Abstract
Myelin plays an important role in learning and memory, and degradation of myelin is a key feature in the pathogenesis of neurological disorders involving cognitive dysfunction. Myelin basic protein (MBP) is one of the most abundant structural proteins in myelin and is essential for myelin formation and compaction. In this study, we first examined changes in the distribution of MBP-immunoreactive myelinated fibers and MBP levels according to hippocampal subregion in mice following chronic systemic treatment with 1 mg/kg scopolamine (SCO) for 4 weeks. We found that SCO-induced cognitive impairments, as assayed by the water maze and passive avoidance tests, were significantly reduced 1 week after SCO treatment and the impairments were maintained without any hippocampal neuronal loss. MBP-immunoreactive myelinated fibers were easily detected in the stratum radiatum and lacunosum-moleculare of the hippocampus proper (CA1–3 region) and in the molecular and polymorphic layers of the dentate gyrus. The distribution of MBP-immunoreactive myelinated fibers was not altered 1 week after SCO treatment. However, the density of MBP-immunoreactive myelinated fibers was significantly decreased 2 weeks after SCO treatment; thereafter, the density gradually, though not significantly, decreased with time. In addition, the changing pattern of MBP levels in the hippocampus following SCO treatment corresponded to immunohistochemical changes. In brief, this study shows that chronic systemic treatment with SCO induced significant degradation of MBP in the hippocampus without neuronal loss at least 2 weeks after SCO treatment, although cognitive impairments occurred 1 week after SCO treatment.
Similar content being viewed by others
References
Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414
Bartzokis G, Lu PH, Tishler TA, Fong SM, Oluwadara B, Finn JP, Huang D, Bordelon Y, Mintz J, Perlman S (2007) Myelin breakdown and iron changes in Huntington’s disease: pathogenesis and treatment implications. Neurochem Res 32:1655–1664
Blokland A (2005) Scopolamine-induced deficits in cognitive performance: a review of animal studies. Scopolamine Rev 1–76
Dineen RA, Vilisaar J, Hlinka J, Bradshaw CM, Morgan PS, Constantinescu CS, Auer DP (2009) Disconnection as a mechanism for cognitive dysfunction in multiple sclerosis. Brain 132:239–249
Dutta R, Chang A, Doud MK, Kidd GJ, Ribaudo MV, Young EA, Fox RJ, Staugaitis SM, Trapp BD (2011) Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann Neurol 69:445–454
Ebert U, Kirch W (1998) Scopolamine model of dementia: electroencephalogram findings and cognitive performance. Eur J Clin Investig 28:944–949
Fields RD (2008) White matter in learning, cognition and psychiatric disorders. Trends Neurosci 31:361–370
Geurts JJ, Bo L, Roosendaal SD, Hazes T, Daniels R, Barkhof F, Witter MP, Huitinga I, van der Valk P (2007) Extensive hippocampal demyelination in multiple sclerosis. J Neuropathol Exp Neurol 66:819–827
Gold PE (2003) Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol Learn Mem 80:194–210
Hami J, Kheradmand H, Haghir H (2014) Sex differences and laterality of insulin receptor distribution in developing rat hippocampus: an immunohistochemical study. J Mol Neurosci 54:100–108
Hasselmo ME (2006) The role of acetylcholine in learning and memory. Curr Opin Neurobiol 16:710–715
Hjorth-Simonsen A (1973) Some intrinsic connections of the hippocampus in the rat: an experimental analysis. J Comp Neurol 147:145–161
Horisawa T, Ishibashi T, Nishikawa H, Enomoto T, Toma S, Ishiyama T, Taiji M (2011) The effects of selective antagonists of serotonin 5-HT7 and 5-HT1A receptors on MK-801-induced impairment of learning and memory in the passive avoidance and Morris water maze tests in rats: mechanistic implications for the beneficial effects of the novel atypical antipsychotic lurasidone. Behav Brain Res 220:83–90
Huang W, Cao J, Liu X, Meng F, Li M, Chen B, Zhang J (2015) AMPK plays a dual role in regulation of CREB/BDNF pathway in mouse primary hippocampal cells. J Mol Neurosci 56:782–788
Huang Z, Liu J, Cheung PY, Chen C (2009) Long-term cognitive impairment and myelination deficiency in a rat model of perinatal hypoxic-ischemic brain injury. Brain Res 1301:100–109
Ihara M, Polvikoski TM, Hall R, Slade JY, Perry RH, Oakley AE, Englund E, O’Brien JT, Ince PG, Kalaria RN (2010) Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies. Acta Neuropathol 119:579–589
Klinkenberg I, Blokland A (2010) The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neurosci Biobehav Rev 34:1307–1350
Kong Y, Bai PS, Sun H, Nan KJ (2012) Expression of the newly identified gene CAC1 in the hippocampus of Alzheimer’s disease patients. J Mol Neurosci 47:207–218
Laurberg S (1979) Commissural and intrinsic connections of the rat hippocampus. J Comp Neurol 184:685–708
Lee B, Sur B, Shim J, Hahm DH, Lee H (2014) Acupuncture stimulation improves scopolamine-induced cognitive impairment via activation of cholinergic system and regulation of BDNF and CREB expressions in rats. BMC Complement Altern Med 14:338
Lee JC, Park JH, Ahn JH, Kim IH, Cho JH, Choi JH, Yoo KY, Lee CH, Hwang IK, Kwon YG, Kim YM, Kang IJ, Won MH (2015) New GABAergic neurogenesis in the hippocampal CA1 region of a gerbil model of long-term survival after transient cerebral ischemic injury. Brain Pathol
Lin S, Rhodes PG, Lei M, Zhang F, Cai Z (2004) Alpha-phenyl-n-tert-butyl-nitrone attenuates hypoxic-ischemic white matter injury in the neonatal rat brain. Brain Res 1007:132–141
Lippa AS, Critchett DJ, Ehlert F, Yamamura HI, Enna SJ, Bartus RT (1981) Age-related alterations in neurotransmitter receptors: an electrophysiological and biochemical analysis. Neurobiol Aging 2:3–8
Maccaferri G (2011) Modulation of hippocampal stratum lacunosum-moleculare microcircuits. J Physiol 589:1885–1891
Miki K, Ishibashi S, Sun L, Xu H, Ohashi W, Kuroiwa T, Mizusawa H (2009) Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice. J Neurosci Res 87:1270–1281
National Research Council (U.S.). Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research (U.S.), National Academies Press (U.S.) (2011) Guide for the care and use of laboratory animals. 8th edn. National Academies Press, Washington, D.C.
Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468:244–252
Park JH, Lee CH, Yoo KY, Choi JH, Hwang IK, Lee JY, Kang IJ, Won MH (2011) FoxO3a immunoreactivity is markedly decreased in the dentate gyrus, not the hippocampus proper, of the aged gerbil. Exp Gerontol 46:836–840
Paz Soldan MM, Pirko I (2012) Biogenesis and significance of central nervous system myelin. Semin Neurol 32:9–14
Richter-Landsberg C (2000) The oligodendroglia cytoskeleton in health and disease. J Neurosci Res 59:11–18
Shi Z, Chen L, Li S, Chen S, Sun X, Sun L, Li Y, Zeng J, He Y, Liu X (2013) Chronic scopolamine-injection-induced cognitive deficit on reward-directed instrumental learning in rat is associated with CREB signaling activity in the cerebral cortex and dorsal hippocampus. Psychopharmacology 230:245–260
Stoffel W (1990) The myelin membrane of the central nervous system—essential macromolecular structure and function. Angew Chem Int Ed Eng 29:958–976
Swanson LW, Wyss JM, Cowan WM (1978) An autoradiographic study of the organization of intrahippocampal association pathways in the rat. J Comp Neurol 181:681–715
Vijayan VK (1977) Cholinergic enzymes in the cerebellum and the hippocampus of the senescent mouse. Exp Gerontol 12:7–11
Vincze A, Mazlo M, Seress L, Komoly S, Abraham H (2008) A correlative light and electron microscopic study of postnatal myelination in the murine corpus callosum. Int J Dev Neurosci 26:575–584
Wang X, Wang ZH, Wu YY, Tang H, Tan L, Gao XY, Xiong YS, Liu D, Wang JZ, Zhu LQ (2013) Melatonin attenuates scopolamine-induced memory/synaptic disorder by rescuing EPACs/miR-124/Egr1 pathway. Mol Neurobiol 47:373–381
Wang Z, Li J, Xue L, Zhang Y, Chen Y, Su J, Li Z (2012) L-tyrosine improves neuroendocrine function in a mouse model of chronic stress. Neural Regen Res 7:1413–1419
Yan BC, Park JH, Chen BH, Cho JH, Kim IH, Ahn JH, Lee JC, Hwang IK, Lee YL, Kang IJ, Won MH (2014) Long-term administration of scopolamine interferes with nerve cell proliferation, differentiation and migration in adult mouse hippocampal dentate gyrus, but it does not induce cell death. Neural Regen Res 9:1731–1739
Yoo DY, Choi JH, Kim W, Nam SM, Jung HY, Kim JH, Won MH, Yoon YS, Hwang IK (2013) Effects of luteolin on spatial memory, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a scopolamine-induced amnesia model. Neurol Res 35:813–820
Zhan X, Jickling GC, Ander BP, Liu D, Stamova B, Cox C, Jin LW, DeCarli C, Sharp FR (2014) Myelin injury and degraded myelin vesicles in Alzheimer’s disease. Curr Alzheimer Res 11:232–238
Zhao L, Sun C, Xiong L, Yang Y, Gao Y, Wang L, Zuo H, Xu X, Dong J, Zhou H, Peng R (2014) MicroRNAs: novel mechanism involved in the pathogenesis of microwave exposure on rats’ hippocampus. J Mol Neurosci 53:222–230
Zhou J, Zhuang J, Li J, Ooi E, Bloom J, Poon C, Lax D, Rosenbaum DM, Barone FC (2013) Long-term post-stroke changes include myelin loss, specific deficits in sensory and motor behaviors and complex cognitive impairment detected using active place avoidance. PLoS One 8:e57503
Acknowledgments
The authors would like to thank Mr. Seung Uk Lee for his technical help in this study. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NO2011-0022812), and by the Bio-Synergy Research Project (NRF-2015M3A9C4076322) of the Ministry of Science, ICT and Future Planning through the National Research Foundation.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no potential conflicts of interest.
Additional information
Joon Ha Park and Hyun Young Choi have contributed equally to this article.
Rights and permissions
About this article
Cite this article
Park, J.H., Choi, H.Y., Cho, JH. et al. Effects of Chronic Scopolamine Treatment on Cognitive Impairments and Myelin Basic Protein Expression in the Mouse Hippocampus. J Mol Neurosci 59, 579–589 (2016). https://doi.org/10.1007/s12031-016-0780-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-016-0780-1