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      Exercise alters LPS-induced glial activation in the mouse brain

      Neuronal Signaling
      Portland Press Ltd.
      astrocytes, Exercise, microglia, neuroinflammation

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          Experimental and epidemiological evidence suggest that modifiable lifestyle factors, including physical exercise, can build structural and cognitive reserve in the brain, increasing resilience to injury and insult. Accordingly, exercise can reduce the increased expression of proinflammatory cytokines in the brain associated with ageing or experimentally induced neuroinflammation. However, the cellular mechanisms by which exercise exerts this effect are unknown, including the effects of exercise on classic or alternative activation of astrocytes and microglia. In the present study, we assess the effects of nine consecutive days of treadmill running on the glial cell response to a single systemic injection of lipopolysaccharide (LPS) and, in parallel, the effects on spatial learning and memory. We show that prior exercise protects against LPS-induced impairment of performance in the object displacement task concomitant with attenuation of IL-1β, TNFα and IL-10 mRNA expression in the hippocampus. Assessment of isolated astrocytes and microglia revealed that LPS induced a proinflammatory response in these cells that was not observed in cells prepared from the brains of mice who had undergone prior exercise. The results suggest that exercise modulates neuroinflammation by reducing the proinflammatory microglial response, suggesting a mechanism by which exercise may be neuroprotective.

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          Astrocytes: biology and pathology

          Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.
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            Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.

            Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease. (c) 2007 Wiley-Liss, Inc.
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              Reactive Astrocytes: Production, Function, and Therapeutic Potential.

              Astrocytes constitute approximately 30% of the cells in the mammalian central nervous system (CNS). They are integral to brain and spinal-cord physiology and perform many functions important for normal neuronal development, synapse formation, and proper propagation of action potentials. We still know very little, however, about how these functions change in response to immune attack, chronic neurodegenerative disease, or acute trauma. In this review, we summarize recent studies that demonstrate that different initiating CNS injuries can elicit at least two types of "reactive" astrocytes with strikingly different properties, one type being helpful and the other harmful. We will also discuss new methods for purifying and investigating reactive-astrocyte functions and provide an overview of new markers for delineating these different states of reactive astrocytes. The discovery that astrocytes have different types of reactive states has important implications for the development of new therapies for CNS injury and diseases.

                Author and article information

                Role: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Writing – original draft
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Neuronal Signal
                Neuronal Signal
                Neuronal Signaling
                Portland Press Ltd.
                December 2020
                02 December 2020
                : 4
                : 4
                : NS20200003
                Department of Physiology, School of Medicine and Trinity College Institute of Neuroscience and Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin, Dublin, Ireland
                Author notes
                Correspondence: Áine M. Kelly ( aikelly@ 123456tcd.ie )
                Author information
                © 2020 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the .

                : 17 February 2020
                : 23 October 2020
                : 05 November 2020
                : 06 November 2020
                Page count
                Pages: 14
                Cell Death & Injury
                Immunology & Inflammation
                Molecular Bases of Health & Disease
                Research Articles

                astrocytes, exercise, microglia, neuroinflammation


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