Brain matters: unveiling the distinct contributions of region, age, and sex to glia diversity and CNS function

The myelinated white matter tracts of the central nervous system (CNS) are essential for fast transmission of electrical impulses and are often differentially affected in human neurodegenerative diseases across CNS region, age and sex. We hypothesize that this selective vulnerability is underpinned by physiological variation in white matter glia. Using single nucleus RNA sequencing of human post-mortem white matter samples from the brain, cerebellum and spinal cord and subsequent tissue-based validation we found substantial glial heterogeneity with tissue region: we identified region-specific oligodendrocyte precursor cells (OPCs) that retain developmental origin markers into adulthood, distinguishing them from mouse OPCs. Region-specific OPCs give rise to similar oligodendrocyte populations, however spinal cord oligodendrocytes exhibit markers such as SKAP2 which are associated with increased myelin production and we found a spinal cord selective population particularly equipped for producing long and thick myelin sheaths based on the expression of genes/proteins such as HCN2. Spinal cord microglia exhibit a more activated phenotype compared to brain microglia, suggesting that the spinal cord is a more pro-inflammatory environment, a difference that intensifies with age. Astrocyte gene expression correlates strongly with CNS region, however, astrocytes do not show a more activated state with region or age. Across all glia, sex differences are subtle but the consistent increased expression of protein-folding genes in male donors hints at pathways that may contribute to sex differences in disease susceptibility. These findings are essential to consider for understanding selective CNS pathologies and developing tailored therapeutic strategies

Functionally distinct subgroups of oligodendrocyte precursor cells integrate neural activity and execute myelin formation

Oligodendrocyte precursor cells divide or differentiate in response to external stimuli to control their numbers and to form new myelin. Using zebrafish, we show that these two functions are accomplished by distinct subgroups of cells. Recent reports have revealed that oligodendrocyte precursor cells (OPCs) are heterogeneous. It remains unclear whether such heterogeneity reflects different subtypes of cells with distinct functions or instead reflects transiently acquired states of cells with the same function. By integrating lineage formation of individual OPC clones, single-cell transcriptomics, calcium imaging and neural activity manipulation, we show that OPCs in the zebrafish spinal cord can be divided into two functionally distinct groups. One subgroup forms elaborate networks of processes and exhibits a high degree of calcium signaling, but infrequently differentiates despite contact with permissive axons. Instead, these OPCs divide in an activity- and calcium-dependent manner to produce another subgroup, with higher process motility and less calcium signaling and that readily differentiates. Our data show that OPC subgroups are functionally diverse in their response to neurons and that activity regulates the proliferation of a subset of OPCs that is distinct from the cells that generate differentiated oligodendrocytes

Compensatory plasticity in the congenitally deaf for visual tasks is restricted to the horizontal plane

Congenitally deaf individuals, compared to hearing individuals, typically show differential performance (improvements or impairments) on certain nonauditory tasks. Concomitantly, their auditory cortex is recruited to process information from the spared senses. Are these compensatory behavioral strategies equally observable across the sensory fields of each particular unaffected sense (e.g., across the full visual field for vision-related compensatory plasticity)? There are neural data in human and nonhuman mammals that may be suggestive of there being a differential processing advantage for stimuli presented in the horizontal visual plane than in the vertical visual plane. To test for these visual field asymmetries in compensatory behavioral performance, we used a direction of motion discrimination task and found that deaf participants were better at determining the direction of motion of dot patterns presented in the horizontal plane compared to those presented in the vertical plane and in the center-that is, we show that the neuroplasticity-induced bias toward the horizontal plane is also present in the behavioral advantage that deaf individuals present. These data may suggest that the neuroplastically changed auditory cortex of deaf individuals is functionally responsible for the enhanced processing of information from the spared senses. (PsycINFO Database Recor

Wnt2 Regulates Progenitor Proliferation in the Developing Ventral Midbrain*

Wnts are secreted, lipidated proteins that regulate multiple aspects of brain development, including dopaminergic neuron development. In this study, we perform the first purification and signaling analysis of Wnt2 and define the function of Wnt2 in ventral midbrain precursor cultures, as well as in Wnt2-null mice in vivo. We found that purified Wnt2 induces the phosphorylation of both Lrp5/6 and Dvl-2/3, and activates β-catenin in SN4741 dopaminergic cells. Moreover, purified Wnt2 increases progenitor proliferation, and the number of dopaminergic neurons in ventral midbrain precursor cultures. In agreement with these findings, analysis of the ventral midbrain of developing Wnt2-null mice revealed a decrease in progenitor proliferation and neurogenesis that lead to a decrease in the number of postmitotic precursors and dopaminergic neurons. Collectively, our observations identify Wnt2 as a novel regulator of dopaminergic progenitors and dopaminergic neuron development

Transcriptional Convergence of Oligodendrocyte Lineage Progenitors during Development

Pdgfra+ oligodendrocyte precursor cells (OPCs) arise in distinct specification waves during embryogenesis in the central nervous system (CNS). It is unclear whether there is a correlation between these waves and different oligodendrocyte (OL) states at adult stages. Here, we present bulk and single-cell transcriptomics resources providing insights on how transitions between these states occur. We found that post-natal OPCs from brain and spinal cord present similar transcriptional signatures. Moreover, post-natal OPC progeny of E13.5 Pdgfra+ cells present electrophysiological and transcriptional profiles similar to OPCs derived from subsequent specification waves, indicating that Pdgfra+ pre-OPCs rewire their transcriptional network during development. Single-cell RNA-seq and lineage tracing indicates that a subset of E13.5 Pdgfra+ cells originates cells of the pericyte lineage. Thus, our results indicate that embryonic Pdgfra+ cells in the CNS give rise to distinct post-natal cell lineages, including OPCs with convergent transcriptional profiles in different CNS regions

Positional differences of axon growth rates between sensory neurons encoded by runx3

The formation of functional connectivity in the nervous system is governed by axon guidance that instructs nerve growth and branching during development, implying a similarity between neuronal subtypes in terms of nerve extension. We demonstrate the molecular mechanism of another layer of complexity in vertebrates by defining a transcriptional program underlying growth differences between positionally different neurons. The rate of axon extension of the early subset of embryonic dorsal root ganglion sensory neurons is encoded in neurons at different axial levels. This code is determined by a segmental pattern of axial levels of Runx family transcription factor Runx3. Runx3 in turn determines transcription levels of genes encoding cytoskeletal proteins involved in axon extension, including Rock1 and Rock2 which have ongoing activities determining axon growth in early sensory neurons and blocking Rock activity reverses axon extension deficits of Runx3−/− neurons. Thus, Runx3 acts to regulate positional differences in axon extension properties apparently without affecting nerve guidance and branching, a principle that could be relevant to other parts of the nervous system.Fil: Lallemend, Francois. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Sterzenbach, Ulrich. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Hadjab Lallemend, Saida. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Aquino, Jorge Benjamin. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Castelo Branco, Goncalo. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Sinha, Indranil. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Villaescusa, J. Carlos. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Levanon, Ditsa. The Weizmann Institute of Science; IsraelFil: Wang, Yiqiao. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Franck, Marina C. M.. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Kharchenko, Olga. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Adameyko, Igor. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Linnarsson, Sten. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Groner, Yoram. The Weizmann Institute of Science; IsraelFil: Turner, Eric. Seattle Children's Research Institute; Estados UnidosFil: Ernfors, Patrik. Karolinska Huddinge Hospital. Karolinska Institutet; Sueci

Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility

Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-g) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-g leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological based therapies for MS

Erg inhibition decreased stiffness in mESCs.

<p>(A) A representative image of the cantilever placed over a mESC during atomic force microscopy. (B) In control conditions, blebbing cells showed a trend towards higher stiffness than non-blebbing cells (n=7, p=0.17, median indicated in box) and control cells that were subjected for hypertonic medium (sucrose 20 mM) for one hour showed reduced stiffness (n=11, p<0.001). (C) After 7 h of Erg inhibition (E4031; 10 µM) treated cells (n=8) were significantly (p=0.02, t-test unequal variance) less stiff than control cells (n=18).</p