Shared patterns of glial transcriptional dysregulation link Huntington's disease and schizophrenia.

Huntington's disease and juvenile-onset schizophrenia have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we used comparative correlation network approaches to analyse RNA-sequencing data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells.

Engagement of mental effort in response to mental fatigue: A psychophysiological analysis.

Acute mental fatigue, characterized by a transient decline in cognitive efficiency during or following prolonged cognitive tasks, can be managed through adaptive effort deployment. In response to mental fatigue, individuals can employ two main behavioral patterns: engaging a compensatory effort to limit performance decrements, or disengaging effort, leading to performance deterioration. This study investigated the behavioral pattern used by participants in mental fatigue conditions.

Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells.

Human glial progenitor cells (hGPCs) exhibit diminished expansion competence with age, as well as after recurrent demyelination. Using RNA-sequencing to compare the gene expression of fetal and adult hGPCs, we identify age-related changes in transcription consistent with the repression of genes enabling mitotic expansion, concurrent with the onset of aging-associated transcriptional programs. Adult hGPCs develop a repressive transcription factor network centered on MYC, and regulated by ZNF274, MAX, IKZF3, and E2F6.

Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain.

Competition among adult brain cells has not been extensively researched. To investigate whether healthy glia can outcompete diseased human glia in the adult forebrain, we engrafted wild-type (WT) human glial progenitor cells (hGPCs) produced from human embryonic stem cells into the striata of adult mice that had been neonatally chimerized with mutant Huntingtin (mHTT)-expressing hGPCs. The WT hGPCs outcompeted and ultimately eliminated their human Huntington's disease (HD) counterparts, repopulating the host striata with healthy glia.

Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington's disease.

Astroglial dysfunction contributes to the pathogenesis of Huntington's disease (HD), and glial replacement can ameliorate the disease course. To establish the topographic relationship of diseased astrocytes to medium spiny neuron (MSN) synapses in HD, we used 2-photon imaging to map the relationship of turboRFP-tagged striatal astrocytes and rabies-traced, EGFP-tagged coupled neuronal pairs in R6/2 HD and wild-type (WT) mice. The tagged, prospectively identified corticostriatal synapses were then studied by correlated light electron microscopy followed by serial block-face scanning EM, allowing nanometer-scale assessment of synaptic structure in 3D.

A plausible link between the time-on-task effect and the sequential task effect.

Mental fatigue can be studied by using either the time-on-task protocol or the sequential task protocol. In the time-on-task protocol, participants perform a long and effortful task and a decrease in performance in this task is generally observed over time. In the sequential task protocol, a first effortful or control task is followed by a second effortful task.

A TCF7L2-responsive suppression of both homeostatic and compensatory remyelination in Huntington disease mice.

Huntington's disease (HD) is characterized by defective oligodendroglial differentiation and white matter disease. Here, we investigate the role of oligodendrocyte progenitor cell (OPC) dysfunction in adult myelin maintenance in HD. We first note a progressive, age-related loss of myelin in both R6/2 and zQ175 HD mice compared with wild-type controls.

Cell-intrinsic glial pathology is conserved across human and murine models of Huntington's disease.

Glial pathology is a causal contributor to the striatal neuronal dysfunction of Huntington's disease (HD). We investigate mutant HTT-associated changes in gene expression by mouse and human striatal astrocytes, as well as in mouse microglia, to identify commonalities in glial pathobiology across species and models. Mouse striatal astrocytes are fluorescence-activated cell sorted (FACS) from R6/2 and zQ175 mice, which respectively express exon1-only or full-length mHTT, and human astrocytes are generated either from human embryonic stem cells (hESCs) expressing full-length mHTT or from fetal striatal astrocytes transduced with exon1-only mHTT.

Dysregulated Glial Differentiation in Schizophrenia May Be Relieved by Suppression of SMAD4- and REST-Dependent Signaling.

Astrocytic differentiation is developmentally impaired in patients with childhood-onset schizophrenia (SCZ). To determine why, we used genetic gain- and loss-of-function studies to establish the contributions of differentially expressed transcriptional regulators to the defective differentiation of glial progenitor cells (GPCs) produced from SCZ patient-derived induced pluripotent cells (iPSCs). Negative regulators of the bone morphogenetic protein (BMP) pathway were upregulated in SCZ GPCs, including BAMBI, FST, and GREM1, whose overexpression retained SCZ GPCs at the progenitor stage.

Impacts of the MHC class I-like XNC10 and innate-like T cells on tumor tolerance and rejection in the amphibian Xenopus.

The conditions that lead to antitumor or protumor functions of natural killer T (NKT) cells against mammalian tumors are only partially understood. Therefore, insights into the evolutionary conservation of NKT and their analogs-innate-like T (iT) cells-may reveal factors that contribute to tumor eradication. As such, we investigated the amphibian Xenopus laevis iT cells and interacting MHC class I-like (XNC or mhc1b.

PDGF-B Is Required for Development of the Glymphatic System.

The glymphatic system is a highly polarized cerebrospinal fluid (CSF) transport system that facilitates the clearance of neurotoxic molecules through a brain-wide network of perivascular pathways. Herein we have mapped the development of the glymphatic system in mice. Perivascular CSF transport first emerges in hippocampus in newborn mice, and a mature glymphatic system is established in the cortex at 2 weeks of age.

Human ESC-Derived Chimeric Mouse Models of Huntington's Disease Reveal Cell-Intrinsic Defects in Glial Progenitor Cell Differentiation.

Huntington's disease (HD) is characterized by hypomyelination and neuronal loss. To assess the basis for myelin loss in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs) derived from mutant Huntingtin (mHTT) embryos or normal controls and performed RNA sequencing (RNA-seq) to assess mHTT-dependent changes in gene expression. In human GPCs (hGPCs) derived from 3 mHTT hESC lines, transcription factors associated with glial differentiation and myelin synthesis were sharply downregulated relative to normal hESC GPCs; NKX2.

Modulation of parafoveal word processing by cognitive load during modified visual search tasks.

During visual search for simple items, the amount of information that can be processed in parafoveal vision depends on the cognitive resources that are available. However, whether this applies to the semantic processing of words remains controversial. This work was designed to manipulate simultaneously two sources of cognitive load to study their impact on the depth of parafoveal word processing during a modified visual search task.

Fluorescent Ca indicators directly inhibit the Na,K-ATPase and disrupt cellular functions.

Fluorescent Ca indicators have been essential for the analysis of Ca signaling events in various cell types. We showed that chemical Ca indicators, but not a genetically encoded Ca indicator, potently suppressed the activity of Na- and K-dependent adenosine triphosphatase (Na,K-ATPase), independently of their Ca chelating activity. Loading of commonly used Ca indicators, including Fluo-4 acetoxymethyl (AM), Rhod-2 AM, and Fura-2 AM, and of the Ca chelator BAPTA AM into cultured mouse or human neurons, astrocytes, cardiomyocytes, or kidney proximal tubule epithelial cells suppressed Na,K-ATPase activity by 30 to 80%.

SOX9 Is an Astrocyte-Specific Nuclear Marker in the Adult Brain Outside the Neurogenic Regions.

Astrocytes have in recent years become the focus of intense experimental interest, yet markers for their definitive identification remain both scarce and imperfect. Astrocytes may be recognized as such by their expression of glial fibrillary acidic protein, glutamine synthetase, glutamate transporter 1 (GLT1), aquaporin-4, aldehyde dehydrogenase 1 family member L1, and other proteins. However, these proteins may all be regulated both developmentally and functionally, restricting their utility.

Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation.

Background: Apolipoprotein E (apoE) is a major carrier of cholesterol and essential for synaptic plasticity. In brain, it's expressed by many cells but highly expressed by the choroid plexus and the predominant apolipoprotein in cerebrospinal fluid (CSF). The role of apoE in the CSF is unclear.

Human glia can both induce and rescue aspects of disease phenotype in Huntington disease.

The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable.

PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo.

Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overexpressed by A2B5-sorted TPCs isolated from gliomas at all stages of malignant development. In this study, we asked if PAR1 is causally associated with glioma progression.

Task-dependent modulation of word processing mechanisms during modified visual search tasks.

During visual search for words, the impact of the visual and semantic features of words varies as a function of the search task. This event-related potential (ERP) study focused on the way these features of words are used to detect similarities between the distractor words that are glanced at and the target word, as well as to then reject the distractor words. The participants had to search for a target word that was either given literally or defined by a semantic clue among words presented sequentially.

Neuronal transgene expression in dominant-negative SNARE mice.

Experimental advances in the study of neuroglia signaling have been greatly accelerated by the generation of transgenic mouse models. In particular, an elegant manipulation that interferes with astrocyte vesicular release of gliotransmitters via overexpression of a dominant-negative domain of vesicular SNARE (dnSNARE) has led to documented astrocytic involvement in processes that were traditionally considered strictly neuronal, including the sleep-wake cycle, LTP, cognition, cortical slow waves, depression, and pain. A key premise leading to these conclusions was that expression of the dnSNARE was specific to astrocytes.

Sustained mobilization of endogenous neural progenitors delays disease progression in a transgenic model of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disease characterized in part by the loss of striatopallidal medium spiny projection neurons (MSNs). Expression of BDNF and noggin via intracerebroventricular (ICV) delivery in an adenoviral vector triggers the addition of new neurons to the neostriatum. In this study, we found that a single ICV injection of the adeno-associated viruses AAV4-BDNF and AAV4-noggin triggered the sustained recruitment of new MSNs in both wild-type and R6/2 mice, a model of HD.

Transcriptional differences between normal and glioma-derived glial progenitor cells identify a core set of dysregulated genes.

Glial progenitor cells (GPCs) are a potential source of malignant gliomas. We used A2B5-based sorting to extract tumorigenic GPCs from human gliomas spanning World Health Organization grades II-IV. Messenger RNA profiling identified a cohort of genes that distinguished A2B5+ glioma tumor progenitor cells (TPCs) from A2B5+ GPCs isolated from normal white matter.

Cellular therapy and induced neuronal replacement for Huntington's disease.

Huntington's disease (HD) is an inherited, relentlessly progressive neurodegenerative disease with an invariably fatal outcome. HD is inherited in an autosomal dominant fashion, and is characterized pathologically by the loss of cortical and striatal neurons, and clinically by involuntary choreiform movements accompanied by progressive cognitive impairment and emotional lability. The disorder is caused by an expanded cystosine adenine guanine (CAG) tri-nucleotide repeat encoding polyglutamine (polyQ) in the first exon of the Huntingtin gene.

Sustained induction of neuronal addition to the adult rat neostriatum by AAV4-delivered noggin and BDNF.

Intraventricular ependymal infection by adenoviruses expressing brain-derived neurotrophic factor (BDNF) and noggin is sufficient to induce the heterotopic recruitment of new medium spiny neurons to the adult neostriatum, from endogenous subependymal neural progenitor cells. This approach was found to slow disease progression and extend survival in an R6/2 mouse model of Huntington's disease (HD). However, the practical therapeutic value of this strategy is limited by the transient expression and immunogenicity of adenoviral vectors.