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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Effects of environmental enrichment on white matter glial responses in a mouse model of chronic cerebral hypoperfusion

Authors: Yoshiki Hase, Lucinda Craggs, Mai Hase, William Stevenson, Janet Slade, Dianne Lopez, Rubin Mehta, Aiqing Chen, Di Liang, Arthur Oakley, Masafumi Ihara, Karen Horsburgh, Raj N. Kalaria

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

This study was designed to explore the beneficial effects of environmental enrichment (EE) on white matter glial changes in a mouse model of chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS).

Methods

A total of 74 wild-type male C57BL/6J mice underwent BCAS or sham surgery. One week after surgery, the mice were randomly assigned into three different groups having varied amounts of EE—standard housing with no EE conditions (std), limited exposure with 3 h EE a day (3 h) and full-time exposure to EE (full) for 12 weeks. At 16 weeks after BCAS surgery, behavioural and cognitive function were assessed prior to euthanasia. Brain tissues were analysed for the degree of gliosis including morphological changes in astrocytes and microglia.

Results

Chronic cerebral hypoperfusion (or BCAS) increased clasmatodendrocytes (damaged astrocytes) with disruption of aquaporin-4 immunoreactivity and an increased degree of microglial activation/proliferation. BCAS also impaired behavioural and cognitive function. These changes were significantly attenuated, by limited exposure compared to full-time exposure to EE.

Conclusions

Our results suggest that moderate or limited exposure to EE substantially reduced glial damage/activation. Our findings also suggest moderate rather than continuous exposure to EE is beneficial for patients with subcortical ischaemic vascular dementia characterised by white matter disease-related inflammation.
Literature
1.
Kalaria RN. Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease. Acta Neuropathol. 2016;131:659–85.CrossRefPubMedPubMedCentral
2.
Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol. 2002;1:426–36.CrossRefPubMed
3.
Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K, Ohmori S, Nomiyama K, Kawano H, Ueda K, et al. Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama Study. Neurology. 1995;45:1161–8.CrossRefPubMed
4.
Shindo A, Liang AC, Maki T, Miyamoto N, Tomimoto H, Lo EH, Arai K. Subcortical ischemic vascular disease: roles of oligodendrocyte function in experimental models of subcortical white-matter injury. J Cereb Blood Flow Metab. 2016;36:187–98.CrossRefPubMedPubMedCentral
5.
Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701.CrossRefPubMed
6.
Tullberg M, Fletcher E, DeCarli C, Mungas D, Reed BR, Harvey DJ, Weiner MW, Chui HC, Jagust WJ. White matter lesions impair frontal lobe function regardless of their location. Neurology. 2004;63:246–53.CrossRefPubMedPubMedCentral
7.
de Groot JC, de Leeuw FE, Oudkerk M, van Gijn J, Hofman A, Jolles J, Breteler MM. Cerebral white matter lesions and cognitive function: the Rotterdam Scan Study. Ann Neurol. 2000;47:145–51.CrossRefPubMed
8.
Poggesi A, Pantoni L, Inzitari D, Fazekas F, Ferro J, O'Brien J, Hennerici M, Scheltens P, Erkinjuntti T, Visser M, et al. 2001-2011: a decade of the LADIS (Leukoaraiosis And DISability) study: what have we learned about white matter changes and small-vessel disease? Cerebrovasc Dis. 2011;32:577–88.CrossRefPubMed
9.
Longstreth Jr WT, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, Enright PL, O'Leary D, Fried L. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke. 1996;27:1274–82.CrossRefPubMed
10.
Wakita H, Tomimoto H, Akiguchi I, Kimura J. Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study. Acta Neuropathol. 1994;87:484–92.CrossRefPubMed
11.
Wakita H, Tomimoto H, Akiguchi I, Kimura J. Protective effect of cyclosporin A on white matter changes in the rat brain after chronic cerebral hypoperfusion. Stroke. 1995;26:1415–22.CrossRefPubMed
12.
Farkas E, Donka G, de Vos RA, Mihaly A, Bari F, Luiten PG. Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain. Acta Neuropathol. 2004;108:57–64.CrossRefPubMed
13.
Bueche CZ, Hawkes C, Garz C, Vielhaber S, Attems J, Knight RT, Reymann K, Heinze HJ, Carare RO, Schreiber S. Hypertension drives parenchymal beta-amyloid accumulation in the brain parenchyma. Ann Clin Transl Neurol. 2014;1:124–9.CrossRefPubMedPubMedCentral
14.
Kudo T, Tada K, Takeda M, Nishimura T. Learning impairment and microtubule-associated protein 2 decrease in gerbils under chronic cerebral hypoperfusion. Stroke. 1990;21:1205–9.CrossRefPubMed
15.
Shibata M, Ohtani R, Ihara M, Tomimoto H. White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke. 2004;35:2598–603.CrossRefPubMed
16.
Shibata M, Yamasaki N, Miyakawa T, Kalaria RN, Fujita Y, Ohtani R, Ihara M, Takahashi R, Tomimoto H. Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion. Stroke. 2007;38:2826–32.CrossRefPubMed
17.
Kitamura A, Fujita Y, Oishi N, Kalaria RN, Washida K, Maki T, Okamoto Y, Hase Y, Yamada M, Takahashi J, et al. Selective white matter abnormalities in a novel rat model of vascular dementia. Neurobiol Aging. 2012;33:1012.e1025–1035.CrossRef
18.
Hattori Y, Enmi J, Kitamura A, Yamamoto Y, Saito S, Takahashi Y, Iguchi S, Tsuji M, Yamahara K, Nagatsuka K, et al. A novel mouse model of subcortical infarcts with dementia. J Neurosci. 2015;35:3915–28.CrossRefPubMed
19.
Hattori Y, Enmi J, Iguchi S, Saito S, Yamamoto Y, Tsuji M, Nagatsuka K, Kalaria RN, Iida H, Ihara M. Gradual carotid artery stenosis in mice closely replicates hypoperfusive vascular dementia in humans. J Am Heart Assoc. 2016;5(2):e002757.
20.
Kitamura A, Saito S, Maki T, Oishi N, Ayaki T, Hattori Y, Yamamoto Y, Urushitani M, Kalaria RN, Fukuyama H, et al. Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory. J Cereb Blood Flow Metab. 2016;36:1592–602.CrossRefPubMed
21.
Bink DI, Ritz K, Aronica E, van der Weerd L, Daemen MJ. Mouse models to study the effect of cardiovascular risk factors on brain structure and cognition. J Cereb Blood Flow Metab. 2013;33:1666–84.CrossRefPubMedPubMedCentral
22.
Ihara M, Tomimoto H. Lessons from a mouse model characterizing features of vascular cognitive impairment with white matter changes. J Aging Res. 2011;2011:978761.CrossRefPubMedPubMedCentral
23.
Madigan JB, Wilcock DM, Hainsworth AH. Vascular contributions to cognitive impairment and dementia: topical review of animal models. Stroke. 2016;47:1953–9.
24.
Verkhratsky A, Parpura V. Astrogliopathology in neurological, neurodevelopmental and psychiatric disorders. Neurobiol Dis. 2016;85:254–61.CrossRefPubMed
25.
26.
Choudhury GR, Ding S. Reactive astrocytes and therapeutic potential in focal ischemic stroke. Neurobiol Dis. 2016;85:234–44.CrossRefPubMed
27.
28.
Chisholm NC, Sohrabji F. Astrocytic response to cerebral ischemia is influenced by sex differences and impaired by aging. Neurobiol Dis. 2016;85:245–53.CrossRefPubMed
29.
Gomez-Nicola D, Fransen NL, Suzzi S, Perry VH. Regulation of microglial proliferation during chronic neurodegeneration. J Neurosci. 2013;33:2481–93.CrossRefPubMed
30.
Rawji KS, Mishra MK, Michaels NJ, Rivest S, Stys PK, Yong VW. Immunosenescence of microglia and macrophages: impact on the ageing central nervous system. Brain. 2016;139:653–61.CrossRefPubMed
31.
Wu W, Shao J, Lu H, Xu J, Zhu A, Fang W, Hui G. Guard of delinquency? A role of microglia in inflammatory neurodegenerative diseases of the CNS. Cell Biochem Biophys. 2014;70:1–8.CrossRefPubMed
32.
Sakalem ME, Seidenbecher T, Zhang M, Saffari R, Kravchenko M, Wordemann S, Diederich K, Schwamborn JC, Zhang W, Ambree O. Environmental enrichment and physical exercise revert behavioral and electrophysiological impairments caused by reduced adult neurogenesis. Hippocampus. 2017;27:36–51.CrossRefPubMed
33.
Sun H, Zhang J, Zhang L, Liu H, Zhu H, Yang Y. Environmental enrichment influences BDNF and NR1 levels in the hippocampus and restores cognitive impairment in chronic cerebral hypoperfused rats. Curr Neurovasc Res. 2010;7:268–80.CrossRefPubMed
34.
Cechetti F, Worm PV, Lovatel G, Moyses F, Siqueira IR, Netto CA. Environmental enrichment prevents behavioral deficits and oxidative stress caused by chronic cerebral hypoperfusion in the rat. Life Sci. 2012;91:29–36.CrossRefPubMed
35.
Bayat M, Sharifi MD, Haghani M, Shabani M. Enriched environment improves synaptic plasticity and cognitive deficiency in chronic cerebral hypoperfused rats. Brain Res Bull. 2015;119:34–40.CrossRefPubMed
36.
Fischer A. Environmental enrichment as a method to improve cognitive function. What can we learn from animal models? Neuroimage. 2016;131:42–7.CrossRefPubMed
37.
Ihara M, Okamoto Y, Hase Y, Takahashi R. Association of physical activity with the visuospatial/executive functions of the Montreal Cognitive Assessment in patients with vascular cognitive impairment. J Stroke Cerebrovasc Dis. 2013;22:e146–51.CrossRefPubMed
38.
Quattromani MJ, Cordeau P, Ruscher K, Kriz J, Wieloch T. Enriched housing down-regulates the Toll-like receptor 2 response in the mouse brain after experimental stroke. Neurobiol Dis. 2014;66:66–73.CrossRefPubMed
39.
Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM, Hersh LB, Sapolsky RM, Mirnics K, Sisodia SS. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell. 2005;120:701–13.CrossRefPubMed
40.
41.
Ennaceur A, Michalikova S, van Rensburg R, Chazot PL. Detailed analysis of the behavior and memory performance of middle-aged male and female CD-1 mice in a 3D maze. Behav Brain Res. 2008;187:312–26.CrossRefPubMed
42.
Ennaceur A. Omission of the habituation procedure in the acquisition of a working memory task - evidence from Balb/c, C57/BL6J, and CD-1 mice. Behav Brain Res. 2011;223:203–10.CrossRefPubMed
43.
Ennaceur A, Michalikova S, van Rensburg R, Chazot PL. MK-801 increases the baseline level of anxiety in mice introduced to a spatial memory task without prior habituation. Neuropharmacology. 2011;61:981–91.CrossRefPubMed
44.
Chen A, Akinyemi RO, Hase Y, Firbank MJ, Ndung'u MN, Foster V, Craggs LJ, Washida K, Okamoto Y, Thomas AJ, et al. Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia. Brain. 2016;139:242–58.CrossRefPubMed
45.
Tomimoto H, Akiguchi I, Wakita H, Suenaga T, Nakamura S, Kimura J. Regressive changes of astroglia in white matter lesions in cerebrovascular disease and Alzheimer’s disease patients. Acta Neuropathol. 1997;94:146–52.CrossRefPubMed
46.
Lukaszevicz AC, Sampaio N, Guegan C, Benchoua A, Couriaud C, Chevalier E, Sola B, Lacombe P, Onteniente B. High sensitivity of protoplasmic cortical astroglia to focal ischemia. J Cereb Blood Flow Metab. 2002;22:289–98.CrossRefPubMed
47.
Kim JH, Kwon SJ, Stankewich MC, Huh GY, Glantz SB, Morrow JS. Reactive protoplasmic and fibrous astrocytes contain high levels of calpain-cleaved alpha 2 spectrin. Exp Mol Pathol. 2016;100:1–7.CrossRefPubMed
48.
Mueller SM, Luft FC. The blood-brain barrier in renovascular hypertension. Stroke. 1982;13:229–34.CrossRefPubMed
49.
Tang JP, Xu ZQ, Douglas FL, Rakhit A, Melethil S. Increased blood-brain barrier permeability of amino acids in chronic hypertension. Life Sci. 1993;53:Pl417–20.CrossRefPubMed
50.
Tomimoto H, Akiguchi I, Suenaga T, Nishimura M, Wakita H, Nakamura S, Kimura J. Alterations of the blood-brain barrier and glial cells in white-matter lesions in cerebrovascular and Alzheimer’s disease patients. Stroke. 1996;27:2069–74.CrossRefPubMed
51.
Nahirnyj A, Livne-Bar I, Guo X, Sivak JM. ROS detoxification and proinflammatory cytokines are linked by p38 MAPK signaling in a model of mature astrocyte activation. PLoS One. 2013;8, e83049.CrossRefPubMedPubMedCentral
52.
Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J. 2010;429:403–17.CrossRefPubMed
53.
Badaut J, Lasbennes F, Magistretti PJ, Regli L. Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab. 2002;22:367–78.CrossRefPubMed
54.
El-Khoury N, Braun A, Hu F, Pandey M, Nedergaard M, Lagamma EF, Ballabh P. Astrocyte end-feet in germinal matrix, cerebral cortex, and white matter in developing infants. Pediatr Res. 2006;59:673–9.CrossRefPubMed
55.
Taniguchi M, Yamashita T, Kumura E, Tamatani M, Kobayashi A, Yokawa T, Maruno M, Kato A, Ohnishi T, Kohmura E, et al. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Brain Res Mol Brain Res. 2000;78:131–7.CrossRefPubMed
56.
Holland PR, Searcy JL, Salvadores N, Scullion G, Chen G, Lawson G, Scott F, Bastin ME, Ihara M, Kalaria R, et al. Gliovascular disruption and cognitive deficits in a mouse model with features of small vessel disease. J Cereb Blood Flow Metab. 2015;35:1005–14.CrossRefPubMedPubMedCentral
57.
Washida K, Ihara M, Nishio K, Fujita Y, Maki T, Yamada M, Takahashi J, Wu X, Kihara T, Ito H, et al. Nonhypotensive dose of telmisartan attenuates cognitive impairment partially due to peroxisome proliferator-activated receptor-gamma activation in mice with chronic cerebral hypoperfusion. Stroke. 2010;41:1798–806.CrossRefPubMed
58.
Hase Y, Okamoto Y, Fujita Y, Kitamura A, Nakabayashi H, Ito H, Maki T, Washida K, Takahashi R, Ihara M. Cilostazol, a phosphodiesterase inhibitor, prevents no-reflow and hemorrhage in mice with focal cerebral ischemia. Exp Neurol. 2012;233:523–33.CrossRefPubMed
59.
Zinnhardt B, Viel T, Wachsmuth L, Vrachimis A, Wagner S, Breyholz HJ, Faust A, Hermann S, Kopka K, Faber C, et al. Multimodal imaging reveals temporal and spatial microglia and matrix metalloproteinase activity after experimental stroke. J Cereb Blood Flow Metab. 2015;35:1711–21.CrossRefPubMedPubMedCentral
60.
Cameron B, Landreth GE. Inflammation, microglia, and Alzheimer’s disease. Neurobiol Dis. 2010;37:503–9.CrossRefPubMed
61.
Bhaskar K, Maphis N, Xu G, Varvel NH, Kokiko-Cochran ON, Weick JP, Staugaitis SM, Cardona A, Ransohoff RM, Herrup K, Lamb BT. Microglial derived tumor necrosis factor-alpha drives Alzheimer’s disease-related neuronal cell cycle events. Neurobiol Dis. 2014;62:273–85.CrossRefPubMed
62.
Olmos-Alonso A, Schetters ST, Sri S, Askew K, Mancuso R, Vargas-Caballero M, Holscher C, Perry VH, Gomez-Nicola D. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain. 2016;139:891–907.CrossRefPubMedPubMedCentral
63.
Zielasek J, Hartung HP. Molecular mechanisms of microglial activation. Adv Neuroimmunol. 1996;6:191–22.CrossRefPubMed
64.
65.
Planas AM, Sole S, Justicia C. Expression and activation of matrix metalloproteinase-2 and -9 in rat brain after transient focal cerebral ischemia. Neurobiol Dis. 2001;8:834–46.CrossRefPubMed
66.
Ihara M, Tomimoto H, Kinoshita M, Oh J, Noda M, Wakita H, Akiguchi I, Shibasaki H. Chronic cerebral hypoperfusion induces MMP-2 but not MMP-9 expression in the microglia and vascular endothelium of white matter. J Cereb Blood Flow Metab. 2001;21:828–34.CrossRefPubMed
67.
Nakaji K, Ihara M, Takahashi C, Itohara S, Noda M, Takahashi R, Tomimoto H. Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke. 2006;37:2816–23.CrossRefPubMed
68.
Wang LW, Tu YF, Huang CC, Ho CJ. JNK signaling is the shared pathway linking neuroinflammation, blood-brain barrier disruption, and oligodendroglial apoptosis in the white matter injury of the immature brain. J Neuroinflammation. 2012;9:175.PubMedPubMedCentral
69.
Fan LW, Lin S, Pang Y, Rhodes PG, Cai Z. Minocycline attenuates hypoxia-ischemia-induced neurological dysfunction and brain injury in the juvenile rat. Eur J Neurosci. 2006;24:341–50.CrossRefPubMed
70.
Shen H, Hu X, Liu C, Wang S, Zhang W, Gao H, Stetler RA, Gao Y, Chen J. Ethyl pyruvate protects against hypoxic-ischemic brain injury via anti-cell death and anti-inflammatory mechanisms. Neurobiol Dis. 2010;37:711–22.CrossRefPubMed
71.
Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 2009;29:3974–80.CrossRefPubMed
72.
Hase Y, Craggs L, Stevenson W, Hase M, Slade JY, Oakley AE, Ihara M, Horsburgh K, Kalaria RN. Effects of environmental enrichment/physical exercise on white matter integrity and stroke injury in a mouse model of chronic cerebral hypoperfusion. Cerebrovasc Dis. 2016;41 Suppl 1:199.
73.
Hase Y, Craggs L, Hase M, Stevenson W, Slade J, Chen A, Liang D, Ennaceur A, Oakley A, Ihara M, et al. Effects of environmental enrichment on white matter pathology in a mouse model of chronic cerebral hypoperfusion. J Cereb Blood Flow Metab. 2017;1:271678X17694904. doi:10.​1177/​0271678X17694904​.
Metadata
Title
Effects of environmental enrichment on white matter glial responses in a mouse model of chronic cerebral hypoperfusion
Authors
Yoshiki Hase
Lucinda Craggs
Mai Hase
William Stevenson
Janet Slade
Dianne Lopez
Rubin Mehta
Aiqing Chen
Di Liang
Arthur Oakley
Masafumi Ihara
Karen Horsburgh
Raj N. Kalaria
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-0850-5

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