The preclinical stage of Parkinson’s disease (PD), when most dopaminergic neurons in the nigrostriatal system of the brain are still intact and compensatory mechanisms have not yet been overwhelmed, is the most effective “therapeutic window.” Much attention in recent years has therefore been focused on seeking early markers for the neurodegenerative process and developing experimental models. The present study addressed the task of analyzing early behavioral changes reflecting impairments in the cognitive and affective domains on modeling the premotor stage of PD in rats, with identification of the most informative tests. A model developed in our laboratory is based on a prolonged (21 days) preclinical stage of PD in rats by increasing suppression of the ubiquitin-proteasome system of the brain induced by two intranasal doses of the specific proteasome inhibitor lactacystin. Cognitive impairments were assessed using the novel object recognition and Y maze tests and the what–where–when paradigm. Anxiety was assessed in the elevated plus maze and open field tests. Administration of lactacystin was found to degrade spatial memory, episodic memory, and recognition of novel objects in rats on the background of a transient increase in the level of anxiety. These data suggest that impairments in the cognitive and affective domains may be early signs of the development of neurodegeneration in the brain.
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References
Abdurasulova, I. N., Ekimova, I. V., Matsulevich, A. V., et al., “Impairments to nonassociative learning in rats in an experimental model of the preclinical stage of Parkinson’s disease,” Dokl. Akad. Nauk, 476, No. 3, 353–356 (2017).
Anchan, D., Clark, S., Pollard, K., and Vasudevan, N., “GPR30 activation decreases anxiety in the open field test but not in the elevated plus maze test in female mice,” Brain Behav., 4, No. 1, 51–59 (2014), https://doi.org/10.1002/brb3.197.
Asano, Y., “Characteristics of open field behaviour of Wistar and Sprague–Dawley rats,” Exp. Anim., 35, No. 4, 505–508 (1986).
Barker, G. R. and Warburton, E. C., “Critical role of the cholinergic system for object-in-place associative recognition memory,” Learn. Mem., 16, No. 1, 8–11 (2008), https://doi.org/10.1101/lm.1121309.
Bertaina-Anglade, V., Enjuanes, E., Morillon, D., and Drieu la Roshelle, C., “The object recognition task in rats and mice: a simple and rapid model in safety pharmacology to detect amnestic properties of a new chemical entity,” J. Pharmacol. Toxicol. Meth., 54, No. 2, 99–105 (2006), https://doi.org/10.1016/j.vascn.2006.04.001.
Bevins, R. A. and Besheer, J., “Object recognition in rats and mice: A one-trial non-matching-to-sample learning task to study recognition memory,” Nat. Protoc., 1, No. 3, 1306–1311 (2006), https://doi.org/10.1038/neuroprotective.205.
Biundo, R., Weis, L., and Antonini, A., “Cognitive decline in Parkinson’s disease: the complex picture,” NPJ Parkinsons Dis.,2, 16018 (2006), https://doi.org/10.1038/npjparkd.2016.18.
Bohnen, N. I. and Albin, R. L., “The cholinergic system and Parkinson disease,” Behav. Brain Res., 221, No. 2, 564–573 (2011), https://doi.org/10.1016/j.bbr.2009.12.048.
Botton, P. H., Costa, M. S., Ardais, A. P., et al., “Caffeine prevents disruption of memory consolidation in the inhibitory avoidance and novel object recognition tasks by scopolamine in adult mice,” Behav. Brain Res., 214, No. 2, 254–259 (2010), https://doi.org/10.1016/j.bbr.2010.05.034.
Bower, J. H., Grossardt, B. R., Maraganore, D. M., et al., “Anxious personality predicts an increased risk of Parkinson’s disease,” Mov. Disord., 25, No. 13, 2105–2113 (2010), https://doi.org/10.1002/mds.23230.
Broeders, M., Velseboer, D. C., de Bie, R., et al., “Cognitive change in newly-diagnosed patients with Parkinson’s disease: A 5-year follow-up study,” J. Int. Neuropsychol. Soc., 19, No. 6, 695–708 (2013), https://doi.org/10.1017/S1355617713000295.
Bruck, A., Kurki, T., Kaasinen, V., et al., “Hippocampal and prefrontal atrophy in patients with early non-demented Parkinson’s disease is related to cognitive impairment,” J. Neurol. Neurosurg. Psychiatry, 75, No. 10, 1467–1469 (2004), https://doi.org/10.1136/jnnp.2003.031237.
Buresh, Ya., Bureshova, O., and Houston, D. P., Methods and Basis of Experiments in Brain and Behavior Research, Vysshaya Shkola, Moscow (1991), pp. 119–122.
Calatayud, F., Belzung, C., and Aubert, A., “Ethological validation and the assessment of anxiety-like behaviours: methodological comparison of classical analyses and structural approaches,” Behav. Processes, 67, No. 2, 195–206 (2004), https://doi.org/10.1016/j.beproc.2004.04.002.
Ciechanover, A. and Kwon, Y. T., “Protein quality control by molecular chaperones in neurodegeneration,” Front. Neurosci., 11, 185 (2017), https://doi.org/10.3389/fnins.2017.00185.
Davidson, P. S., Troyer, A. K., and Moscovitch, M., “Frontal lobe contributions to recognition and recall: Linking basic research with clinical evaluation and remediation,” J. Int. Neuropsychol. Soc., 12, No. 2, 210–223 (2006), https://doi.org/10.1017/S1355617706060334.
de Lima, M. N., Laranja, D. C., Bromberg, E., et al., “Pre- or post-training administration of the NMDA receptor blocker MK-801 impairs object recognition memory in rats,” Bеhav. Brain Res., 156, No. 1, 139–143 (2005), https://doi.org/10.1016/j.bbr.2004.05.016.
Dere, E., Pause, B., and Pietrowsky, R., “Emotion and episodic memory in neuropsychiatric disorders,” Behav. Brain Res., 215, No. 2, 162–171 (2010), https://doi.org/10.1016/j.bbr.2010.03.017.
Dissanayaka, N. N. W., Lawson, R. A., Yarnall, A. J., et al., ICICLE-PD study group, “Anxiety is associated with cognitive impairment in newly-diagnosed Parkinson’s disease,” Parkins. Relat. Disord., 36, 63–68 (2017), https://doi.org/10.1016/j.parkreldis.2017.01.001.
Dissanayaka, N. N., Sellbach, A., Matheson, S., et al., “Anxiety disorders in Parkinson’s disease: prevalence and risk factors,” Mov. Disord., 25, No. 7, 838–845 (2010), https://doi.org/10.1002/mds.22833.
Ekimova, I. V., Plaksina, D. V., Lapshina, K. V., et al., “Pathological and compensatory processes in a new model of the preclinical stage of Parkinson’s disease in rats,” Acta Naturae, Spec. Iss. 1, 50 (2016a).
Ekimova, I. V., Simonova, V. V., Guzeev, M. A., et al., “Changes in the characteristics of sleep in a model of the preclinical stage of Parkinson’s disease in rats based on weakening of the activity of the brain ubiquitin-proteasome system,” Zh. Evolyuts. Biokhim. Fiziol., 52, No. 6, 413–422 (2016b).
Elgh, E., Domellof, M., Linder, J., et al., “Cognitive function in early Parkinson’s disease: a population-based study,” Eur. J. Neurol, 16, No. 12, 1278–1284 (2009), https://doi.org/10.1111/j.1468-1331.2009.02707.
Fellini, L. and Morellini, F., “Mice create what–where–when hippocampus-dependent memories of unique experiences,” J. Neurosci., 33, No. 3, 1038–1043 (2013), https://doi.org/10.1523/JNEUROSCI.2280-12.2013.
Flint, J., “Animal models of anxiety and their molecular dissection,” Semin. Cell. Dev. Biol., 14, No. 1, 37–42 (2003), https://doi.org/10.1016/S1084-9521(02)00170-2.
Floresco, S. B., “Prefrontal dopamine and behavioral flexibility: shifting from an ‘inverted-U’ toward a family of functions,” Front. Neurosci., 7, 62 (2013), https://doi.org/10.3389/fnins.2013.00062.
Fox, S. H., Chuang, R., and Brotchie, J. M., “Serotonin and Parkinson’s disease: On movement, mood, and madness,” Mov. Disord., 24, No. 9, 1255–1266 (2009), https://doi.org/10.1002/mds.22473.
Goetz, C. G., “New developments in depression, anxiety, compulsiveness, and hallucinations in Parkinson’s disease,” Mov. Disord., Suppl. 1, S104–109 (2010), https://doi.org/10.1002/mds.22636.
Griffith, H. R., Okonkwo, O. C., O’Brien, T., and Hollander, J. A., “Reduced brain glutamate in patients with Parkinson’s disease,” NMR Biomed., 21, No. 4, 381–387 (2008), https://doi.org/10.1002/nbm.1203.1.
Halpin, Z. T., “Individual odors among mammals: Origins and functions,” Adv. Study Behav., 16, 39–70 (1986), https://doi.org/10.1016/S0065-3454(08)60187-4.
Hidaka, N., Suemaru, K., Takechi, K., et al., “Inhibitory effects of valproate on impairment of Y-maze alternation behavior induced by repeated electroconvulsive seizures and c-Fos protein levels in rat brains,” Acta Med. Okayama, 65, No. 4, 269–277 (2011), https://doi.org/10.18926/AMO/46853.
Holmes, A., Kinney, J. W., Wrenn, C. C., et al., “Galanin GAL-R1 receptor null mutant mice display increased anxiety-like behavior specific to the elevated plus-maze,” Neuropsychopharmacology, 28, No. 6, 1031–1044 (2003), https://doi.org/10.1038/sj.npp.1300164.
Illarioshkin, S. N., “The nonmotor signs of Parkinson’s disease,” Zh. Nervy, 1, 7–9 (2007).
Karpenko, M. N., Muruzheva, Z. M., Pestereva, N. S., and Ekimova, I. V., “An infection hypothesis for Parkinson’s disease,” Ros. Fiziol. Zh., 103, No. 8, 841–853 (2017).
Kertesz, A. and McMonagle, P., “Behavior and cognition in corticobasal degeneration and progressive supranuclear palsy,” J. Neurol. Sci, 289, No. 1–2, 138 (2010), https://doi.org/10.1016/j.jns.2009.08.036.
Laatu, S., Revonsuo, A., Pihko, L., et al., “Visual object recognition deficits in early Parkinson’s disease,” Parkins. Relat. Disord., 10, No. 4, 227–233 (2004), https://doi.org/10.1016/j.parkreldis.2004.02.001.
Lam, H. A., Wu, N., Cely, I., et al., “Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α-synuclein,” J. Neurosci. Res., 89, No. 7, 1091–1102 (2011), https://doi.org/10.1002/jnr.22611.
Le, W., Sayana, P., and Jankovic, J., “Animal models of Parkinson’s disease: a gateway to therapeutics? Neurotherapeutics 11, No. 1, 92–110 (2014), https://doi.org/10.1007/s13311-013-0234-1.
Leentjens, A. F., Dujadin, K., Marsh, L., et al., “Symptomatology and markers of anxiety disorders in Parkinson’s disease: a cross-sectional study,” Mov. Disord., 26, No. 3, 484–492 (2011), https://doi.org/10.1002/mds.23528.
Leger, M., Quiedeville, A., Bouet, V., et al., “Object recognition test in mice,” Nat. Protoc., 8, No. 12, 2531–2537 (2013), https://doi.org/10.1038/nprot.2013.155.
Li, B., Arime, Y., Hall, F. S., et al., “Impaired spatial working memory and decreased frontal cortex BDNF protein level in dopamine transporter knockout mice,” Eur. J. Pharmacol., 628, No. 1–3, 104–107 (2010), https://doi.org/10.1016/j.ejphar.2009.11.036.
Li, X., Redus, L., Chen, C., et al., “Cognitive dysfunction precedes the onset of motor symptoms in the mitoPark mouse model of Parkinson’s disease,” PLoS One, 8, No. 8, e71341 (2013), https://doi.org/10.1371/journal.pone.0071341.
Lister, R. G., “Ethologically-based animal models of anxiety disorders,” Pharmacol. Ther., 46, No. 3, 321–340 (1990), https://doi.org/10.1016/0163-7258(90)90021-S.
Magen, I., Fleming, S. M., Zhu, C., et al., “Cognitive deficits in a mouse model of pre-manifest Parkinson’s disease,” Eur. J. Neurosci., 35, No. 6, 870–82 (2012), https://doi.org/10.1111/j.1460-9568.2012.08012.x.
Maiti, P., Manna, J., and Dunbar, G. L., “Current understanding of the molecular mechanisms in Parkinson’s disease: Targets for potential treatments,” Transl. Neurodegener., 6, 28 (2017), https://doi.org/10.1186/s40035-017-0099-z.
Mällo, T., Alttoa, A., Kõiv, K., et al., “Rats with persistently low or high exploratory activity: Behaviour in tests of anxiety and depression, and extracellular level of dopamine,” Behav. Brain Res., 177, No. 2, 269–281 (2007), https://doi.org/10.1016/j.bbr.2006.11.022.
Mamikonyan E, Moberg, P. J., Siderowf, A., et al., “Mild cognitive impairment is common in Parkinson’s disease patients with normal Mini-Mental State Examination (MMSE) scores,” Parkins. Relat. Disord., 15, No. 3, 226–231 (2009), https://doi.org/10.1016/j.parkreldis.2008.05.006.
Marino, M. J., Valenti, O., and Conn, P. J., “Glutamate receptors and Parkinson’s disease: opportunities for intervention,” Drugs Aging, 20, No. 5, 377–397 (2003), https://doi.org/10.2165/00002512-200320050-00006.
Mattila, P. M., Röyttä, M., Lönnberg, P., et al., “Choline I (acetyltransferase) activity and striatal dopamine receptors in Parkinson’s disease in relation to cognitive impairment,” Acta Neuropathol., 102, No. 2, 160–166 (2001), https://doi.org/10.1007/s004010100372.
Meyer, L., Caston, J., and Mensah-Nyagan, A. G., “Seasonal variation of the impact of a stressful procedure on open field behaviour and blood corticosterone in laboratory mice,” Behav. Brain Res., 167, No. 2, 342–348 (2006), https://doi.org/10.1016/j.bbr.2005.09.023.
Mingazov, E. R., Khakimova, G. R., Kozina, E. A., et al., “MPTP mouse model of preclinical and clinical Parkinson’s disease as an instrument for translational medicine,” Mol. Neurobiol. (2017), https://doi.org/10.1007/s12035-017-0559-6.
Molewijk, H. E., van der Poel, A. M., and Olivier, B., “The ambivalent behavior ‘stretched approach posture’ in the rat as a paradigm to characterize anxiolytic drugs,” Psychopharmacology (Berlin), 121, No. 1, 81–90 (1995), https://doi.org/10.1007/BF02245594.
Moriguchi, S., Yabuki, Y., and Fukunaga, K., “Reduced calcium/calmodulin-dependent protein kinase II activity in the hippocampus is associated with impaired cognitive function in MPTP-treated mice,” J. Neurochem., 120, No. 4, 541–551 (2012), https://doi.org/10.1111/j.1471-4159.2011.07608.x.
Muslimovic, D., Post, B., Speelman, J. D., and Schmand, B., “Cognitive profile of patients with newly diagnosed Parkinson disease,” Neurology, 65, No. 8, 1239–1245 (2005), https://doi.org/10.1212/01.wnl.0000180516.69442.95.
Nègre-Pagès, L., Grandjean, H., Lapeyre-Mestre, M., et al., Rascol OPaMiP Study Group, “Anxious and depressive symptoms in Parkinson’s disease: the French cross-sectional DoPaMiP study,” Mov. Disord., 25, No. 2, 157–166 (2010), https://doi.org/10.1002/mds.22760.
Owen, A. M., “Cognitive dysfunction in Parkinson’s disease: The role of frontostriatal circuitry,” Neuroscientist, 10, No. 6, 525–537 (2004), https://doi.org/10.1177/1073858404266776.
Pastukhov, Yu. F., “Changes in the characteristics of paradoxical sleep as an early sign of Parkinson’s disease,” Zh. Vyssh. Nerv. Deyat., 63, No. 1, 75–85 (2013).
Pastukhov, Yu. F., Ekimova, I. V., and Chesnokova, A. V., “Molecular mechanisms of the pathogenesis of Parkinson’s disease and potentials for preventive therapy. Part 1: Motor function and its regulation in health and pathology,” in: Neurodegenerative Diseases – from the Genome to the Whole Body, M. V. Ugrumov (ed.), Nauchnyi Mir, Moscow (2014), Vol. 1, pp. 316–356.
Pastukhov, Yu. F., Simonova, V. V., Chernyshev, M. V., et al., “Signs of sleep and behavior impairment signaling the initial stage neurodegeneration in a model of Parkinson’s disease,” Zh. Evolyuts. Biokhim. Fiziol., 53, No. 5, 383–386 (2017).
Pellow, S., Chopin, P., File, S., and Briley, M., “Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat,” J. Neurosci. Meth., 14, 149–167 (1985), https://doi.org/10.1016/0165-0270(85)90031-7.
Pfeiffer, H., Løkkegaard, A., Zoetmulder, M., et al., “Cognitive impairment in early-stage non-demented Parkinson’s disease patients,” Acta Neurol. Scand., 129, No. 5, 307–318 (2014), https://doi.org/10.1111/ane.12189.
Pirogovsky-Turk, E., Filoteo, J. V., Litvan, I., and Harrington, D. L., “Structural MRI correlates of episodic memory processes in Parkinson’s disease without mild cognitive impairment,” J. Parkinsons Dis., 5, No. 4, 971–981 (2015), https://doi.org/10.3233/JPD-150652.
Plaksina, D. V. and Ekimova, I. V., “Age-related characteristics of α-synuclein pathology in the brain in a model of the preclinical stage of Parkinson’s disease in rats,” Ros. Fiziol. Zh., 104, No. 6, 709–716 (2018).
Plaksina, D. V., Chernyshev, M. V., Karpenko, M. N., et al., “Experimental modeling of a preclinical Parkinson’s disease stage in rats by intranasal lactacystin administration,” Neurodeg. Dis., 17, Suppl. 1, 1655 (2017a), https://doi.org/10.1159/000464378.
Plaksina, D. V., Ekimova, I. V., Karpenko, M. N., and Pastukhov, Yu. F., “Assessment of the functional state of the nigrostriatal system of the brain in an experimental model of the preclinical stage of Parkinson’s disease in rats,” Zh. Evolyuts. Biokhim. Fiziol., 53, No. 5, 386–388 (2017b).
Ray, N. J. and Strafella, A. P., “The neurobiology and neural circuitry of cognitive changes in Parkinson’s disease revealed by functional neuroimaging,” Mov. Disord., 27, No. 12, 1484–1492 (2012), https://doi.org/10.1002/mds.25173.
Rodgers, R. J. and Johnson, N. J. T., “Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety,” Pharmacol. Biochem. Behav., 52, 297–303 (1995), https://doi.org/10.1016/0091-3057(95)00138-M.
Rosen, J. B., Pagani, J. H., Rolla, K. L. G., and Davis, C., “Analysis of behavioral constraints and the neuroanatomy of fear to the predator odor trimethylthiazoline: A model for animal phobias,” Neurosci. Biobehav. Rev., 32, 1267–1276 (2008), https://doi.org/10.1016/j.neubiorev.2008.05.006.
Rugg, M. D., Otten, L. J., and Henson, R. N., “The neural basis of episodic memory: Evidence from functional neuroimaging,” Philos. Trans. R. Soc. Lond. B Biol. Sci., 357, No. 1424, 1097–1110 (2002), https://doi.org/10.1098/rstb.2002.1102.
Sawada, M., Imamura, K., and Nagatsu, T., “Role of cytokines in inflammatory process in Parkinson’s disease,” J. Neural Transm. (Vienna), Supplement, 70, 373–381 (2006), https://doi.org/10.1007/978-3-211-45295-0_57.
Schneider, J. S., “Chronic exposure to low doses of MPTP. II. Neurochemical and pathological consequences in cognitively-impaired, motor asymptomatic monkeys,” Brain Res., 534, No. 1–2, 25–36 (1990), https://doi.org/10.1016/0006-8993(90)90108-N.
Shiba, M., Bower, J. H., Maraganore, D. M., et al., “Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case-control study,” Mov. Disord., 15, No. 4, 669–677 (2000), https://doi.org/10.1002/1531-8257(200007).
Sudakov, S. K., Nazarova, G. A., Alekseeva, E. V., and Bashkatova, V. G., “Determination of levels of anxiety in rats: divergence of results in the open field, elevated plus maze, and Vogel tests,” Byull. Eksperim. Biol. Med., 155, No. 3, 268–270 (2013).
Sy, H. N., Wu, S. L., Wang, W. F., et al., “MPTP-induced dopaminergic degeneration and deficits in object recognition in rats are accompanied by neuroinflammation in the hippocampus,” Pharmacol. Biochem. Behav., 95, No. 2, 158–165 (2010), https://doi.org/10.1016/j.pbb.2009.12.020.
Tadaiesky, M. T., Dombrowski, P. A., Fiqueiredo, C. P., et al., “Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson’s disease,” Neuroscience, 156, No. 4, 830–840 (2008), https://doi.org/10.1016/j.neuroscience.2008.08.035.
Tissingh, G., Bergmans, P., Booij, J., et al., “Drug-naive patients with Parkinson’s disease in Hoehn and Yahr stages I and II show a bilateral decrease in striatal dopamine transporters as revealed by [123I] beta-CIT SPECT,” J. Neurol., 245, No. 1, 14–20 (1998), https://doi.org/10.1007/s004150050168.
Ugrumov, M. V., Khaindrava, V. G., Kozina, E. A., et al., “Modeling of presymptomatic and symptomatic stages of parkinsonism in mice,” Neuroscience, 181, 175–188 (2011), https://doi.org/10.1016/j.neuroscience.2011.03.007.
Ugrumov, M. V., Neurodegenerative Diseases – from the Genome to the Whole Body, Nauchnyi Mir, Moscow (2014), pp. 22–44.
Vazey, E. M. and Aston-Jones, G., “The emerging role of norepinephrine in cognitive dysfunctions of Parkinson’s disease,” Front. Behav. Neurosci., 6, 48 (2012), https://doi.org/10.3389/fnbeh.2012.00048.
Verhave, P. S., Jonqsma, M. J., Van den Berg, R. M., et al., “REM Sleep behavior disorder in the marmoset MPTP model of early Parkinson disease,” Sleep, 34, No. 8, 1119–1125 (2011), https://doi.org/10.5665/SLEEP.1174.
Walf, A. A. and Frye, C. A., “The use of the elevated plus maze as an assay of anxiety-related behavior in rodents,” Nat. Protoc., 2, No. 2, 322–328 (2007), https://doi.org/10.1038/nprot.2007.44.
Wall, P. M. and Messier, C., “Infralimbic kappa opioid and muscarinic M1 receptor interactions in the concurrent modulation of anxiety and memory,” Psychopharmacology (Berlin), 160, No. 3, 233–244 (2002), https://doi.org/10.1007/s00213-001-0979-9.
Weisskopf, M. G., Chen, H., Schwarzschild, M. A., et al., “Prospective study of phobic anxiety and risk of Parkinson’s disease,” Mov. Disord., 18, No. 6, 646–651 (2003), https://doi.org/10.1002/mds.10425.
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Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 69, No. 3, pp. 364–381, May–June, 2019.
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Abdurasulova, N.N., Ekimova, I.V., Chernyshev, M.V. et al. Impairment to Cognitive Functions in Wistar Rats in a Model of the Preclinical Stage of Parkinson’s Disease. Neurosci Behav Physi 50, 439–450 (2020). https://doi.org/10.1007/s11055-020-00919-w
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DOI: https://doi.org/10.1007/s11055-020-00919-w