGB genes were expanded by a local duplication of CNGA and the subsequent chromosome duplications in the basal vertebrate WGD events. Upon some losses, this resulted in the gnathostome ancestor having three members in the visual CNGA subfamily (CNGA1-3), a single CNGA4 gene, and two members in the CNGB subfamily (CNGB1 and CNGB3). The nature of chromosomal rearrangements in the vertebrate CNGA paralogon was resolved by including the genomes of a non-teleost actinopterygian and an elasmobranch. After the teleost-specific WGD, additional duplicates were generated and retained for CNGA1, CNGA2, CNGA3 and CNGB1. Furthermore, teleosts retain a local duplicate of CNGB3. The retention of duplicated CNG genes is explained by their subfunctionalisation and photoreceptor-specific expression. In conclusion, this study provides evidence for four previously unknown CNG subfamilies in metazoans and further evidence that the early vertebrate WGD events were instrumental in the evolution of the vertebrate visual and central nervous systems.

MPTP induces neurodegeneration by modulating dopaminergic activity in catfish brain

Tyrosine hydroxylase (Th) is an allosteric rate-limiting enzyme in catecholamine (CA) biosynthesis. The CAs, dopamine (DA), norepinephrine (NE), and epinephrine are important neurotransmitters wherein DA contributes a key role in the central nervous system of vertebrates. The present study evaluated DA and Th’s significance in DA-ergic activity and neurodegeneration upon 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure in catfish. Further, the expression of certain brain-and ovary-related genes measured through qPCR were downregulated upon MPTP treatment which is in accordance with the decreased levels of L-Dopa, DA, and NE levels estimated through HPLC-ECD. Additionally, TEM analysis depicted structural disarray of brain upon MPTP exposure and also decreased serum levels of testosterone, 11-ketotestosterone, and estradiol-17β. MPTP treatment, in vitro, using primary brain cell culture resulted in diminished cell viability and increased ROS levels leading to elevated apoptotic cells significantly. Consequently, the study highlights the MPTP-induced neurodegeneration of the Th and DA-ergic activity in corroboration with female brain-related genes downregulation, also gonadal function as evidenced by depleted sex steroids level and low expression of ovary-related genes.

KLF9 and KLF13 transcription factors boost myelin gene expression in oligodendrocytes as partners of SOX10 and MYRF.

Differentiated oligodendrocytes produce myelin and thereby ensure rapid nerve impulse conduction and efficient information processing in the vertebrate central nervous system. The Krüppel-like transcription factor KLF9 enhances oligodendrocyte differentiation in culture, but appears dispensable in vivo. Its mode of action and role within the oligodendroglial gene regulatory network are unclear. Here we show that KLF9 shares its expression in differentiating oligodendrocytes with the closely related KLF13 protein. Both KLF9 and KLF13 bind to regulatory regions of genes that are important for oligodendrocyte differentiation and equally recognized by the central differentiation promoting transcription factors SOX10 and MYRF. KLF9 and KLF13 physically interact and synergistically activate oligodendrocyte-specific regulatory regions with SOX10 and MYRF. Similar to KLF9, KLF13 promotes differentiation and myelination in primary oligodendroglial cultures. Oligodendrocyte differentiation is also altered in KLF13-deficient mice as demonstrated by a transiently reduced myelin gene expression during the first postnatal week. Considering mouse phenotypes, the similarities in expression pattern and genomic binding and the behaviour in functional assays, KLF9 and KLF13 are important and largely redundant components of the gene regulatory network in charge of oligodendrocyte differentiation and myelination.

Molecular evolution of the BRINP and ASTN genes and expression profles in response to pathogens and spinal cord injury repair in lamprey (Lethenteron reissneri)

Bone morphogenic protein/retinoic acid inducible neural-specific proteins (BRINPs) and astrotactins (ASTNs) are two members of membrane attack complex/perforin-like (MACPF) superfamily proteins that present high expression in the growing and mature vertebrate neurons. Lamprey has a unique evolutionary status as a representative of the oldest jawless vertebrates, making it an ideal animal model for understanding vertebrate evolution. The evolutionary origins of BRINPs and ASTNs genes in vertebrates, however, have not been shown in lampreys. Here, BRINP and ASTN genes were found in lamprey genomes and the evolutionary relationships of them were investigated by phylogenetic analysis. Protein domains, motifs, genetic structure, and crystal structure analysis revealed that the features of BRINP and ASTN appear to be conserved in vertebrates. Genomic synteny analysis indicated that lamprey BRINP and ASTN neighbor genes differed dramatically from jawed vertebrate. Real-time quantitative results illustrated that the BRINP and ASTN genes family might take part in immune defence and spinal cord injury repair. This study not only enriches a better understanding of the evolution of the BRINP and ASTN genes but also offers a foundation for exploring their roles in the development of the vertebrate central nervous system (CNS).

Wnt/β-Catenin Signaling Pathway Is Strongly Implicated in Cadmium-Induced Developmental Neurotoxicity and Neuroinflammation: Clues from Zebrafish Neurobehavior and In Vivo Neuroimaging.

Cadmium (Cd) is a toxic heavy metal and worldwide environmental pollutant which seriously threatens human health and ecosystems. It is easy to be adsorbed and deposited in organisms, exerting adverse effects on various organs including the brain. In a very recent study, making full use of a zebrafish model in both high-throughput behavioral tracking and live neuroimaging, we explored the potential developmental neurotoxicity of Cd2+ at environmentally relevant levels and identified multiple connections between Cd2+ exposure and neurodevelopmental disorders as well as microglia-mediated neuroinflammation, whereas the underlying neurotoxic mechanisms remained unclear. The canonical Wnt/β-catenin signaling pathway plays crucial roles in many biological processes including neurodevelopment, cell survival, and cell cycle regulation, as well as microglial activation, thereby potentially presenting one of the key targets of Cd2+ neurotoxicity. Therefore, in this follow-up study, we investigated the implication of the Wnt/β-catenin signaling pathway in Cd2+-induced developmental disorders and neuroinflammation and revealed that environmental Cd2+ exposure significantly affected the expression of key factors in the zebrafish Wnt/β-catenin signaling pathway. In addition, pharmacological intervention of this pathway via TWS119, which can increase the protein level of β-catenin and act as a classical activator of the Wnt signaling pathway, could significantly repress the Cd2+-induced cell cycle arrest and apoptosis, thereby attenuating the inhibitory effects of Cd2+ on the early development, behavior, and activity, as well as neurodevelopment of zebrafish larvae to a certain degree. Furthermore, activation and proliferation of microglia, as well as the altered expression profiles of genes associated with neuroimmune homeostasis triggered by Cd2+ exposure could also be significantly alleviated by the activation of the Wnt/β-catenin signaling pathway. Thus, this study provided novel insights into the cellular and molecular mechanisms of Cd2+ toxicity on the vertebrate central nervous system (CNS), which might be helpful in developing pharmacotherapies to mitigate the neurological disorders resulting from exposure to Cd2+ and many other environmental heavy metals.

Tissue Rotation of the Xenopus Anterior-Posterior Neural Axis Reveals Profound but Transient Plasticity at the Mid-Gastrula Stage.

The establishment of anterior–posterior (AP) regional identity is an essential step in the appropriate development of the vertebrate central nervous system. An important aspect of AP neural axis formation is the inherent plasticity that allows developing cells to respond to and recover from the various perturbations that embryos continually face during the course of development. While the mechanisms governing the regionalization of the nervous system have been extensively studied, relatively less is known about the nature and limits of early neural plasticity of the anterior–posterior neural axis. This study aims to characterize the degree of neural axis plasticity in Xenopus laevis by investigating the response of embryos to a 180-degree rotation of their AP neural axis during gastrula stages by assessing the expression of regional marker genes using in situ hybridization. Our results reveal the presence of a narrow window of time between the mid- and late gastrula stage, during which embryos are able undergo significant recovery following a 180-degree rotation of their neural axis and eventually express appropriate regional marker genes including Otx, Engrailed, and Krox. By the late gastrula stage, embryos show misregulation of regional marker genes following neural axis rotation, suggesting that this profound axial plasticity is a transient phenomenon that is lost by late gastrula stages.