Skip to main content
Top
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Voluntary exercise attenuates LPS-induced reductions in neurogenesis and increases microglia expression of a proneurogenic phenotype in aged mice

Authors: Alyssa M. Littlefield, Sharay E. Setti, Carolina Priester, Rachel A. Kohman

Published in: Journal of Neuroinflammation | Issue 1/2015

Login to get access

Abstract

Background

Microglia can acquire various phenotypes of activation that mediate their inflammatory and neuroprotective effects. Aging causes microglia to become partially activated towards an inflammatory phenotype. As a result, aged animals display a prolonged neuroinflammatory response following an immune challenge. Currently unknown is whether this persistent neuroinflammation leads to greater reductions in hippocampal neurogenesis. Exercise has been shown to alter microglia activation in aged animals, but the nature of these changes has yet to be fully elucidated. The present study assessed whether aged mice show enhanced reductions in hippocampal neurogenesis following an acute immune challenge with lipopolysaccharide (LPS). Further, we assessed whether voluntary wheel running protects against the effects of LPS.

Methods

Adult (4 months) and aged (22 months) male C57BL6/J mice were individually housed with or without a running wheel for a total of 9 weeks. After 5 weeks, mice received a single intraperitoneal LPS or saline injection in combination with four daily injections of bromodeoxyuridine (BrdU) to label dividing cells. Tissue was collected 4 weeks later and immunohistochemistry was conducted to measure new cell survival, new neuron numbers, and microglia activation.

Results

Data show that LPS reduced the number of new neurons in aged, but not adult, mice. These LPS-induced reductions in neurogenesis in the aged mice were prevented by wheel running. Further, exercise increased the proportion of microglia co-labeled with brain-derived neurotrophic factor (BDNF) in the aged.

Conclusions

Collectively, findings indicate that voluntary wheel running may promote a neuroprotective microglia phenotype and protect against inflammation-induced reductions in hippocampal neurogenesis in the aged brain.
Literature
2.
7.
go back to reference Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31(1):149–60. doi:10.1016/j.mcn.2005.10.006.PubMedCrossRef Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31(1):149–60. doi:10.​1016/​j.​mcn.​2005.​10.​006.PubMedCrossRef
9.
10.
go back to reference Keohane A, Ryan S, Maloney E, Sullivan AM, Nolan YM. Tumour necrosis factor-alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: Role of Hes1. Mol Cell Neurosci. 2010;43(1):127–35. doi:10.1016/j.mcn.2009.10.003.PubMedCrossRef Keohane A, Ryan S, Maloney E, Sullivan AM, Nolan YM. Tumour necrosis factor-alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: Role of Hes1. Mol Cell Neurosci. 2010;43(1):127–35. doi:10.​1016/​j.​mcn.​2009.​10.​003.PubMedCrossRef
12.
go back to reference Thored P, Heldmann U, Gomes-Leal W, Gisler R, Darsalia V, Taneera J, et al. Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia. 2009;57(8):835–49. doi:10.1002/glia.20810.PubMedCrossRef Thored P, Heldmann U, Gomes-Leal W, Gisler R, Darsalia V, Taneera J, et al. Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia. 2009;57(8):835–49. doi:10.​1002/​glia.​20810.PubMedCrossRef
13.
go back to reference Nakajima K, Tohyama Y, Kohsaka S, Kurihara T. Ceramide activates microglia to enhance the production/secretion of brain-derived neurotrophic factor (BDNF) without induction of deleterious factors in vitro. J Neurochem. 2002;80(4):697–705.PubMedCrossRef Nakajima K, Tohyama Y, Kohsaka S, Kurihara T. Ceramide activates microglia to enhance the production/secretion of brain-derived neurotrophic factor (BDNF) without induction of deleterious factors in vitro. J Neurochem. 2002;80(4):697–705.PubMedCrossRef
18.
go back to reference Marlatt MW, Bauer J, Aronica E, van Haastert ES, Hoozemans JJ, Joels M, et al. Proliferation in the Alzheimer hippocampus is due to microglia, not astroglia, and occurs at sites of amyloid deposition. Neural Plast. 2014;2014:693851. doi:10.1155/2014/693851.PubMedCentralPubMed Marlatt MW, Bauer J, Aronica E, van Haastert ES, Hoozemans JJ, Joels M, et al. Proliferation in the Alzheimer hippocampus is due to microglia, not astroglia, and occurs at sites of amyloid deposition. Neural Plast. 2014;2014:693851. doi:10.​1155/​2014/​693851.PubMedCentralPubMed
23.
go back to reference Nakajima S, Ohsawa I, Ohta S, Ohno M, Mikami T. Regular voluntary exercise cures stress-induced impairment of cognitive function and cell proliferation accompanied by increases in cerebral IGF-1 and GST activity in mice. Behav Brain Res. 2010;211(2):178–84. doi:10.1016/j.bbr.2010.03.028.PubMedCrossRef Nakajima S, Ohsawa I, Ohta S, Ohno M, Mikami T. Regular voluntary exercise cures stress-induced impairment of cognitive function and cell proliferation accompanied by increases in cerebral IGF-1 and GST activity in mice. Behav Brain Res. 2010;211(2):178–84. doi:10.​1016/​j.​bbr.​2010.​03.​028.PubMedCrossRef
26.
go back to reference Persson AI, Naylor AS, Jonsdottir IH, Nyberg F, Eriksson PS, Thorlin T. Differential regulation of hippocampal progenitor proliferation by opioid receptor antagonists in running and non-running spontaneously hypertensive rats. Eur J Neurosci. 2004;19(7):1847–55. doi:10.1111/j.1460-9568.2004.03268.x.PubMedCrossRef Persson AI, Naylor AS, Jonsdottir IH, Nyberg F, Eriksson PS, Thorlin T. Differential regulation of hippocampal progenitor proliferation by opioid receptor antagonists in running and non-running spontaneously hypertensive rats. Eur J Neurosci. 2004;19(7):1847–55. doi:10.​1111/​j.​1460-9568.​2004.​03268.​x.PubMedCrossRef
27.
go back to reference Barrientos RM, Frank MG, Crysdale NY, Chapman TR, Ahrendsen JT, Day HE, et al. Little exercise, big effects: reversing aging and infection-induced memory deficits, and underlying processes. J neurosci off j Soc Neurosci. 2011;31(32):11578–86. doi:10.1523/JNEUROSCI.2266-11.2011.CrossRef Barrientos RM, Frank MG, Crysdale NY, Chapman TR, Ahrendsen JT, Day HE, et al. Little exercise, big effects: reversing aging and infection-induced memory deficits, and underlying processes. J neurosci off j Soc Neurosci. 2011;31(32):11578–86. doi:10.​1523/​JNEUROSCI.​2266-11.​2011.CrossRef
28.
go back to reference Nichol KE, Poon WW, Parachikova AI, Cribbs DH, Glabe CG, Cotman CW. Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J Neuroinflammation. 2008;5:13. doi:10.1186/1742-2094-5-13.PubMedCentralPubMedCrossRef Nichol KE, Poon WW, Parachikova AI, Cribbs DH, Glabe CG, Cotman CW. Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J Neuroinflammation. 2008;5:13. doi:10.​1186/​1742-2094-5-13.PubMedCentralPubMedCrossRef
30.
go back to reference Ehninger D, Kempermann G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb Cortex. 2003;13(8):845–51.PubMedCrossRef Ehninger D, Kempermann G. Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb Cortex. 2003;13(8):845–51.PubMedCrossRef
31.
go back to reference Olah M, Ping G, De Haas AH, Brouwer N, Meerlo P, Van Der Zee EA, et al. Enhanced hippocampal neurogenesis in the absence of microglia T cell interaction and microglia activation in the murine running wheel model. Glia. 2009;57(10):1046–61. doi:10.1002/glia.20828.PubMedCrossRef Olah M, Ping G, De Haas AH, Brouwer N, Meerlo P, Van Der Zee EA, et al. Enhanced hippocampal neurogenesis in the absence of microglia T cell interaction and microglia activation in the murine running wheel model. Glia. 2009;57(10):1046–61. doi:10.​1002/​glia.​20828.PubMedCrossRef
33.
go back to reference Rhodes JS, Koteja P, Swallow JG, Carter PA, Garland T. Body temperatures of house mice artificially selected for high voluntary wheel-running behavior: repeatability and effect of genetic selection. J therm biol. 2000;25(5):391–400.PubMedCrossRef Rhodes JS, Koteja P, Swallow JG, Carter PA, Garland T. Body temperatures of house mice artificially selected for high voluntary wheel-running behavior: repeatability and effect of genetic selection. J therm biol. 2000;25(5):391–400.PubMedCrossRef
34.
go back to reference Clark PJ, Bhattacharya TK, Miller DS, Kohman RA, DeYoung EK, Rhodes JS. New neurons generated from running are broadly recruited into neuronal activation associated with three different hippocampus-involved tasks. Hippocampus. 2012;22(9):1860–7. doi:10.1002/hipo.22020.PubMedCentralPubMedCrossRef Clark PJ, Bhattacharya TK, Miller DS, Kohman RA, DeYoung EK, Rhodes JS. New neurons generated from running are broadly recruited into neuronal activation associated with three different hippocampus-involved tasks. Hippocampus. 2012;22(9):1860–7. doi:10.​1002/​hipo.​22020.PubMedCentralPubMedCrossRef
36.
go back to reference van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999;2(3):266–70. doi:10.1038/6368.PubMedCrossRef van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999;2(3):266–70. doi:10.​1038/​6368.PubMedCrossRef
41.
go back to reference Chapman TR, Barrientos RM, Ahrendsen JT, Maier SF, Patterson SL. Synaptic correlates of increased cognitive vulnerability with aging: peripheral immune challenge and aging interact to disrupt theta-burst late-phase long-term potentiation in hippocampal area CA1. J neurosci off j Soc Neurosci. 2010;30(22):7598–603. doi:10.1523/JNEUROSCI.5172-09.2010.CrossRef Chapman TR, Barrientos RM, Ahrendsen JT, Maier SF, Patterson SL. Synaptic correlates of increased cognitive vulnerability with aging: peripheral immune challenge and aging interact to disrupt theta-burst late-phase long-term potentiation in hippocampal area CA1. J neurosci off j Soc Neurosci. 2010;30(22):7598–603. doi:10.​1523/​JNEUROSCI.​5172-09.​2010.CrossRef
45.
go back to reference Fuss J, Ben Abdallah NM, Vogt MA, Touma C, Pacifici PG, Palme R, et al. Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis. Hippocampus. 2010;20(3):364–76. doi:10.1002/hipo.20634.PubMed Fuss J, Ben Abdallah NM, Vogt MA, Touma C, Pacifici PG, Palme R, et al. Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis. Hippocampus. 2010;20(3):364–76. doi:10.​1002/​hipo.​20634.PubMed
46.
go back to reference Hutchinson KJ, Gomez-Pinilla F, Crowe MJ, Ying Z, Basso DM. Three exercise paradigms differentially improve sensory recovery after spinal cord contusion in rats. Brain : a journal of neurology. 2004;127(Pt 6):1403–14. doi:10.1093/brain/awh160.CrossRef Hutchinson KJ, Gomez-Pinilla F, Crowe MJ, Ying Z, Basso DM. Three exercise paradigms differentially improve sensory recovery after spinal cord contusion in rats. Brain : a journal of neurology. 2004;127(Pt 6):1403–14. doi:10.​1093/​brain/​awh160.CrossRef
47.
48.
go back to reference Naylor AS, Persson AI, Eriksson PS, Jonsdottir IH, Thorlin T. Extended voluntary running inhibits exercise-induced adult hippocampal progenitor proliferation in the spontaneously hypertensive rat. J Neurophysiol. 2005;93(5):2406–14. doi:10.1152/jn.01085.2004.PubMedCrossRef Naylor AS, Persson AI, Eriksson PS, Jonsdottir IH, Thorlin T. Extended voluntary running inhibits exercise-induced adult hippocampal progenitor proliferation in the spontaneously hypertensive rat. J Neurophysiol. 2005;93(5):2406–14. doi:10.​1152/​jn.​01085.​2004.PubMedCrossRef
52.
53.
go back to reference Batchelor PE, Liberatore GT, Wong JY, Porritt MJ, Frerichs F, Donnan GA, et al. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J neurosci off j Soc Neurosci. 1999;19(5):1708–16. Batchelor PE, Liberatore GT, Wong JY, Porritt MJ, Frerichs F, Donnan GA, et al. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J neurosci off j Soc Neurosci. 1999;19(5):1708–16.
54.
go back to reference Yang H, Feng GD, Liang Z, Vitale A, Jiao XY, Ju G, et al. In vitro beneficial activation of microglial cells by mechanically-injured astrocytes enhances the synthesis and secretion of BDNF through p38MAPK. Neurochem Int. 2012;61(2):175–86. doi:10.1016/j.neuint.2012.04.020.PubMedCrossRef Yang H, Feng GD, Liang Z, Vitale A, Jiao XY, Ju G, et al. In vitro beneficial activation of microglial cells by mechanically-injured astrocytes enhances the synthesis and secretion of BDNF through p38MAPK. Neurochem Int. 2012;61(2):175–86. doi:10.​1016/​j.​neuint.​2012.​04.​020.PubMedCrossRef
59.
go back to reference Hare BD, Beierle JA, Toufexis DJ, Hammack SE, Falls WA. Exercise-associated changes in the corticosterone response to acute restraint stress: evidence for increased adrenal sensitivity and reduced corticosterone response duration. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2014;39(5):1262–9. doi:10.1038/npp.2013.329.CrossRef Hare BD, Beierle JA, Toufexis DJ, Hammack SE, Falls WA. Exercise-associated changes in the corticosterone response to acute restraint stress: evidence for increased adrenal sensitivity and reduced corticosterone response duration. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2014;39(5):1262–9. doi:10.​1038/​npp.​2013.​329.CrossRef
Metadata
Title
Voluntary exercise attenuates LPS-induced reductions in neurogenesis and increases microglia expression of a proneurogenic phenotype in aged mice
Authors
Alyssa M. Littlefield
Sharay E. Setti
Carolina Priester
Rachel A. Kohman
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0362-0

Other articles of this Issue 1/2015

Journal of Neuroinflammation 1/2015 Go to the issue