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      Chemogenetic and Optogenetic Manipulations of Microglia in Chronic Pain

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          Abstract

          Chronic pain relief remains an unmet medical need. Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis. Particularly, microglia play a crucial role in the development of chronic pain. To better understand the microglial contribution to chronic pain, specific regional and temporal manipulations of microglia are necessary. Recently, two new approaches have emerged that meet these demands. Chemogenetic tools allow the expression of designer receptors exclusively activated by designer drugs (DREADDs) specifically in microglia. Similarly, optogenetic tools allow for microglial manipulation via the activation of artificially expressed, light-sensitive proteins. Chemo- and optogenetic manipulations of microglia in vivo are powerful in interrogating microglial function in chronic pain. This review summarizes these emerging tools in studying the role of microglia in chronic pain and highlights their potential applications in microglia-related neurological disorders.

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          Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo.

          Axel Nimmerjahn, Frank Kirchhoff, Fritjof Helmchen (2005)
          Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions. Furthermore, blood-brain barrier disruption provoked immediate and focal activation of microglia, switching their behavior from patroling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain.
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            ATP mediates rapid microglial response to local brain injury in vivo.

            Dimitrios Davalos, Jaime Grutzendler, Guang. Yang … (2005)
            Parenchymal microglia are the principal immune cells of the brain. Time-lapse two-photon imaging of GFP-labeled microglia demonstrates that the fine termini of microglial processes are highly dynamic in the intact mouse cortex. Upon traumatic brain injury, microglial processes rapidly and autonomously converge on the site of injury without cell body movement, establishing a potential barrier between the healthy and injured tissue. This rapid chemotactic response can be mimicked by local injection of ATP and can be inhibited by the ATP-hydrolyzing enzyme apyrase or by blockers of G protein-coupled purinergic receptors and connexin channels, which are highly expressed in astrocytes. The baseline motility of microglial processes is also reduced significantly in the presence of apyrase and connexin channel inhibitors. Thus, extracellular ATP regulates microglial branch dynamics in the intact brain, and its release from the damaged tissue and surrounding astrocytes mediates a rapid microglial response towards injury.
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              Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor.

              Christopher N. Parkhurst, Guang. Yang, Ipe Ninan … (2013)
              Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1(CreER) mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1(CreER) to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in motor-learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal tropomyosin-related kinase receptor B phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal that microglia serve important physiological functions in learning and memory by promoting learning-related synapse formation through BDNF signaling. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Long-Jun Wu:
                ORCID: http://orcid.org/0000-0001-8019-3380
                wu.longjun@mayo.edu
                Journal
                Journal ID (nlm-ta): Neurosci Bull
                Journal ID (iso-abbrev): Neurosci Bull
                Title: Neuroscience Bulletin
                Publisher: Springer Nature Singapore (Singapore )
                ISSN (Print): 1673-7067
                ISSN (Electronic): 1995-8218
                Publication date (Electronic): 17 August 2022
                Publication date PMC-release: 17 August 2022
                Publication date Collection: March 2023
                Volume: 39
                Issue: 3
                Pages: 368-378
                Affiliations
                [1 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Department of Neurology, , Mayo Clinic, ; Rochester, MN 55905 USA
                [2 ]GRID grid.5012.6, ISNI 0000 0001 0481 6099, Faculty of Psychology and Neuroscience, , Maastricht University, ; Maastricht, MD, 6200 The Netherlands
                [3 ]GRID grid.417467.7, ISNI 0000 0004 0443 9942, Department of Pain Medicine, , Mayo Clinic, ; Jacksonville, FL 32224 USA
                [4 ]GRID grid.417467.7, ISNI 0000 0004 0443 9942, Department of Neuroscience, , Mayo Clinic, ; Jacksonville, FL 32224 USA
                [5 ]GRID grid.66875.3a, ISNI 0000 0004 0459 167X, Department of Immunology, , Mayo Clinic, ; Rochester, MN 55905 USA
                Author information
                http://orcid.org/0000-0001-8019-3380
                Article
                Publisher ID: 937
                DOI: 10.1007/s12264-022-00937-3
                PMC ID: 10043090
                PubMed ID: 35976535
                SO-VID: 78e87753-35d4-4573-8531-ff890ad90612
                Copyright © © The Author(s) 2022
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 4 April 2022
                Date accepted : 3 June 2022
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences 2023

                Keywords: chronic pain,microglia,optogenetics,chemogenetics,dreadds,reachr
                Data availability:
                Keywords: chronic pain, microglia, optogenetics, chemogenetics, dreadds, reachr

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