Multiple sclerosis (MS) is a common central nervous system disease associated with progressive physical impairment. To study the mechanisms of the disease, we used experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE is induced by myelin oligodendrocyte peptide, and the severity of paralysis in the disease is generally measured using the EAE score. Here, we compared EAE scores and traveled distance using the open-field test for an assessment of EAE progression. EAE scores were obtained with a 6-step observational scoring system for paralysis, and the traveled distance was obtained by automatic trajectory analysis of natural exploratory behaviors detected by a computer. The traveled distance of the EAE mice started to decrease significantly at day 7 of the EAE process, when the EAE score still did not reflect a change. Moreover, in the relationship between the traveled distance and paralysis as measured by the EAE score after day 14, there was a high coefficient of determination between the distance and the score. The results suggest that traveled distance is a sensitive marker of motor dysfunction in the early phases of EAE progression and that it reflects the degree of motor dysfunction after the onset of paralysis in EAE. 1. Introduction Multiple sclerosis (MS) is the most common demyelinating disease in young adults and is associated with progressive physical impairment [1]. The most frequent clinical form is characterized by episodes of relapse and remission with multifocal demyelination in the central nervous system. To investigate the mechanisms of MS, we used experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE is induced by myelin oligodendrocyte peptide [2–4], and the severity of paralysis in EAE is generally examined using the EAE score. EAE score is known to be useful to estimate the severity of the paralysis, but is inappropriate to detect a decline in motor activity in the early phase before appearance of definite paralysis. In addition, there is no standard scoring system for EAE signs and there is variability between research groups. The open field test is used to evaluate the activity and anxiety of mice by measuring the walking distance of mice with normal motor function, but we are also able to quantify changes in motor dysfunction, including the progression of paralysis, by repetitive observations in a mouse model of neuromuscular disease. As mice exposed to the same open field box repeatedly over short time scales become acclimated to the environment and decrease their traveled distance
References
[1]
J. H. Noseworthy, C. Lucchinetti, M. Rodriguez, and B. G. Weinshenker, “Multiple sclerosis,” The New England Journal of Medicine, vol. 343, no. 13, pp. 938–952, 2000.
[2]
I. Mendel, N. Kerlero de Rosbo, and A. Ben-Nun, “A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor Vβ expression of encephalitogenic T cells,” European Journal of Immunology, vol. 25, no. 7, pp. 1951–1959, 1995.
[3]
A. Iglesias, J. Bauer, T. Litzenburger, A. Schubart, and C. Linington, “T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis,” GLIA, vol. 36, no. 2, pp. 220–234, 2001.
[4]
C. Takeuchi, Y. Matsumoto, K. Kohyama et al., “Microsomal prostaglandin E synthase-1 aggravates inflammation and demyelination,” Neurochemistry International, vol. 62, pp. 271–280, 2013.
[5]
Y. Matsumoto and M. Fujiwara, “The immunopathology of adoptively transferred experimental allergic encephalomyelitis (EAE) in Lewis rats. Part I. Immunohistochemical examination of developing lesions of EAE,” Journal of the Neurological Sciences, vol. 77, no. 1, pp. 35–47, 1987.
[6]
R. H. Swanborg, “Experimental allergic encephalomyelitis,” Methods in Enzymology, vol. 162, pp. 413–421, 1988.
[7]
I. M. Stromnes and J. M. Goverman, “Active induction of experimental allergic encephalomyelitis,” Nature Protocols, vol. 1, no. 4, pp. 1810–1819, 2006.
[8]
I. M. Stromnes and J. M. Goverman, “Passive induction of experimental allergic encephalomyelitis,” Nature Protocols, vol. 1, no. 4, pp. 1952–1960, 2006.
[9]
I. Tsunoda, L.-Q. Kuang, N. D. Tolley, J. L. Whitton, and R. S. Fujinami, “Enhancement of experimental allergic encephalomyelitis (EAE) by DNA immunization with myelin proteolipid protein (PLP) plasmid DNA,” Journal of Neuropathology and Experimental Neurology, vol. 57, no. 8, pp. 758–767, 1998.
[10]
A. Kalyvas and S. David, “Cytosolic phospholipase A2 plays a key role in the pathogenesis of multiple sclerosis-like disease,” Neuron, vol. 41, pp. 323–335, 2004.
[11]
Y. Kihara, T. Matsushita, Y. Kita et al., “Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 51, pp. 21807–21812, 2009.
[12]
R. A. Sobel, V. K. Tuohy, Z. Lu, R. A. Laursen, and M. B. Lees, “Acute experimental allergic encephalomyelitis in SJL/J mice induced by a synthetic peptide of myelin proteolipid protein,” Journal of Neuropathology and Experimental Neurology, vol. 49, no. 5, pp. 468–479, 1990.
[13]
M. K. Storch, A. Stefferl, U. Brehm et al., “Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology,” Brain Pathology, vol. 8, no. 4, pp. 681–694, 1998.
[14]
Y. Pollak, H. Ovadia, I. Goshen et al., “Behavioral aspects of experimental autoimmune encephalomyelitis,” Journal of Neuroimmunology, vol. 104, no. 1, pp. 31–36, 2000.
[15]
Y. Pollak, H. Ovadia, E. Orion, and R. Yirmiya, “The EAE-associated behavioral syndrome: II. Modulation by anti-inflammatory treatments,” Journal of Neuroimmunology, vol. 137, no. 1-2, pp. 100–108, 2003.
[16]
M. Greter, F. L. Heppner, M. P. Lemos et al., “Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis,” Nature Medicine, vol. 11, no. 3, pp. 328–334, 2005.
[17]
A. Matejuk, C. Hopke, A. A. Vandenbark, P. D. Hurn, and H. Offner, “Middle-age male mice have increased severity of experimental autoimmune encephalomyelitis and are unresponsive to testosterone therapy,” Journal of Immunology, vol. 174, no. 4, pp. 2387–2395, 2005.
[18]
J. L. Croxford, S. Miyake, Y.-Y. Huang, M. Shimamura, and T. Yamamura, “Invariant Vα19i T cells regulate autoimmune inflammation,” Nature Immunology, vol. 7, no. 9, pp. 987–994, 2006.
