Exercise induces region‐specific remodeling of astrocyte morphology and reactive astrocyte gene expression patterns in male mice

Lundquist, Adam J.; Parizher, Jacqueline; Petzinger, Giselle M.; Jakowec, Michael W.

doi:10.1002/jnr.24430

Cited by 36 publications

(43 citation statements)

References 54 publications

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“…Previous experimental work has shown that physical exercise was able to increase the levels of the astrocyte marker, GFAP, in the hippocampus [63] and induce changes in the astrocyte morphology, suggesting beneficial effects on neuronal activity and plasticity [63]. In a recent study, an increase in the number of astrocytic processes during the exercise protocol was observed in other brain areas, such as the prefrontal cortex, striatum, and entorhinal cortex of mice [64].…”

Section: Discussionmentioning

confidence: 92%

Physical exercise promotes astrocyte coverage of microvessels in a model of chronic cerebral hypoperfusion

Leardini-Tristão

Andrade

García

et al. 2020

J Neuroinflammation

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Background: Brain circulation disorders such as chronic cerebral hypoperfusion have been associated with a decline in cognitive function during the development of dementia. Astrocytes together with microglia participate in the immune response in the CNS and make them potential sentinels in the brain parenchyma. In addition, astrocytes coverage integrity has been related to brain homeostasis. Currently, physical exercise has been proposed as an effective intervention to promote brain function improvement. However, the neuroprotective effects of early physical exercise on the astrocyte communication with the microcirculation and the microglial activation in a chronic cerebral hypoperfusion model are still unclear. The aim of this study was to investigate the impact of early intervention with physical exercise on cognition, brain microcirculatory, and inflammatory parameters in an experimental model of chronic cerebral hypoperfusion induced by permanent bilateral occlusion of the common carotid arteries (2VO). Methods: Wistar rats aged 12 weeks were randomly divided into four groups: Sham-sedentary group (Sham-Sed), Sham-exercised group (Sham-Ex), 2VO-sedentary group (2VO-Sed), and 2VO-exercised group (2VO-Ex). The early intervention with physical exercise started 3 days after 2VO or Sham surgery during 12 weeks. Then, the brain functional capillary density and endothelial-leukocyte interactions were evaluated by intravital microscopy; cognitive function was evaluated by open-field test; hippocampus postsynaptic density protein 95 and synaptophysin were evaluated by western blotting; astrocytic coverage of the capillaries, microglial activation, and structural capillary density were evaluated by immunohistochemistry.Results: Early moderate physical exercise was able to normalize functional capillary density and reduce leukocyte rolling in the brain of animals with chronic cerebral hypoperfusion. These effects were accompanied by restore synaptic protein and the improvement of cognitive function. In addition, early moderate exercise improves astrocytes coverage in blood vessels of the cerebral cortex and hippocampus, decreases microglial activation in the hippocampus, and improves structural capillaries in the hippocampus.(Continued on next page) (Continued from previous page)Conclusions: Microcirculatory and inflammatory changes in the brain appear to be involved in triggering a cognitive decline in animals with chronic cerebral ischemia. Therefore, early intervention with physical exercise may represent a preventive approach to neurodegeneration caused by chronic cerebral hypoperfusion.

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Section: Discussionmentioning

confidence: 92%

Physical exercise promotes astrocyte coverage of microvessels in a model of chronic cerebral hypoperfusion

Leardini-Tristão

Andrade

García

et al. 2020

J Neuroinflammation

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“…The most commonly reported exercise-induced effects in astrocytes include morphological changes, together with elevation or suppression in the levels of glial fibrillary acidic protein (GFAP) [ 14 – 19 ] . The reported difference in GFAP levels may be explained partly by astrocyte heterogeneity and partly by differences in the type of exercise intervention.…”

Section: Introductionmentioning

confidence: 99%

Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer’s disease

Belaya

Ivanovа

Sorvari

et al. 2020

J Neuroinflammation

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Background Increased physical exercise improves cognitive function and reduces pathology associated with Alzheimer’s disease (AD). However, the mechanisms underlying the beneficial effects of exercise in AD on the level of specific brain cell types remain poorly investigated. The involvement of astrocytes in AD pathology is widely described, but their exact role in exercise-mediated neuroprotection warrant further investigation. Here, we investigated the effect of long-term voluntary physical exercise on the modulation of the astrocyte state. Methods Male 5xFAD mice and their wild-type littermates had free access to a running wheel from 1.5 to 7 months of age. A battery of behavioral tests was used to assess the effects of voluntary exercise on cognition and learning. Neuronal loss, impairment in neurogenesis, beta-amyloid (Aβ) deposition, and inflammation were evaluated using a variety of histological and biochemical measurements. Sophisticated morphological analyses were performed to delineate the specific involvement of astrocytes in exercise-induced neuroprotection in the 5xFAD mice. Results Long-term voluntary physical exercise reversed cognitive impairment in 7-month-old 5xFAD mice without affecting neurogenesis, neuronal loss, Aβ plaque deposition, or microglia activation. Exercise increased glial fibrillary acid protein (GFAP) immunoreactivity and the number of GFAP-positive astrocytes in 5xFAD hippocampi. GFAP-positive astrocytes in hippocampi of the exercised 5xFAD mice displayed increases in the numbers of primary branches and in the soma area. In general, astrocytes distant from Aβ plaques were smaller in size and possessed simplified processes in comparison to plaque-associated GFAP-positive astrocytes. Morphological alterations of GFAP-positive astrocytes occurred concomitantly with increased astrocytic brain-derived neurotrophic factor (BDNF) and restoration of postsynaptic protein PSD-95. Conclusions Voluntary physical exercise modulates the reactive astrocyte state, which could be linked via astrocytic BDNF and PSD-95 to improved cognition in 5xFAD hippocampi. The molecular pathways involved in this modulation could potentially be targeted for benefit against AD.

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“…All statistical tests were carried out and graphs made in Prism 8.3 (GraphPad, San Diego, CA) with statistical significance set at p < 0.05. No sample size calculations were performed prior to the start of the study but are based on previous publications from our lab (Halliday et al, 2019;Lundquist et al, 2019). All data included was normally distributed as assessed by Shapiro-Wilk normality testing, and no data points 10 were excluded from analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemical Staining: Whole brains (fixed) were sliced in coronal sections (30 μm thickness) on a sliding freezing microtome (Leica CM1900, Leica Microsystems, Wetzlar, Germany) as previously described (Lundquist, Parizher, Petzinger, & Jakowec, 2019). Briefly, sections were washed in Tris- Immunocytochemical Staining: Primary astrocytes grown on PDL-coated coverslips were washed twice with ice-cold DPBS before being fixed with ice-cold 4% PFA-PBS (pH 7.2) for 10 minutes.…”

Section: Immunofluorescent Stainingmentioning

confidence: 99%

“…Complementary DNA (cDNA) was synthesized from either 200 ng (astrocyte cultures) or 400 ng (brain tissue) of isolated RNA using the qPCRBIO cDNA Synthesis Kit (Cat.# PB30.11-10, PCR Biosystems, Wayne, PA) following manufacturer's guidelines before being diluted 1:5 in DNAse/RNAse free water and stored at -20°C. Gene expression changes were measured with quantitative RT-PCR (qRT-PCR) similarly as previously described (Halliday et al, 2019;Lundquist et al, 2019). Briefly, qRT-PCR was run with 2 μl of cDNA and qPCRBIO SyGreen master mix (Cat.# PB20.11-01, PCR Biosystems) on an Eppendorf Mastercycler Ep Realplex (Eppendorf, Hauppauge, NY) using a program of 15 min at 95°C, followed by 40 cycles of 15 seconds at 94°C, 30 seconds at 55°C, and 30 seconds at 72°C.…”

Section: Complementary Dna Synthesis and Quantitative Rt-pcrmentioning

confidence: 99%

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Exogenous L-lactate promotes astrocyte plasticity but is not sufficient for enhancing striatal synaptogenesis or motor behavior in mice

Lundquist

Gallagher

Petzinger

et al. 2020

Preprint

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L-lactate is an energetic and signaling molecule that is key to the metabolic and neuroplastic connection between astrocytes and neurons and may be involved in exercise-induced neuroplasticity. This study sought to explore the role of L-lactate in astrocyte reactivity and neuroplasticity. Using in vitro cultures of primary astrocytes, we show L-lactate increased expression of plasticity-related genes, including neurotrophic factors, Bdnf, Gdnf, Cntf and the immediate early gene cFos. L-lactate's promotion of neurotrophic factor expression may be mediated in part by the lactate receptor HCAR1 since application of the HCAR1 agonist 3,5-DHBA also increased expression of Bdnf in primary astrocytes. In vivo L-lactate administration to healthy mice caused a similar increase in the expression of plasticity-related genes as well as increased astrocyte morphological complexity in a region-specific manner, with increased astrocytic response found in the striatum but not the ectorhinal cortex, regions of the brain where increases in regional cerebral blood flow are increased or unaltered, respectively, with motor behavior. Additionally, L-lactate administration did not cause synaptogenesis or improve motor behavior based on the latency to fall on the accelerating rotarod, suggesting that L-lactate administration can initiate astrocyte-specific gene expression, but the activation of motor circuits is necessary to initiate striatal neuroplasticity. These results suggest that peripheral L-lactate is likely an important molecular component of exercise-induced neuroplasticity by acting in an astrocyte-specific manner to prime the brain for neuroplasticity.

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Exercise induces region‐specific remodeling of astrocyte morphology and reactive astrocyte gene expression patterns in male mice

Cited by 36 publications

References 54 publications

Physical exercise promotes astrocyte coverage of microvessels in a model of chronic cerebral hypoperfusion

Physical exercise promotes astrocyte coverage of microvessels in a model of chronic cerebral hypoperfusion

Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer’s disease

Exogenous L-lactate promotes astrocyte plasticity but is not sufficient for enhancing striatal synaptogenesis or motor behavior in mice

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