Abstract
Behavioral analysis is a high-end read-out of aging impact on an organism, and here, we have analyzed behaviors in 4-, 22-, and 28-month-old male C57BL/6J with a broad range of tests. For comparison, a group of 28-month-old males maintained on dietary restriction (DR) was included. The most conspicuous alteration was the decline in exploration activity with advancing age. Aging also affected other behaviors such as motor skill acquisition and grip strength, in contrast to latency to thermal stimuli and visual placement which were unchanged. Object recognition tests revealed intact working memory at 28 months while memory recollection was impaired already at 22 months. Comparison with female C57BL/6J (Fahlström et al., Neurobiol Aging 32:1868–1880, 2011) revealed that alterations in aged males and females are similar and that several of the behavioral indices correlate with age in both sexes. Moreover, we examined if behavioral indices in 22-month-old males could predict remaining life span as suggested in the study by Ingram and Reynolds (Exp Aging Res 12(3):155–162, 1986) and found that exploratory activity and motor skills accounted for up to 65% of the variance. Consistent with that a high level of exploratory activity and preserved motor capacity indicated a long post-test survival, 28-month-old males maintained on DR were more successful in such tests than ad libitum fed age-matched males. In summary, aged C57BL/6J males are marked by a reduced exploratory activity, an alteration that DR impedes. In light of recently published data, we discuss if a diminishing drive to explore may associate with aging-related impairment of central aminergic pathways.
Similar content being viewed by others
References
Altun M, Bergman E, Edstrom E, Johnson H, Ulfhake B (2007) Behavioral impairments of the aging rat. Physiol Behav 92(5):911–923. doi:10.1016/j.physbeh.2007.06.017
Anderson RM, Weindruch R (2010) Metabolic reprogramming, caloric restriction and aging. Trends Endocrinol Metab 21(3):134–141. doi:10.1016/j.tem.2009.11.005
Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus–norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28:403–450. doi:10.1146/annurev.neuro.28.061604.135709
Baur JA, Chen D, Chini EN, Chua K, Cohen HY, de Cabo R, Deng C, Dimmeler S, Gius D, Guarente LP, Helfand SL, Imai S, Itoh H, Kadowaki T, Koya D, Leeuwenburgh C, McBurney M, Nabeshima Y, Neri C, Oberdoerffer P, Pestell RG, Rogina B, Sadoshima J, Sartorelli V, Serrano M, Sinclair DA, Steegborn C, Tatar M, Tissenbaum HA, Tong Q, Tsubota K, Vaquero A, Verdin E (2010) Dietary restriction: standing up for sirtuins. Science 329(5995):1012–1013. doi:10.1126/science.329.5995.1012329/5995/1012, author reply 1013–1014
Bendesky A, Tsunozaki M, Rockman MV, Kruglyak L, Bargmann CI (2011) Catecholamine receptor polymorphisms affect decision-making in C. elegans. Nature 472(7343):313–318. doi:10.1038/nature09821
Benice TS, Rizk A, Kohama S, Pfankuch T, Raber J (2006) Sex-differences in age-related cognitive decline in C57BL/6J mice associated with increased brain microtubule-associated protein 2 and synaptophysin immunoreactivity. Neuroscience 137(2):413–423
Bothe GW, Bolivar VJ, Vedder MJ, Geistfeld JG (2004) Genetic and behavioral differences among five inbred mouse strains commonly used in the production of transgenic and knockout mice. Genes Brain Behav 3(3):149–157. doi:10.1111/j.1601-183x.2004.00064.x
Bryant CD, Zhang NN, Sokoloff G, Fanselow MS, Ennes HS, Palmer AA, McRoberts JA (2008) Behavioral differences among C57BL/6 substrains: implications for transgenic and knockout studies. J Neurogenet 22(4):315–331. doi:10.1080/01677060802357388
Bucan M, Abel T (2002) The mouse: genetics meets behaviour. Nat Rev Genet 3(2):114–123. doi:10.1038/nrg728
Burger JM, Buechel SD, Kawecki TJ (2010) Dietary restriction affects lifespan but not cognitive aging in Drosophila melanogaster. Aging Cell 9(3):327–335. doi:10.1111/j.1474-9726.2010.00560.x
Carter RJ, Morton J, Dunnett SB (2001) Motor coordination and balance in rodents. Curr Protoc Neurosci Chapter 8:Unit 8 12
Chen D, Steele AD, Lindquist S, Guarente L (2005) Increase in activity during calorie restriction requires Sirt1. Science 310(5754):1641. doi:10.1126/science.1118357
Chia R, Achilli F, Festing MF, Fisher EM (2005) The origins and uses of mouse outbred stocks. Nat Genet 37(11):1181–1186. doi:10.1038/ng1665
Clifton GL, Jiang JY, Lyeth BG, Jenkins LW, Hamm RJ, Hayes RL (1991) Marked protection by moderate hypothermia after experimental traumatic brain injury. J Cerebral Blood Flow and Metabolism 11:114–121
Collier TJ, Coleman PD (1991) Divergence of biological and chronological aging: evidence from rodent studies. Neurobiol Aging 12(6):685–693
Cowen T, Ulfhake B, King RHM (2005) Aging in the peripheral nervous system. In: Dyck PJ, Thomas PK (eds) Peripheral neuropathy, vol 1. Elsevier Saunders, Philadelphia, pp 483–507
Crabbe JC, Wahlsten D, Dudek BC (1999) Genetics of mouse behavior: interactions with laboratory environment. Science 284(5420):1670–1672
Crawley JN, Belknap JK, Collins A, Crabbe JC, Frankel W, Henderson N, Hitzemann RJ, Maxson SC, Miner LL, Silva AJ, Wehner JM, Wynshaw-Boris A, Paylor R (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology (Berl) 132(2):107–124
Crawley JN, Paylor R (1997) A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm Behav 31(3):197–211
Crusio WE, Goldowitz D, Holmes A, Wolfer D (2009) Standards for the publication of mouse mutant studies. Genes Brain Behav 8(1):1–4. doi:10.1111/j.1601-183X.2008.00438.x
Dean RL III, Scozzafava J, Goas JA, Regan B, Beer B, Bartus RT (1981) Age-related differences in behavior across life span of the C57BL/6J mouse. Experimental Aging Res 7(4):427–451
Diaz Heijtz R, Scott L, Forssberg H (2004) Alteration of dopamine D1 receptor-mediated motor inhibition and stimulation during development in rats is associated with distinct patterns of c-fos mRNA expression in the frontal–striatal circuitry. Eur J Neurosci 19(4):945–956
Edstrom E, Ulfhake B (2005) Sarcopenia is not due to lack of regenerative drive in senescent skeletal muscle. Aging Cell 4(2):65–77
Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res 31(1):47–59
Espejo EF, Mir D (1993) Structure of the rat’s behaviour in the hot plate test. Behavioural Brain Res 56(2):171–176
Fahlström A, Yu Q, Ulfhake B (2011) Behavioral changes in aging female C57BL/6 mice. Neurobiol Aging 32(10):1868–1880
Fernandez SM, Lewis MC, Pechenino AS, Harburger LL, Orr PT, Gresack JE, Schafe GE, Frick KM (2008) Estradiol-induced enhancement of object memory consolidation involves hippocampal extracellular signal-regulated kinase activation and membrane-bound estrogen receptors. J Neurosci 28(35):8660–8667
Fontan-Lozano A, Saez-Cassanelli JL, Inda MC, de los Santos-Arteaga M, Sierra-Dominguez SA, Lopez-Lluch G, Delgado-Garcia JM, Carrion AM (2007) Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on NR2B subunits of the NMDA receptor. J Neurosci 27(38):10185–10195. doi:10.1523/JNEUROSCI.2757-07.2007
Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H, Sohal RS (1996) Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc Natl Acad Sci USA 93(10):4765–4769
Fox WM (1965) Reflex-ontogeny and behavioural development of the mouse. Anim Behav 13(2):234–241
Frick KM (2009) Estrogens and age-related memory decline in rodents: what have we learned and where do we go from here? Horm Behav 55(1):2–23. doi:10.1016/j.yhbeh.2008.08.015
Frick KM, Burlingame LA, Arters JA, Berger-Sweeney J (2000) Reference memory, anxiety and estrous cyclicity in C57BL/6NIA mice are affected by age and sex. Neuroscience 95(1):293–307
Goodrick CL (1967) Behavioral characteristics of young and senescent inbred female mice of the C57BL-6J strain. J Gerontol 22(4):459–464
Goodrick CL (1973) Exploration activity and emotionality of albino and pigmented mice: inheritance and effects of test illumination. J Comp Physiol Psychol 84(1):73–81
Goodrick CL (1975) Behavioral differences in young and aged mice: strain differences for activity measures, operant learning, sensory discrimination, and alcohol preference. Exp Aging Res 1(2):191–207
Guarente L, Picard F (2005) Calorie restriction—the SIR2 connection. Cell 120(4):473–482. doi:10.1016/j.cell.2005.01.029
Holloszy JO, Schechtman KB (1991) Interaction between exercise and food restriction: effects on longevity of male rats. J Appl Physiol 70(4):1529–1535
Idrobo F, Nandy K, Mostofsky DI, Blatt L, Nandy L (1987) Dietary restriction: effects on radial maze learning and lipofuscin pigment deposition in the hippocampus and frontal cortex. Arch Gerontol Geriatr 6(4):355–362
Ikeno Y, Hubbard GB, Lee S, Richardson A, Strong R, Diaz V, Nelson JF (2005) Housing density does not influence the longevity effect of calorie restriction. J Gerontol A Biol Sci Med Sci 60(12):1510–1517
Ingram DK (1988) Motor performance variability during aging in rodents assessment of reliability and validity of individual differences. Ann N Y Acad Sci 515:70–96
Ingram DK (1996) Brain-behavior linkages in aged rodent models: strategies for examining individual differences. Neurobiol Aging 17(3):497–499, discussion 500
Ingram DK, Archer JR, Harrison DE, Reynolds MA (1982) Physiological and behavioral correlates of lifespan in aged C57BL/6J mice. Exp Gerontol 17(4):295–303
Ingram DK, Jucker M (1999) Developing mouse models of aging: a consideration of strain differences in age-related behavioral and neural parameters. Neurobiol Aging 20(2):137–145
Ingram DK, London ED, Reynolds MA, Waller SB, Goodrick CL (1981) Differential effects of age on motor performance in two mouse strains. Neurobiol Aging 2(3):221–227
Ingram DK, Reynolds MA (1983) Effects of protein, dietary restriction, and exercise on survival in adult rats: a re-analysis of McCay, Maynard, Sperling, and Osgood [1941]. Exp Aging Res 9(1):41–42
Ingram DK, Reynolds MA (1986) Assessing the predictive validity of psychomotor tests as measures of biological age in mice. Exp Aging Res 12(3):155–162
Ingram DK, Reynolds MA (1987) The relationship of body weight to longevity within laboratory rodent species. Basic Life Sci 42:247–282
Irwin S, Banuazizi A, Kalsner S, Curtis A (1968) One trial learning in the mouse I. Its characteristics and modification by experimental–seasonal variables. Psychopharmacologia 12(4):286–302
Johnson H, Ulfhake B, Dagerlind A, Bennett GW, Fone KC TH (1993) The serotoninergic bulbospinal system and brainstem-spinal cord content of serotonin-, TRH-, and substance P-like immunoreactivity in the aged rat with special reference to the spinal cord motor nucleus. Synapse 15:63–89
Karl T, Pabst R, von Horsten S (2003) Behavioral phenotyping of mice in pharmacological and toxicological research. Exp Toxicol Pathol 55(1):69–83
Langerman L, Zakowski MI, Piskoun B, Grant GJ (1995) Hot plate versus tail flick: evaluation of acute tolerance to continuous morphine infusion in the rat model. J Pharmacol Toxicol Meth 34(1):23–27
Lau AA, Crawley AC, Hopwood JJ, Hemsley KM (2008) Open field locomotor activity and anxiety-related behaviors in mucopolysaccharidosis type IIIA mice. Behav Brain Res 191(1):130–136
Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berl) 92(2):180–185
Matsuo N, Takao K, Nakanishi K, Yamasaki N, Tanda K, Miyakawa T (2010) Behavioral profiles of three C57BL/6 substrains. Front Behav Neurosci 4:29. doi:10.3389/fnbeh.2010.00029
Mattson MP (2010) The impact of dietary energy intake on cognitive aging. Front Aging Neurosci 2:5. doi:10.3389/neuro.24.005.2010
McCarter RJ, Shimokawa I, Ikeno Y, Higami Y, Hubbard GB, Yu BP, McMahan CA (1997) Physical activity as a factor in the action of dietary restriction on aging: effects in Fischer 344 rats. Aging (Milano) 9(1–2):73–79
McCay CM, Crowell MF, Maynard LA (1989) The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition 5(3):155–171, discussion 172
McIlwain KL, Merriweather MY, Yuva-Paylor LA, Paylor R (2001) The use of behavioral test batteries: effects of training history. Physiol Behav 73(5):705–717
Mekada K, Abe K, Murakami A, Nakamura S, Nakata H, Moriwaki K, Obata Y, Yoshiki A (2009) Genetic differences among C57BL/6 substrains. Exp Anim 58(2):141–149
Metz GA, Schwab ME (2004) Behavioral characterization in a comprehensive mouse test battery reveals motor and sensory impairments in growth-associated protein-43 null mutant mice. Neuroscience 129(3):563–574
Minor RK, Villarreal J, McGraw M, Percival SS, Ingram DK, de Cabo R (2008) Calorie restriction alters physical performance but not cognition in two models of altered neuroendocrine signaling. Behav Brain Res 189(1):202–211. doi:10.1016/j.bbr.2007.12.030
Moldin SO, Farmer ME, Chin HR, Battey JF Jr (2001) Trans-NIH neuroscience initiatives on mouse phenotyping and mutagenesis. Mamm Genome 12(8):575–581
Montgomery KC (1958) The relation between fear induced by novel stimulation and exploratory behavior. J Comp Physiol Psychol 4(8):254–260
Paigen K, Eppig JT (2000) A mouse phenome project. Mamm Genome 11(9):715–717. doi:10.1007/s003350010152
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14(3):149–167
Rogers DC, Fisher EM, Brown SD, Peters J, Hunter AJ, Martin JE (1997) Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm Genome 8(10):711–713
Rogers DC, Jones DN, Nelson PR, Jones CM, Quilter CA, Robinson TL, Hagan JJ (1999) Use of SHIRPA and discriminant analysis to characterise marked differences in the behavioural phenotype of six inbred mouse strains. Behav Brain Res 105(2):207–217
Southwick CH, Clark LH (1968) Interstrain differences in aggressive behavior and explorative activity of inbred mice. Communications in Behavioral Biology, Part A, 1, 49–59.
Sprott RL, Eleftheriou BE (1974) Open-field behavior in aging inbred mice. Gerontologia 20(3):155–162
Stunkard AJ (1983) Nutrition, aging and obesity: a critical review of a complex relationship. Int J Obes 7(3):201–220
Swindell WR, Harper JM, Miller RA (2008) How long will my mouse live? Machine learning approaches for prediction of mouse life span. J Gerontol A Biol Sci Med Sci 63(9):895–906
Taft RA, Davisson M, Wiles MV (2006) Know thy mouse. Trends Genet 22(12):649–653. doi:10.1016/j.tig.2006.09.010
Thompson WR (1953) The inheritance of behaviour: behavioural differences in fifteen mouse strains. Can J Psychol 7(4):145–155
Ulfhake B, Bergman E, Fundin BT (2002) Impairment of peripheral sensory innervation in senescence. Auton Neurosci 96(1):43–49
Wahlsten D, Metten P, Phillips TJ, Boehm SL 2nd, Burkhart-Kasch S, Dorow J, Doerksen S, Downing C, Fogarty J, Rodd-Henricks K, Hen R, McKinnon CS, Merrill CM, Nolte C, Schalomon M, Schlumbohm JP, Sibert JR, Wenger CD, Dudek BC, Crabbe JC (2003) Different data from different labs: lessons from studies of gene–environment interaction. J Neurobiol 54(1):283–311. doi:10.1002/neu.10173
Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2):322–328
Van Loo PL, Van Zutphen LF, Baumans V (2003) Male management: coping with aggression problems in male laboratory mice. Lab Anim 37(4):300–313. doi:10.1258/002367703322389870
van Luijtelaar MG, Steinbusch HW, Tonnaer JA (1988) Aberrant morphology of serotonergic fibers in the forebrain of the aged rat. Neurosci Lett 95(1–3):93–96
Wax TM, Goodrick CL (1978) Nearness to death and wheelrunning behavior in mice. Exp Gerontol 13(3–4):233–236
Weed JL, Lane MA, Roth GS, Speer DL, Ingram DK (1997) Activity measures in rhesus monkeys on long-term calorie restriction. Physiol Behav 62(1):97–103
Acknowledgments
The use of laboratory animals was under the ethical permits N253/08 and N120/09 (to B. Ulfhake). The work was supported by grants from The Swedish Research Council (VR to B. Ulfhake).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary materials
Below is the link to the electronic supplementary material.
ESM. 1
(DOC 3628 kb)
About this article
Cite this article
Fahlström, A., Zeberg, H. & Ulfhake, B. Changes in behaviors of male C57BL/6J mice across adult life span and effects of dietary restriction. AGE 34, 1435–1452 (2012). https://doi.org/10.1007/s11357-011-9320-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-011-9320-7