Background: The zebrafish has become an established model organism in aging research giving insight into general aging processes in vertebrates. Oxidative stress in aging may damage proteins and lipids in brain cells. Enhanced levels of oxidized macromolecules exert neurotoxic effects that could lead to disturbances in neuronal functioning and cognitive skills. Objective: This study aims to investigate a possible relation between oxidative stress and learning deficits during aging in zebrafish. Methods: We tested zebrafish of different ages in a color discrimination paradigm for associative learning and in a hole board task for spatial learning abilities. Afterwards, we determined the levels of oxidized lipids and proteins as well as the amount of lipofuscin in the learning-relevant brain regions of animals of the same age. Results: While young zebrafish at the age of 1 year successfully completed both learning tasks, cognitive abilities were significantly impaired in older animals. Learning deficits occurred at the age of 2 years, where we also detected significantly increased levels of lipofuscin and oxidized proteins in the zebrafish medial and lateral pallial areas of the dorsal telencephalon. Conclusion: These data suggest that enhanced oxidative stress may contribute to behavioral and cognitive impairments in the aging zebrafish.

1.
Schaie KW: Adult cognitive development from a lifespan developmental perspective; in Annual Report of Meiso University. Tokyo, Meiso University, 2010, vol 28, pp 21-36.
2.
Yu L, Tucci V, Kishi S, Zhdanova IV: Cognitive aging in zebrafish. PLoS One 2006;1:e14.
3.
Sohal RS, Weindruch R: Oxidative stress, caloric restriction, and aging. Science 1996;273:59-63.
4.
Reznick D, Ghalambor C, Nunney L: The evolution of senescence in fish. Mech Ageing Dev 2002;123:773-789.
5.
Kelly KA, Havrilla CM, Brady TC, Abramo KH, Levin ED: Oxidative stress in toxicology: established mammalian and emerging piscine model systems. Environ Health Perspect 1998;106:375-384.
6.
Carvan MJ 3rd, Sonntag DM, Cmar CB, Cook RS, Curran MA, Miller GL: Oxidative stress in zebrafish cells: potential utility of transgenic zebrafish as a deployable sentinel for site hazard ranking. Sci Total Environ 2001;274:183-196.
7.
Gerhard GS, Cheng KC: A call to fins! Zebrafish as a gerontological model. Aging Cell 2002;1:104-111.
8.
Seehafer SS, Pearce DA: You say lipofuscin, we say ceroid: defining autofluorescent storage material. Neurobiol Aging 2006;27:576-588.
9.
Kishi S, Bayliss PE, Uchiyama J, Koshimizu E, Qi J, Nanjappa P, Imamura S, Islam A, Neuberg D, Amsterdam A, Roberts TM: The identification of zebrafish mutants showing alterations in senescence-associated biomarkers. PLoS Genet 2008;4:e1000152.
10.
Kishi S, Slack BE, Uchiyama J, Zhdanova IV: Zebrafish as a genetic model in biological and behavioral gerontology: where development meets aging in vertebrates - a mini-review. Gerontology 2009;55:430-441.
11.
Salas C, Broglio C, Duran E, Gomez A, Ocana FM, Jimenez-Moya F, Rodriguez F: Neuropsychology of learning and memory in teleost fish. Zebrafish 2006;3:157-171.
12.
Arthur D, Levin ED: Spatial and non-spatial discrimination learning in zebrafish (Danio rerio). Anim Cogn 2001;4:125-131.
13.
Colwill RM, Raymond MP, Ferreira L, Escudero H: Visual discrimination learning in zebrafish (Danio rerio). Behav Processes 2005;70:19-31.
14.
Portavella M, Torres B, Salas C, Papini MR: Lesions of the medial pallium, but not of the lateral pallium, disrupt spaced-trial avoidance learning in goldfish (Carassius auratus). Neurosci Lett 2004;362:75-78.
15.
Duran E, Ocana FM, Broglio C, Rodriguez F, Salas C: Lateral but not medial telencephalic pallium ablation impairs the use of goldfish spatial allocentric strategies in a ‘hole-board' task. Behav Brain Res 2010;214:480-487.
16.
Vargas JP, Lopez JC, Portavella M: What are the functions of fish brain pallium? Brain Res Bull 2009;79:436-440.
17.
Wullimann MF, Mueller T: Teleostean and mammalian forebrains contrasted: evidence from genes to behavior. J Comp Neurol 2004;475:143-162.
18.
Ruhl T, Prinz N, Oellers N, Seidel NI, Jonas A, Albayram O, Bilkei-Gorzo A, von der Emde G: Acute administration of THC impairs spatial but not associative memory function in zebrafish. Psychopharmacology (Berl) 2014;231:3829-3842.
19.
Gellermann LW: Chance orders of alternating stimuli in visual discrimination experiments. J Genet Psychol 1933;42:206-208.
20.
Li L, Dowling JE: A dominant form of inherited retinal degeneration caused by a non-photoreceptor cell-specific mutation. Proc Natl Acad Sci USA 1997;94:11645-11650.
21.
Wullimann MF, Rupp B, Reichert H: Neuroanatomy of the Zebrafish Brain. A Topological Atlas. Basel, Birkhäuser, 1996.
22.
Bruce AJ, Baudry M: Oxygen free radicals in rat limbic structures after kainate-induced seizures. Free Radic Biol Med 1995;18:993-1002.
23.
Levine RL, Williams JA, Stadtman ER, Shacter E: Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol 1994;233:346-357.
24.
Barnes CA: Aging and the physiology of spatial memory. Neurobiol Aging 1988;9:563-568.
25.
Rapp PR, Kansky MT, Roberts JA: Impaired spatial information processing in aged monkeys with preserved recognition memory. Neuroreport 1997;8:1923-1928.
26.
Foster TC, Defazio RA, Bizon JL: Characterizing cognitive aging of spatial and contextual memory in animal models. Front Aging Neurosci 2012;4:12.
27.
Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous DN: Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci USA 2003;100:14385-14390.
28.
Fordyce DE, Wehner JM: Effects of aging on spatial learning and hippocampal protein kinase C in mice. Neurobiol Aging 1993;14:309-317.
29.
Frick KM, Fernandez SM: Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice. Neurobiol Aging 2003;24:615-626.
30.
Begega A, Cienfuegos S, Rubio S, Santin JL, Miranda R, Arias JL: Effects of ageing on allocentric and egocentric spatial strategies in the Wistar rat. Behav Processes 2001;53:75-85.
31.
Milgram NW, Head E, Muggenburg B, Holowachuk D, Murphey H, Estrada J, Ikeda-Douglas CJ, Zicker SC, Cotman CW: Landmark discrimination learning in the dog: effects of age, an antioxidant fortified food, and cognitive strategy. Neurosci Biobehav Rev 2002;26:679-695.
32.
Rodgers MK, Sindone JA 3rd, Moffat SD: Effects of age on navigation strategy. Neurobiol Aging 2012;33:202.e15-e22.
33.
Gilbert MJ, Zerulla TC, Tierney KB: Zebrafish (Danio rerio) as a model for the study of aging and exercise: physical ability and trainability decrease with age. Exp Gerontol 2014;50:106-113.
34.
Pakkenberg B, Pelvig D, Marner L, Bundgaard MJ, Gundersen HJ, Nyengaard JR, Regeur L: Aging and the human neocortex. Exp Gerontol 2003;38:95-99.
35.
Woodhead AD, Pond V: Aging changes in the optic tectum of the guppy Poecilia (lebistes) reticulatus. Exp Gerontol 1984;19:305-311.
36.
Double KL, Reyes S, Werry EL, Halliday GM: Selective cell death in neurodegeneration: why are some neurons spared in vulnerable regions? Prog Neurobiol 2010;92:316-329.
37.
West MJ: Regionally specific loss of neurons in the aging human hippocampus. Neurobiol Aging 1993;14:287-293.
38.
Calhoun ME, Kurth D, Phinney AL, Long JM, Hengemihle J, Mouton PR, Ingram DK, Jucker M: Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL/6 mice. Neurobiol Aging 1998;19:599-606.
39.
Rapp PR, Gallagher M: Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci USA 1996;93:9926-9930.
40.
Burke SN, Barnes CA: Neural plasticity in the ageing brain. Nat Rev Neurosci 2006;7:30-40.
41.
Poe BH, Linville C, Riddle DR, Sonntag WE, Brunso-Bechtold JK: Effects of age and insulin-like growth factor-1 on neuron and synapse numbers in area CA3 of hippocampus. Neuroscience 2001;107:231-238.
42.
Shi L, Adams MM, Linville MC, Newton IG, Forbes ME, Long AB, Riddle DR, Brunso-Bechtold JK: Caloric restriction eliminates the aging-related decline in NMDA and AMPA receptor subunits in the rat hippocampus and induces homeostasis. Exp Neurol 2007;206:70-79.
43.
Newton IG, Forbes ME, Linville MC, Pang H, Tucker EW, Riddle DR, Brunso-Bechtold JK: Effects of aging and caloric restriction on dentate gyrus synapses and glutamate receptor subunits. Neurobiol Aging 2008;29:1308-1318.
44.
Smith TD, Adams MM, Gallagher M, Morrison JH, Rapp PR: Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J Neurosci 2000;20:6587-6593.
45.
Adams MM, Shi L, Linville MC, Forbes ME, Long AB, Bennett C, Newton IG, Carter CS, Sonntag WE, Riddle DR, Brunso-Bechtold JK: Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability. Exp Neurol 2008;211:141-149.
46.
Winston GW: Oxidants and antioxidants in aquatic animals. Comp Biochem Physiol C 1991;100:173-176.
47.
Malek RL, Sajadi H, Abraham J, Grundy MA, Gerhard GS: The effects of temperature reduction on gene expression and oxidative stress in skeletal muscle from adult zebrafish. Comp Biochem Physiol C Toxicol Pharmacol 2004;138:363-373.
48.
Mueller T: What is the thalamus in zebrafish? Front Neurosci 2012;6:64.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.