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      Distinct roles of GT1b and CSF-1 in microglia activation in nerve injury-induced neuropathic pain

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      1 , 2 , 1 , 2 , 1 , 2
      Molecular Pain
      SAGE Publications
      Neuropathic pain, microglia, GT1b, CSF-1

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          Abstract

          Although microglia activation plays an important role in the development of nerve injury-induced neuropathic pain, the molecular mechanisms of spinal cord microglia activation in nerve injury are not completely understood. Recently, two injured sensory neuron-derived molecules, colony stimulating factor-1 (CSF-1) and GT1b, were proposed to trigger spinal cord microglia activation, yet their relationship and relative contribution to microglia activation have not been addressed. In the present study, the role of GT1b and CSF-1 in microglia activation and proliferation was characterized. GT1b stimulation upregulated proinflammatory mediators such as IL-1β, TNF-α, and NADPH oxidase 2 (Nox2), without microglia proliferation. Conversely, CSF-1 stimulation induced microglia proliferation with minimal proinflammatory gene induction. Notably, neither GT1b nor CSF-1 induced mechanical hypersensitivity in female mice; however, they induced similar microglial proliferation in both male and female mice. Taken together, our data indicate that injured sensory neuron-derived GT1b and CSF-1 activate spinal cord microglia in concert through distinct activation pathways.

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          Most cited references29

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor.

            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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              Central sensitization: a generator of pain hypersensitivity by central neural plasticity.

              Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy as well as to reduced inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury. The net effect of central sensitization is to recruit previously subthreshold synaptic inputs to nociceptive neurons, generating an increased or augmented action potential output: a state of facilitation, potentiation, augmentation, or amplification. Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and exemplifies the fundamental contribution of the central nervous system to the generation of pain hypersensitivity. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of noxious peripheral stimuli. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations. In this article, we review the major triggers that initiate and maintain central sensitization in healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors.
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                Author and article information

                Journal
                Mol Pain
                Mol Pain
                MPX
                spmpx
                Molecular Pain
                SAGE Publications (Sage CA: Los Angeles, CA )
                1744-8069
                30 May 2021
                2021
                : 17
                : 17448069211020918
                Affiliations
                [1 ]Department of Neuroscience and Physiology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea
                [2 ]Interdisciplinary Program in Neuroscience, College of Natural Science, Seoul National University, Seoul, Republic of Korea
                Author notes
                [*]Sung Joong Lee, Department of Neuroscience and Physiology, School of Dentistry, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea. Email: sjlee87@ 123456snu.ac.kr
                Author information
                https://orcid.org/0000-0001-5841-2946
                Article
                10.1177_17448069211020918
                10.1177/17448069211020918
                8168050
                34056970
                bf8a4eda-3665-4f6b-ba33-7db278a42e3c
                © The Author(s) 2021

                Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 20 October 2020
                : 6 May 2021
                : 10 May 2021
                Funding
                Funded by: National Research Foundation of Korea, FundRef https://doi.org/10.13039/501100003725;
                Award ID: NRF-2016M3C7A1905074
                Award ID: NRF-2019R1A2C2087493
                Categories
                Research Article
                Custom metadata
                January-December 2021
                ts2

                Molecular medicine
                neuropathic pain,microglia,gt1b,csf-1
                Molecular medicine
                neuropathic pain, microglia, gt1b, csf-1

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