Studying the Impact of Aging on Memory Systems: Contribution of Two Behavioral Models in the Mouse

  • Aline MarighettoEmail author
  • Laurent Brayda-Bruno
  • Nicole Etchamendy
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 10)


In the present chapter, we describe our own attempts to improve our understanding of the pathophysiology of memory in aging. First, we tried to improve animal models of memory degradations occurring in aging, and develop common behavioral tools between mice and humans. Second, we began to use these behavioral tools to identify the molecular/intracellular changes occurring within the integrate network of memory systems in order to bridge the gap between the molecular and system level of analysis. The chapter is divided into three parts (i) modeling aging-related degradation in declarative memory (DM) in mice, (ii) assessing the main components of working memory (WM) with a common radial-maze task in mice and humans and (iii) studying the role of the retinoid cellular signaling path in aging-related changes in memory systems.


Declarative memory Working memory Mouse Human Fos imaging 


  1. Addis DR, McAndrews MP (2006) Prefrontal and hippocampal contributions to the generation and binding of semantic associations during successful encoding. Neuroimage 33:1194–1206PubMedCrossRefGoogle Scholar
  2. Baddeley A (1996) The fractionation of working memory. Proc Natl Acad Sci U S A 93:13468–13472PubMedCrossRefGoogle Scholar
  3. Baddeley A, Cocchini G, Della Sala S, Logie RH, Spinnler H (1999) Working memory and vigilance: evidence from normal aging and Alzheimer’s disease. Brain Cogn 41:87–108PubMedCrossRefGoogle Scholar
  4. Blomhoff R, Blomhoff HK (2006) Overview of retinoid metabolism and function. J Neurobiol 66:606–630PubMedCrossRefGoogle Scholar
  5. Blumenfeld RS, Ranganath C (2006) Dorsolateral prefrontal cortex promotes long-term memory formation through its role in working memory organization. J Neurosci 26:916–925PubMedCrossRefGoogle Scholar
  6. Bohbot VD, Lerch J, Thorndycraft B, Iaria G, Zijdenbos AP (2007) Gray matter differences correlate with spontaneous strategies in a human virtual navigation task. J Neurosci 27:10078–10083PubMedCrossRefGoogle Scholar
  7. Bonnet E et al (2008) Retinoic acid restores adult hippocampal neurogenesis and reverses spatial memory deficit in vitamin A deprived rats. PLoS One 3: e3487Google Scholar
  8. Brassen S, Weber-Fahr W, Sommer T, Lehmbeck JT, Braus DF (2006) Hippocampal-prefrontal encoding activation predicts whether words can be successfully recalled or only recognized. Behav Brain Res 171:271–278PubMedCrossRefGoogle Scholar
  9. Brouillette J, Quirion R (2008a) Transthyretin: a key gene involved in the maintenance of memory capacities during aging. Neurobiol Aging 29:1721–1732PubMedCrossRefGoogle Scholar
  10. Brouillette J, Quirion R (2008b) The common environmental pollutant dioxin-induced memory deficits by altering estrogen pathways and a major route of retinol transport involving transthyretin. Neurotoxicology 29:318–327PubMedCrossRefGoogle Scholar
  11. Burke SN, Barnes CA (2010) Senescent synapses and hippocampal circuit dynamics. Trends Neurosci 33:153–161Google Scholar
  12. Bunge SA, Klingberg T, Jacobsen RB, Gabrieli JDA (2000) A resource model of the neural basis of executive working memory. Proc Natl Acad Sci U S A 97:3573–3578PubMedCrossRefGoogle Scholar
  13. Burke SN, Barnes CA (2006) Neural plasticity in the ageing brain. Nat Rev Neurosci 7:30–40PubMedCrossRefGoogle Scholar
  14. Chalfonte BL, Johnson MK (1996) Feature memory and binding in young and older adults. Mem Cognit 24:403–416PubMedCrossRefGoogle Scholar
  15. Chiang MY et al (1998) An essential role for retinoid receptors RARbeta and RXRgamma in long-term potentiation and depression. Neuron 21:1353–1361PubMedCrossRefGoogle Scholar
  16. Cocco S et al (2002) Vitamin A deficiency produces spatial learning and memory impairment in rats. Neuroscience 115:475–482PubMedCrossRefGoogle Scholar
  17. Cohen NJ, Poldrack RA, Eichenbaum H (1997) Memory for items and memory for relations in the procedural/declarative memory framework. Memory 5:131–178PubMedCrossRefGoogle Scholar
  18. Cohen NJ et al (1999) Hippocampal system and declarative (relational) memory: summarizing the data from functional neuroimaging studies. Hippocampus 9:83–98PubMedCrossRefGoogle Scholar
  19. Corcoran JP, So PL, Maden M (2004) Disruption of the retinoid signalling pathway causes a deposition of amyloid beta in the adult rat brain. Eur J Neurosci 20:896–902PubMedCrossRefGoogle Scholar
  20. Craik FI (1990) Changes in memory with normal aging: a functional view. Adv Neurol 51:201–205PubMedGoogle Scholar
  21. Crandall J et al (2004) 13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice. Proc Natl Acad Sci U S A 101:5111–5116PubMedCrossRefGoogle Scholar
  22. Davachi L, Wagner AD (2002) Hippocampal contributions to episodic encoding: insights from relational and item-based learning. J Neurophysiol 88:982–990PubMedGoogle Scholar
  23. Ding Y et al (2008) Retinoic acid attenuates beta-amyloid deposition and rescues memory deficits in an Alzheimer’s disease transgenic mouse model. J Neurosci 28:11622–11634PubMedCrossRefGoogle Scholar
  24. Dunnett SB, Martel FL, Iversen SD (1990) Proactive interference effects on short-term memory in rats: II. Effects in young and aged rats. Behav Neurosci 104:666–670PubMedCrossRefGoogle Scholar
  25. Eichenbaum H, Fagan A, Mathews P, Cohen NJ (1988) Hippocampal system dysfunction and odor discrimination learning in rats: impairment or facilitation depending on representational demands. Behav Neurosci 102:331–339PubMedCrossRefGoogle Scholar
  26. Eichenbaum H, Mathews P, Cohen NJ (1989) Further studies of hippocampal representation during odor discrimination learning. Behav Neurosci 103:1207–1216PubMedCrossRefGoogle Scholar
  27. Eichenbaum H, Otto T, Cohen NJ (1992) The hippocampus–what does it do? Behav Neural Biol 57:2–36PubMedCrossRefGoogle Scholar
  28. Enderlin V et al (1997) Age-related decreases in mRNA for brain nuclear receptors and target genes are reversed by retinoic acid treatment. Neurosci Lett 229:125–129PubMedCrossRefGoogle Scholar
  29. Etchamendy N et al (2001) Alleviation of a selective age-related relational memory deficit in mice by pharmacologically induced normalization of brain retinoid signaling. J Neurosci 21:6423–6429PubMedGoogle Scholar
  30. Etchamendy N, Desmedt A, Cortes-Torrea C, Marighetto A, Jaffard R (2003a) Hippocampal lesions and discrimination performance of mice in the radial maze: sparing or impairment depending on the representational demands of the task. Hippocampus 13:197–211PubMedCrossRefGoogle Scholar
  31. Etchamendy N et al (2003b) Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling. Behav Brain Res 145:37–49PubMedCrossRefGoogle Scholar
  32. Etchamendy N, Konishi K, Pike GB, Marighetto A, Bohbot VD (2011) Evidence for a virtual human analog of a rodent relational memory task: a study of aging and fMRI in young adults. Hippocampus. Jun 8.  doi:10.1002/hipo.20948
  33. Flicker C, Ferris SH, Crook T, Bartus RT (1989) Age differences in the vulnerability of facial recognition memory to proactive interference. Exp Aging Res 15:189–194PubMedCrossRefGoogle Scholar
  34. Friedman D, Nessler D, Johnson R Jr (2007) Memory encoding and retrieval in the aging brain. Clin EEG Neurosci 38:2–7PubMedCrossRefGoogle Scholar
  35. Gabrieli JD (1996) Memory systems analyses of mnemonic disorders in aging and age-related diseases. Proc Natl Acad Sci U S A 93:13534–13540PubMedCrossRefGoogle Scholar
  36. Goodman AB (1998) Three independent lines of evidence suggest retinoids as causal to schizophrenia. Proc Natl Acad Sci U S A 95:7240–7244PubMedCrossRefGoogle Scholar
  37. Goodman AB (2006) Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease. J Cell Physiol 209:598–603PubMedCrossRefGoogle Scholar
  38. Goodman AB, Pardee AB (2003) Evidence for defective retinoid transport and function in late onset Alzheimer’s disease. Proc Natl Acad Sci U S A 100:2901–2905PubMedCrossRefGoogle Scholar
  39. Grady CL (2008) Cognitive neuroscience of aging. Ann NY Acad Sci 1124:127–144PubMedCrossRefGoogle Scholar
  40. Grady CL, Craik FI (2000) Changes in memory processing with age. Curr Opin Neurobiol 10:224–231PubMedCrossRefGoogle Scholar
  41. Grady CL, McIntosh AR, Rajah MN, Beig S, Craik FI (1999) The effects of age on the neural correlates of episodic encoding. Cereb Cortex 9:805–814PubMedCrossRefGoogle Scholar
  42. Hannula DE, Ranganath C (2008) Medial temporal lobe activity predicts successful relational memory binding. J Neurosci 28:116–124PubMedCrossRefGoogle Scholar
  43. Hannula DE, Tranel D, Cohen NJ (2006) The long and the short of it: relational memory impairments in amnesia, even at short lags. J Neurosci 26:8352–8359PubMedCrossRefGoogle Scholar
  44. Jinno S (2011) Decline in adult neurogenesis during aging follows a topographic pattern in the mouse hippocampus. J Comp Neurol 519:451–466Google Scholar
  45. Jonides J et al (2008) The mind and brain of short-term memory. Annu Rev Psychol 59:193–224PubMedCrossRefGoogle Scholar
  46. Kastner P, Mark M, Chambon P (1995) Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83:859–869PubMedCrossRefGoogle Scholar
  47. Krezel W, Kastner P, Chambon P (1999) Differential expression of retinoid receptors in the adult mouse central nervous system. Neuroscience 89:1291–1300PubMedCrossRefGoogle Scholar
  48. Kumaran D (2008) Short-term memory and the human hippocampus. J Neurosci 28:3837–3838PubMedCrossRefGoogle Scholar
  49. Lane MA, Bailey SJ (2005) Role of retinoid signalling in the adult brain. Prog Neurobiol 75:275–293PubMedCrossRefGoogle Scholar
  50. Lee HP et al (2009) All-trans retinoic acid as a novel therapeutic strategy for Alzheimer’s disease. Expert Rev Neurother 9:1615–1621PubMedCrossRefGoogle Scholar
  51. Lefebvre P et al (2005) Transcriptional activities of retinoic acid receptors. Vitam Horm 70:199–264PubMedCrossRefGoogle Scholar
  52. Lund PK et al (2004) Transcriptional mechanisms of hippocampal aging. Exp Gerontol 39:1613–1622PubMedCrossRefGoogle Scholar
  53. Maden M, Sonneveld E, van der Saag PT, Gale E (1998a) The distribution of endogenous retinoic acid in the chick embryo: implications for developmental mechanisms. Development 125:4133–4144PubMedGoogle Scholar
  54. Maden M, Gale E, Zile M (1998b) The role of vitamin A in the development of the central nervous system. J Nutr 128:471S–475SPubMedGoogle Scholar
  55. Malik MA, Blusztajn JK, Greenwood CE (2000) Nutrients as trophic factors in neurons and the central nervous system: role of retinoic acid. J Nutr Biochem 11:2–13PubMedCrossRefGoogle Scholar
  56. Mangelsdorf DJ et al (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839PubMedCrossRefGoogle Scholar
  57. Marighetto A et al (1999) Knowing which and knowing what: a potential mouse model for age-related human declarative memory decline. Eur J Neurosci 11:3312–3322PubMedCrossRefGoogle Scholar
  58. Marighetto A et al (2000) Further evidence for a dissociation between different forms of mnemonic expressions in a mouse model of age-related cognitive decline: effects of tacrine and S 17092, a novel prolyl endopeptidase inhibitor. Learn Mem 7:159–169PubMedCrossRefGoogle Scholar
  59. Marighetto A et al (2008a) The AMPA modulator S 18986 improves declarative and working memory performances in aged mice. Behav Pharmacol 19:235–244PubMedCrossRefGoogle Scholar
  60. Marighetto A et al (2008b) Comparative effects of the dopaminergic agonists piribedil and bromocriptine in three different memory paradigms in rodents. J Psychopharmacol 22:511–521PubMedCrossRefGoogle Scholar
  61. Marighetto A et al (2008c) Comparative effects of the alpha7 nicotinic partial agonist, S 24795, and the cholinesterase inhibitor, donepezil, against aging-related deficits in declarative and working memory in mice. Psychopharmacology (Berl) 197:499–508CrossRefGoogle Scholar
  62. Marill J, Idres N, Capron CC, Nguyen E, Chabot GG (2003) Retinoic acid metabolism and mechanism of action: a review. Curr Drug Metab 4:1–10PubMedCrossRefGoogle Scholar
  63. McCaffery P, Zhang J, Crandall JE (2006) Retinoic acid signaling and function in the adult hippocampus. J Neurobiol 66:780–791PubMedCrossRefGoogle Scholar
  64. Mey J, McCaffery P (2004) Retinoic acid signaling in the nervous system of adult vertebrates. Neuroscientist 10:409–421PubMedCrossRefGoogle Scholar
  65. Mingaud F et al (2007) The hippocampus plays a critical role at encoding discontiguous events for subsequent declarative memory expression in mice. Hippocampus 17:264–270PubMedCrossRefGoogle Scholar
  66. Mingaud F et al (2008) Retinoid hyposignaling contributes to aging-related decline in hippocampal function in short-term/working memory organization and long-term declarative memory encoding in mice. J Neurosci 28:279–291PubMedCrossRefGoogle Scholar
  67. Misner DL et al (2001) Vitamin A deprivation results in reversible loss of hippocampal long-term synaptic plasticity. Proc Natl Acad Sci U S A 98:11714–11719PubMedCrossRefGoogle Scholar
  68. Mitchell KJ, Johnson MK, Raye CL, Mather M, D’Esposito M (2000a) Aging and reflective processes of working memory: binding and test load deficits. Psychol Aging 15:527–541PubMedCrossRefGoogle Scholar
  69. Mitchell KJ, Johnson MK, Raye CL, D’Esposito M (2000b) fMRI evidence of age-related hippocampal dysfunction in feature binding in working memory. Brain Res Cogn Brain Res 10:197–206PubMedCrossRefGoogle Scholar
  70. Mitchell KJ, Johnson MK, Raye CL, Greene EJ (2004) Prefrontal cortex activity associated with source monitoring in a working memory task. J Cogn Neurosci 16:921–934PubMedCrossRefGoogle Scholar
  71. Morcom AM, Good CD, Frackowiak RS, Rugg MD (2003) Age effects on the neural correlates of successful memory encoding. Brain 126:213–229PubMedCrossRefGoogle Scholar
  72. Narayanan NS et al (2005) The role of the prefrontal cortex in the maintenance of verbal working memory: an event-related FMRI analysis. Neuropsychology 19:223–232PubMedCrossRefGoogle Scholar
  73. Olson IR, Page K, Moore KS, Chatterjee A, Verfaellie M (2006) Working memory for conjunctions relies on the medial temporal lobe. J Neurosci 26:4596–4601PubMedCrossRefGoogle Scholar
  74. Palha JA, Goodman AB (2006) Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia. Brain Res Rev 51:61–71PubMedCrossRefGoogle Scholar
  75. Poldrack RA, Packard MG (2003) Competition among multiple memory systems: converging evidence from animal and human brain studies. Neuropsychologia 41:245–251PubMedCrossRefGoogle Scholar
  76. Quinette P et al (2006) The relationship between working memory and episodic memory disorders in transient global amnesia. Neuropsychologia 44:2508–2519PubMedCrossRefGoogle Scholar
  77. Rabinowitz JC, Ackerman BP, Craik FI, Hinchley JL (1982) Aging and metamemory: the roles of relatedness and imagery. J Gerontol 37:688–695PubMedCrossRefGoogle Scholar
  78. Ranganath C, Blumenfeld RS (2005) Doubts about double dissociations between short- and long-term memory. Trends Cogn Sci 9:374–380PubMedCrossRefGoogle Scholar
  79. Repovs G, Baddeley A (2006) The multi-component model of working memory: explorations in experimental cognitive psychology. Neuroscience 139:5–21PubMedCrossRefGoogle Scholar
  80. Ruano D et al (2008) Association of the gene encoding neurogranin with schizophrenia in males. J Psychiatr Res 42:125–133PubMedCrossRefGoogle Scholar
  81. Rypma B, Prabhakaran V, Desmond JE, Gabrieli JD (2001) Age differences in prefrontal cortical activity in working memory. Psychol Aging 16:371–384PubMedCrossRefGoogle Scholar
  82. Sadeh T, Shohamy D, Levy DR, Reggev N, Maril A (2011) Cooperation between the hippocampus and the striatum during episodic encoding. J Cogn Neurosci 23(7):1597–1608 [Epub 28 Jul 2010]PubMedCrossRefGoogle Scholar
  83. Sakai Y, Crandall JE, Brodsky J, McCaffery P (2004) 13-cis Retinoic acid (accutane) suppresses hippocampal cell survival in mice. Ann N Y Acad Sci 1021:436–440PubMedCrossRefGoogle Scholar
  84. Salthouse TA, Mitchell DR, Skovronek E, Babcock RL (1989) Effects of adult age and working memory on reasoning and spatial abilities. J Exp Psychol Learn Mem Cogn 15:507–516PubMedCrossRefGoogle Scholar
  85. Saxe MD et al (2007) Paradoxical influence of hippocampal neurogenesis on working memory. Proc Natl Acad Sci U S A 104:4642–4646PubMedCrossRefGoogle Scholar
  86. Schmidtke K, Manner H, Kaufmann R, Schmolck H (2002) Cognitive procedural learning in patients with fronto-striatal lesions. Learn Mem 9:419–429PubMedCrossRefGoogle Scholar
  87. Shrager Y, Levy DA, Hopkins RO, Squire LR (2008) Working memory and the organization of brain systems. J Neurosci 28:4818–4822PubMedCrossRefGoogle Scholar
  88. Squire LR (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99:195–231PubMedCrossRefGoogle Scholar
  89. Squire LR, Zola SM (1996) Structure and function of declarative and nondeclarative memory systems. Proc Natl Acad Sci U S A 93:13515–13522PubMedCrossRefGoogle Scholar
  90. Takashima A et al (2006) Successful declarative memory formation is associated with ongoing activity during encoding in a distributed neocortical network related to working memory: a magnetoencephalography study. Neuroscience 139:291–297PubMedCrossRefGoogle Scholar
  91. Wietrzych M et al (2005) Working memory deficits in retinoid X receptor gamma-deficient mice. Learn Mem 12:318–326PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Aline Marighetto
    • 1
    Email author
  • Laurent Brayda-Bruno
    • 1
  • Nicole Etchamendy
    • 2
  1. 1.Neurocentre Magendie-Inserm U862Bordeaux-CedexFrance
  2. 2.NutriNeuro Bordeaux UniversityTalenceFrance

Personalised recommendations