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      Vitamin D: Brain and Behavior

      research-article
      1 , 2 ,
      JBMR Plus
      John Wiley & Sons, Inc.
      BRAIN, DEVELOPMENT, VITAMIN D DEFICIENCY, NEUROPROTECTION

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          ABSTRACT

          It has been 20 years since we first proposed vitamin D as a “possible” neurosteroid. ( 1 ) Our work over the last two decades, particularly results from our cellular and animal models, has confirmed the numerous ways in which vitamin D differentiates the developing brain. As a result, vitamin D can now confidently take its place among all other steroids known to regulate brain development. ( 2 ) Others have concentrated on the possible neuroprotective functions of vitamin D in adult brains. Here these data are integrated, and possible mechanisms outlined for the various roles vitamin D appears to play in both developing and mature brains and how such actions shape behavior. There is now also good evidence linking gestational and/or neonatal vitamin D deficiency with an increased risk of neurodevelopmental disorders, such as schizophrenia and autism, and adult vitamin D deficiency with certain degenerative conditions. In this mini‐review, the focus is on what we have learned over these past 20 years regarding the genomic and nongenomic actions of vitamin D in shaping brain development, neurophysiology, and behavior in animal models. © 2020 The Author. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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          Most cited references171

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          Biological Insights From 108 Schizophrenia-Associated Genetic Loci

          Summary Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
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            Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain.

            Despite a growing body of evidence that Vitamin D is involved in mammalian brain functioning, there has been a lack of direct evidence about its role in the human brain. This paper reports, for the first time, the distribution of the 1,25-dihydroxyvitamin D3 receptor (VDR), and 1alpha-hydroxylase (1alpha-OHase), the enzyme responsible for the formation of the active vitamin in the human brain. The receptor and the enzyme were found in both neurons and glial cells in a regional and layer-specific pattern. The VDR was restricted to the nucleus whilst 1alpha-OHase was distributed throughout the cytoplasm. The distribution of the VDR in human brain was strikingly similar to that reported in rodents. Many regions contained equivalent amounts of both the VDR and 1alpha-OHase, however the macrocellular cells within the nucleus basalis of Meynert (NBM) and the Purkinje cells in the cerebellum expressed 1alpha-OHase in the absence of VDR. The strongest immunohistochemical staining for both the receptor and enzyme was in the hypothalamus and in the large (presumably dopaminergic) neurons within the substantia nigra. The observed distribution of the VDR is consistent with the proposal that Vitamin D operates in a similar fashion to the known neurosteroids. The widespread distribution of 1alpha-OHase and the VDR suggests that Vitamin D may have autocrine/paracrine properties in the human brain.
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              1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.

              Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] synthesis also led to an increase in renin expression, whereas 1,25(OH)(2)D(3) injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)(2)D(3) markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)(2)D(3) is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.
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                Author and article information

                Contributors
                eyles@uq.edu.au
                Journal
                JBMR Plus
                JBMR Plus
                10.1002/(ISSN)2473-4039
                JBM4
                JBMR Plus
                John Wiley & Sons, Inc. (Hoboken, USA )
                2473-4039
                18 October 2020
                January 2021
                : 5
                : 1 , Special Issue on Vitamin D in Memory of Dr. Anthony Norman, Ph.D. ( doiID: 10.1002/jbm4.v5.1 )
                : e10419
                Affiliations
                [ 1 ] Queensland Centre for Mental Health Research The Park Centre for Mental Health Wacol Australia
                [ 2 ] Queensland Brain Institute University of Queensland St. Lucia Queensland Australia
                Author notes
                [*] [* ]Address correspondence to: Darryl Eyles, Neurobiology Laboratory, Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia. E‐mail: eyles@ 123456uq.edu.au
                Author information
                https://orcid.org/0000-0002-5023-7095
                Article
                JBM410419
                10.1002/jbm4.10419
                7839822
                33553986
                0169e924-f402-4444-9a71-b2675dd43d92
                © 2020 The Author. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 06 August 2020
                : 17 September 2020
                : 28 September 2020
                Page count
                Figures: 1, Tables: 0, Pages: 12, Words: 14476
                Funding
                Funded by: National Health and Medical Research Council , open-funder-registry 10.13039/501100000925;
                Award ID: APPS 1124721 and 1141699
                Categories
                Special Issue
                Special Issue
                Custom metadata
                2.0
                January 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.7 mode:remove_FC converted:27.01.2021

                brain,development,vitamin d deficiency,neuroprotection
                brain, development, vitamin d deficiency, neuroprotection

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