Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease

Norden, Diana M.; Muccigrosso, Megan M.; Godbout, Jonathan P.

doi:10.1016/j.neuropharm.2014.10.028

Cited by 323 publications

(318 citation statements)

References 149 publications

(230 reference statements)

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“…For instance, aged rodents demonstrate increased expression of mRNA and protein markers of inflammation following LPS challenge (Kumar et al, 2013;Norden and Godbout, 2013;Norden et al, 2015aNorden et al, , 2015b. In addition to aging, similar priming effects have been reported in microglia from patients with neuropsychiatric disorders including traumatic brain injury (Fenn et al, 2014) and neurodegeneration (Norden et al, 2015a). Of note, primed microglia were less responsive to the effects of glutamate reuptake enhancing agent riluzole compared with unprimed microglia from younger individuals (Brothers al, 2013).…”

Section: Alternative Activation and Acquired Deactivation Statesmentioning

confidence: 81%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

414

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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Section: Alternative Activation and Acquired Deactivation Statesmentioning

confidence: 81%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

414

299

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“…Converging evidence indicates that the aged brain contains primed and/or senescent microglia (Dilger & Johnson, 2008; Harry, 2013; Mosher & Wyss‐Coray, 2014), which may contribute to age‐related cognitive deficits and altered brain function (Norden et al, 2015). Therefore, we sought to explore the effects of replacing these resident “aged" microglia with new cells, via administration and withdrawal of CSF1R inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…Neurogenesis in the dentate gyrus (DG) was assessed via administration of the thymidine analogue bromodeoxyuridine (BrdU), which is incorporated into the DNA of dividing cells, as well as staining for doublecortin (DCX), a marker of newly born neurons. A decline in neurogenesis is commonly observed in aging, and studies have indicated that this decline is in part due to chronically activated microglia (Barrientos, Kitt, Watkins, & Maier, 2015; Norden et al, 2015). As a result, aged mice exhibit markedly reduced neurogenesis, as seen by decreased levels of BrdU + cells ( p < 0.001, Figure 5b,d–e) and DCX staining ( p < 0.001, Figure 5b,e–f) in the subgranular zone (SGZ) of the DG compared to young mice.…”

Section: Resultsmentioning

confidence: 99%

“…During aging, microglia undergo marked phenotypic and functional changes compared to the adult brain, including increased cell numbers, dystrophic morphology, impaired phagocytosis, reduced motility, exaggerated response to inflammatory stimuli [reviewed in Mosher and Wyss‐Coray (2014)], as well as altered gene expression (Galatro et al, 2017; Grabert et al, 2016; Soreq, Rose, Soreq, Hardy, & Ule, 2017). These microglia are often described as “primed” or “senescent,” and recent studies suggest that these cells may contribute to age‐related cognitive impairments and confer susceptibility to neurodegenerative disease (Blank & Prinz, 2013; Niraula, Sheridan, & Godbout, 2017; Norden, Muccigrosso, & Godbout, 2015). Here, we explore the effects of replacing the aged microglial tissue with new cells, via CSF1R inhibitor‐dependent microglial elimination and repopulation.…”

Section: Introductionmentioning

confidence: 99%

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Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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“…Notably, one study that also investigated neuronal white matter integrity found that levels of microglial activations correlated with structural changes in the brain 63 . Recent reviews detailing this dysregulated immune response in the brain following neurotrauma highlight the phenomenon of microglial priming as a key component of this harmful pro-inflammatory state 28,29,49 . In short, priming refers to microglia that are in a hypersensitive and hyperactive state; they are "primed" for a future exaggerated response to an internal or external challenge.…”

Section: Immunological Perspectives Of Tbi Sequelaementioning

confidence: 99%

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

Sundman

Chen

Subbian

et al. 2017

Brain, Behavior, and Immunity

158

103

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The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. AbstractAs head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

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Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease

Cited by 323 publications

References 149 publications

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease

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