Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices

Department of Neurobiology and Anatomy and Center for Visual Science, University of Rochester, Rochester, New York 14642, USA.
Glia (Impact Factor: 6.03). 04/2012; 60(4):541-58. DOI: 10.1002/glia.22287
Source: PubMed


Normal aging is often accompanied by a progressive loss of receptor sensitivity in hearing and vision, whose consequences on cellular function in cortical sensory areas have remained largely unknown. By examining the primary auditory (A1) and visual (V1) cortices in two inbred strains of mice undergoing either age-related loss of audition (C57BL/6J) or vision (CBA/CaJ), we were able to describe cellular and subcellular changes that were associated with normal aging (occurring in A1 and V1 of both strains) or specifically with age-related sensory loss (only in A1 of C57BL/6J or V1 of CBA/CaJ), using immunocytochemical electron microscopy and light microscopy. While the changes were subtle in neurons, glial cells and especially microglia were transformed in aged animals. Microglia became more numerous and irregularly distributed, displayed more variable cell body and process morphologies, occupied smaller territories, and accumulated phagocytic inclusions that often displayed ultrastructural features of synaptic elements. Additionally, evidence of myelination defects were observed, and aged oligodendrocytes became more numerous and were more often encountered in contiguous pairs. Most of these effects were profoundly exacerbated by age-related sensory loss. Together, our results suggest that the age-related alteration of glial cells in sensory cortical areas can be accelerated by activity-driven central mechanisms that result from an age-related loss of peripheral sensitivity. In light of our observations, these age-related changes in sensory function should be considered when investigating cellular, cortical, and behavioral functions throughout the lifespan in these commonly used C57BL/6J and CBA/CaJ mouse models.

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Available from: Marie-Ève Tremblay,
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    • "Incidentally microglial densities are increased in normal ageing (Tremblay and others 2012) and at the early stages of neurodegenerative diseases such as AD (Rodríguez and others 2013; Rodríguez and others 2010) and HD (Tai and others 2007). Increase in microglial density in ageing is connected to the decrease in their function (Streit and Xue 2013); and possible early decrease in microglial density in neurodegeneration also indicates their asthenic transformation. "
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    ABSTRACT: Neuroglia are represented by several population of cells heterogeneous in structure and function that provide for the homeostasis of the brain and the spinal cord. Neuroglial cells are also central for neuroprotection and defence of the central nervous system against exo- and endogenous insults. At the early stages of neurodegenerative diseases including Alzheimer's disease neuroglial cells become asthenic and lose some of their homeostatic, neuroprotective, and defensive capabilities. Astroglial reactivity, for example, correlates with preservation of cognitive function in patients with mild cognitive impairment and prodromal Alzheimer's disease. Here, we overview the experimental data indicating glial paralysis in neurodegeneration and argue that loss of glial function is fundamental for defining the progression of neurodegenerative diseases.
    The Neuroscientist 10/2015; 21:552-568. DOI:10.1177/1073858414547132 · 6.84 Impact Factor
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    • " , which is referred as ' ' dystrophic microglia ' ' ( Streit et al . , 2004b ; Conde and Streit , 2006a , b ; Streit , 2006 ; Flanary et al . , 2007 ) . Microglia co - localize with neurodegenerating neurons , and show clumping , with loss of their homogeneous tissue distribution , and accumulation of phagocytic inclusions ( Hart et al . , 2012 ; Tremblay et al . , 2012 ; Hefendehl et al . , 2014 ) . Live imaging shows that the dynamic response of microglia to injury changes with age . Young microglia increase their motility and extend ramifications rapidly when exposed to ATP , an injury - associated signal , or to a focal tissue injury . In contrast , aged microglia are less dynamic and ramified and "
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    ABSTRACT: Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergo phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of cytokines and an exacerbated inflammatory response to pathological changes. Whereas LPS increases nitric oxide secretion in microglia from young mice, induction of reactive oxygen species (ROS) predominates in older mice. Furthermore, there is accumulation of DNA oxidative damage in mitochondria of microglia during aging, and also an increased intracellular ROS production. Increased ROS activates the redox-sensitive nuclear factor kappa B, which promotes more neuroinflammation, and can be translated in functional deficits, such as cognitive impairment. Mitochondria-derived ROS and cathepsin B, are also necessary for the microglial cell production of interleukin-1β, a key inflammatory cytokine. Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists. Assessing this apparent contradiction, we have reported that TGFβ1 induction and activation of Smad3 signaling after inflammatory stimulation are reduced in adult mice. Other protective functions, such as phagocytosis, although observed in aged animals, become not inducible by inflammatory stimuli and TGFβ1. Here, we discuss data suggesting that mitochondrial and endolysosomal dysfunction could at least partially mediate age-associated microglial cell changes, and, together with the impairment of the TGFβ1-Smad3 pathway, could result in a reduction of protective activation and a facilitation of cytotoxic activation of microglia, resulting in the promotion of neurodegeneration.
    Frontiers in Aging Neuroscience 08/2015; 7:124. DOI:10.3389/fnagi.2015.00124 · 4.00 Impact Factor
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    • "The soma and arborization areas were calculated in pixels and converted into micrometers. A morphological index was determined by using the formula: soma area/arborization area (Tremblay et al., 2012). "
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    ABSTRACT: Chronic stress is one of the most relevant triggering factors for major depression. Microglial cells are highly sensitive to stress and, more generally, to environmental challenges. However, the role of these brain immune cells in mediating the effects of stress is still unclear. Fractalkine signaling - which comprises the chemokine CX3CL1, mainly expressed by neurons, and its receptor CX3CR1, almost exclusively present on microglia in the healthy brain - has been reported to critically regulate microglial activity. Here, we investigated whether interfering with microglial function by deleting the Cx3cr1 gene affects the brain's response to chronic stress. To this purpose, we housed Cx3cr1 knockout and wild-type adult mice in either control or stressful environments for 2weeks, and investigated the consequences on microglial phenotype and interactions with synapses, synaptic transmission, behavioral response and corticosterone levels. Our results show that hampering neuron-microglia communication via the CX3CR1-CX3CL1 pathway prevents the effects of chronic unpredictable stress on microglial function, short- and long-term neuronal plasticity and depressive-like behavior. Overall, the present findings suggest that microglia-regulated mechanisms may underlie the differential susceptibility to stress and consequently the vulnerability to diseases triggered by the experience of stressful events, such as major depression. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 07/2015; DOI:10.1016/j.bbi.2015.07.024 · 5.89 Impact Factor
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