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      Hormonal Regulation of Oligodendrogenesis II: Implications for Myelin Repair

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          Abstract

          Alterations in myelin, the protective and insulating sheath surrounding axons, affect brain function, as is evident in demyelinating diseases where the loss of myelin leads to cognitive and motor dysfunction. Recent evidence suggests that changes in myelination, including both hyper- and hypo-myelination, may also play a role in numerous neurological and psychiatric diseases. Protecting myelin and promoting remyelination is thus crucial for a wide range of disorders. Oligodendrocytes (OLs) are the cells that generate myelin, and oligodendrogenesis, the creation of new OLs, continues throughout life and is necessary for myelin plasticity and remyelination. Understanding the regulation of oligodendrogenesis and myelin plasticity within disease contexts is, therefore, critical for the development of novel therapeutic targets. In our companion manuscript, we review literature demonstrating that multiple hormone classes are involved in the regulation of oligodendrogenesis under physiological conditions. The majority of hormones enhance oligodendrogenesis, increasing oligodendrocyte precursor cell differentiation and inducing maturation and myelin production in OLs. Thus, hormonal treatments present a promising route to promote remyelination. Here, we review the literature on hormonal regulation of oligodendrogenesis within the context of disorders. We focus on steroid hormones, including glucocorticoids and sex hormones, peptide hormones such as insulin-like growth factor 1, and thyroid hormones. For each hormone, we describe whether they aid in OL survival, differentiation, or remyelination, and we discuss their mechanisms of action, if known. Several of these hormones have yielded promising results in both animal models and in human conditions; however, a better understanding of hormonal effects, interactions, and their mechanisms will ultimately lead to more targeted therapeutics for myelin repair.

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          Most cited references233

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          An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.

          The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function. To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from mouse cerebral cortex. We generated a transcriptome database for these eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type. Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain. For example, our data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycolytic enzyme pyruvate kinase. This dataset will provide a powerful new resource for understanding the development and function of the brain. To ensure the widespread distribution of these datasets, we have created a user-friendly website (http://web.stanford.edu/group/barres_lab/brain_rnaseq.html) that provides a platform for analyzing and comparing transciption and alternative splicing profiles for various cell classes in the brain. Copyright © 2014 the authors 0270-6474/14/3411929-19$15.00/0.
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            White matter in learning, cognition and psychiatric disorders.

            White matter is the brain region underlying the gray matter cortex, composed of neuronal fibers coated with electrical insulation called myelin. Previously of interest in demyelinating diseases such as multiple sclerosis, myelin is attracting new interest as an unexpected contributor to a wide range of psychiatric disorders, including depression and schizophrenia. This is stimulating research into myelin involvement in normal cognitive function, learning and IQ. Myelination continues for decades in the human brain; it is modifiable by experience, and it affects information processing by regulating the velocity and synchrony of impulse conduction between distant cortical regions. Cell-culture studies have identified molecular mechanisms regulating myelination by electrical activity, and myelin also limits the critical period for learning through inhibitory proteins that suppress axon sprouting and synaptogenesis.
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              Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS).

              Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for the human inflammatory demyelinating disease, multiple sclerosis (MS). EAE is a complex condition in which the interaction between a variety of immunopathological and neuropathological mechanisms leads to an approximation of the key pathological features of MS: inflammation, demyelination, axonal loss and gliosis. The counter-regulatory mechanisms of resolution of inflammation and remyelination also occur in EAE, which, therefore can also serve as a model for these processes. Moreover, EAE is often used as a model of cell-mediated organ-specific autoimmune conditions in general. EAE has a complex neuropharmacology, and many of the drugs that are in current or imminent use in MS have been developed, tested or validated on the basis of EAE studies. There is great heterogeneity in the susceptibility to the induction, the method of induction and the response to various immunological or neuropharmacological interventions, many of which are reviewed here. This makes EAE a very versatile system to use in translational neuro- and immunopharmacology, but the model needs to be tailored to the scientific question being asked. While creating difficulties and underscoring the inherent weaknesses of this model of MS in straightforward translation from EAE to the human disease, this variability also creates an opportunity to explore multiple facets of the immune and neural mechanisms of immune-mediated neuroinflammation and demyelination as well as intrinsic protective mechanisms. This allows the eventual development and preclinical testing of a wide range of potential therapeutic interventions. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                16 February 2021
                February 2021
                : 11
                : 2
                : 290
                Affiliations
                [1 ]Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA; kimberly.long@ 123456ucsf.edu (K.L.P.L.); danielak@ 123456berkeley.edu (D.K.)
                [2 ]Molecular and Cellular Biology, University of California Berkeley, Berkeley, CA 94720, USA; mbarraza@ 123456berkeley.edu
                [3 ]Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA; olga.litvin@ 123456ucsf.edu
                [4 ]Integrative Biology, University of California Berkeley, Berkeley, CA 94720, USA
                [5 ]Canadian Institute for Advanced Research, Toronto, ON M5G1M1, Canada
                Author notes
                [* ]Correspondence: Jocelyn.Breton@ 123456nyspi.columbia.edu ; Tel.: +1-860-519-7319
                [†]

                These authors contributed equally to this work.

                [‡]

                Current address: Department of Psychiatry, Columbia University, New York, NY 10027, USA.

                [§]

                Current address: Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA 94143, USA.

                Author information
                https://orcid.org/0000-0003-0981-1451
                https://orcid.org/0000-0002-4579-8912
                https://orcid.org/0000-0002-6937-6757
                Article
                biomolecules-11-00290
                10.3390/biom11020290
                7919830
                33669242
                118a1dbf-3dc2-482d-9416-27902970c846
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 13 January 2021
                : 13 February 2021
                Categories
                Review

                oligodendrogenesis,remyelination,hormones,steroids,peptides
                oligodendrogenesis, remyelination, hormones, steroids, peptides

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