Age-At-Injury Influences the Glial Response to Traumatic Brain Injury in the Cortex of Male Juvenile Rats

Green, Tabitha R.F.; Murphy, Sean M.; Ortiz, J. Bryce; Rowe, Rachel K.

doi:10.3389/fneur.2021.804139

Cited by 14 publications

(19 citation statements)

References 83 publications

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“…Altered sleep can induce reactivity in microglia and sleep loss can alter microglial morphology and molecular phenotype [ 36 ]. In response to a stimulus, reactive microglia enlarge their cell bodies, retract their processes, and adopt a less complex branching structure [ 112 , 113 ]. We detected changes in microglial morphology following repeated exposure to LPS in mice with repopulated microglia compared to control mice.…”

Section: Discussionmentioning

confidence: 99%

Microglia Are Necessary to Regulate Sleep after an Immune Challenge

Rowe

Green

Giordano

et al. 2022

Biology

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Microglia play a critical role in the neuroimmune response, but little is known about the role of microglia in sleep following an inflammatory trigger. Nevertheless, decades of research have been predicated on the assumption that an inflammatory trigger increases sleep through microglial activation. We hypothesized that mice (n = 30) with depleted microglia using PLX5622 (PLX) would sleep less following the administration of lipopolysaccharide (LPS) to induce inflammation. Brains were collected and microglial morphology was assessed using quantitative skeletal analyses and physiological parameters were recorded using non-invasive piezoelectric cages. Mice fed PLX diet had a transient increase in sleep that dissipated by week 2. Subsequently, following a first LPS injection (0.4 mg/kg), mice with depleted microglia slept more than mice on the control diet. All mice were returned to normal rodent chow to repopulate microglia in the PLX group (10 days). Nominal differences in sleep existed during the microglia repopulation period. However, following a second LPS injection, mice with repopulated microglia slept similarly to control mice during the dark period but with longer bouts during the light period. Comparing sleep after the first LPS injection to sleep after the second LPS injection, controls exhibited temporal changes in sleep patterns but no change in cumulative minutes slept, whereas cumulative sleep in mice with repopulated microglia decreased during the dark period across all days. Repopulated microglia had a reactive morphology. We conclude that microglia are necessary to regulate sleep after an immune challenge.

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Section: Discussionmentioning

confidence: 99%

Microglia Are Necessary to Regulate Sleep after an Immune Challenge

Rowe

Green

Giordano

et al. 2022

Biology

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“…Anti-Iba1 antibody was used to mark all microglia in the brain, regardless of their stage of the cell cycle ( Morrison et al, 2017 ; Green et al, 2021 ). Anti-KI67 antibody was used to stain all cells undergoing cell division ( Kuno et al, 2005 ; Inwald et al, 2013 ; Pyo et al, 2016 ).…”

Section: Methodsmentioning

confidence: 99%

“…body (Doorn et al, 2014;Morrison et al, 2017;York et al, 2018;Savage et al, 2019;Green et al, 2021). In severe cases, microglia adopt an ameboid morphology, much like circulating macrophages (Doorn et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Through fast movement of their branches, microglia actively survey the CNS ( Davalos et al, 2005 ; Nimmerjahn et al, 2005 ). This scanning activity allows microglia to rapidly detect abnormal perturbations in the microenvironment that are associated with many types of injury or infection ( Morrison et al, 2017 ; George et al, 2019 ; Mbagwu et al, 2019 ; Green et al, 2021 ). Upon detecting neuropathological stimuli, microglia quickly respond and attempt to protect the brain from further injury ( Wake et al, 2011 ; Eyo et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…The microglial response to a pathological microenvironment is hallmarked by a change in cellular morphology and proliferation ( Morrison et al, 2017 ; Savage et al, 2019 ). Reactive microglia retract their processes and adopt a less complex branching structure and an enlarged cell body ( Doorn et al, 2014 ; Morrison et al, 2017 ; York et al, 2018 ; Savage et al, 2019 ; Green et al, 2021 ). In severe cases, microglia adopt an ameboid morphology, much like circulating macrophages ( Doorn et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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Reactive morphology of dividing microglia following kainic acid administration

et al. 2022

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The microglial response to a pathological microenvironment is hallmarked by a change in cellular morphology. Following a pathological stimulus, microglia become reactive and simultaneously divide to create daughter cells. Although a wide array of microglial morphologies has been observed, the exact functions of these distinct morphologies are unknown, as are the morphology and reactivity status of dividing microglia. In this study, we used kainic acid to trigger microglial activation and cell division. Following a cortical kainic acid injection, microglial morphology and proliferation were examined at 3 days post-injection using immunohistochemistry for ionized calcium binding adapter molecule 1 (Iba1) to stain for microglia, and KI67 as a marker of cell division. Individual microglial cells were isolated from photomicrographs and skeletal and fractal analyses were used to examine cell size and spatial complexity. We examined the morphology of microglia in both wildtype and microglia-specific tumor necrosis factor (TNF)-α knockout mice. Data were analyzed using generalized linear mixed models or a two-way ANOVA. We found that dividing microglia had a more reactive morphology (larger cell body area, longer cell perimeter, and less ramification) compared to microglia that were not dividing, regardless of microglial release of TNF-α. However, we also observed dividing microglia with a complex, more ramified morphology. Changes in microglial morphology and division were greatest near the kainic acid injection site. This study uses robust and quantitative techniques to better understand microglial cell division, morphology, and population dynamics, which are essential for the development of novel therapeutics that target microglia.

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Temporal changes in the microglial proteome of male and female mice after a diffuse brain injury using label‐free quantitative proteomics

Doust

Bindoff

Holloway

et al. 2022

Glia

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Traumatic brain injury (TBI) triggers neuroinflammatory cascades mediated by microglia, which promotes tissue repair in the short-term. These cascades may exacerbate TBI-induced tissue damage and symptoms in the months to years post-injury. However, the progression of the microglial function across time postinjury and whether this differs between biological sexes is not well understood. In this study, we examined the microglial proteome at 3-, 7-, or 28-days after a midline fluid percussion injury (mFPI) in male and female mice using label-free quantitative proteomics. Data are available via ProteomeXchange with identifier PXD033628. We identified a reduction in microglial proteins involved with clearance of neuronal debris via phagocytosis at 3-and 7-days post-injury. At 28 days post-injury, pro-inflammatory proteins were decreased and anti-inflammatory proteins were increased in microglia. These results indicate a reduction in microglial clearance of neuronal debris in the days post-injury with a shift to antiinflammatory function by 28 days following TBI. The changes in the microglial proteome that occurred across time post-injury did not differ between biological sexes. However, we did identify an increase in microglial proteins related to proinflammation and phagocytosis as well as insulin and estrogen signaling in males compared with female mice that occurred with or without a brain injury. Although the microglial response was similar between males and females up to 28 days following TBI, biological sex differences in the microglial proteome, regardless of TBI, has implications for the efficacy of treatment strategies targeting the microglial response post-injury.

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Age-At-Injury Influences the Glial Response to Traumatic Brain Injury in the Cortex of Male Juvenile Rats

Cited by 14 publications

References 83 publications

Microglia Are Necessary to Regulate Sleep after an Immune Challenge

Microglia Are Necessary to Regulate Sleep after an Immune Challenge

Reactive morphology of dividing microglia following kainic acid administration

Temporal changes in the microglial proteome of male and female mice after a diffuse brain injury using label‐free quantitative proteomics

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