Age-related Deficits in Recognition Memory are Protocol-Dependent
Diano F. Marrone1,2,*, Elham Satvat3, Anuj Patel1
1Dept. of Psychology, Wilfrid Laurier University, Waterloo, ON N2L 3C5, Canada 2McKnight Brain Institute, University of Arizona, Tucson, AZ 85724, USA, 3School of Public Health & Health Systems, University of Waterloo, Waterloo, ON N2L 3G1, Canada
The perirhinal cortex (PRh) is a critical mediator of recognition memory, and a wealth of evidence points to impairment in PRh function with age. Despite this evidence, age-related deficits in recognition memory are not consistently observed. This may be partially due to the fact that older animals also have well-established deficits in hippocampal function, and many protocols that assess perirhinal function are also sensitive to hippocampal damage. When using one of these protocols, spontaneous object recognition in an open field, we are able to replicate published age-related deficits using pairs of complex objects. However, when using zero-delay object recognition, a task that is more resistant to the influence of changes in hippocampal function, we find no significant age-related differences in recognition memory in the same animals. These data highlight the importance of the protocol used for testing recognition memory, and may place constraints on the role of the PRh in age-related recognition memory impairment as it is typically tested in much of the literature.
Table 1 Mean object exploration time across all conditions
Figure 1. Changes in testing protocol determine the presence of age-related recognition memory deficits
Examples of object pairs used are shown (A). All objects were junk items purchased from local stores and included dog toys, children’s toys, and small household decorative items such as candlesticks. The procedures (B) for zero-delay object recognition (ZOR, left) and spontaneous object recognition (SOR, right) are depicted. In ZOR, sample trial 1 consists of 2 identical pairs of objects pairs (AB) presented in each arm of a y-maze that remained until the animal had explored one of the objects for at least 25 sec. After this criterion is met, barriers are removed to reveal a new identical pair of objects (CD). Once the rat explored one of these objects for at least 25 sec, the second barrier was removed to reveal a familiar (AB) object and a novel pair of two unique objects (EF, easy condition), or a novel combination of previously seen objects (AC, hard). The SOR task uses similar methodology in an open field. In SOR, sample trial 1 consists of 2 identical pairs of objects (GH) presented within an open field until the animal had explored one of the objects for at least 25 sec. The rat was then removed from the open field for 120 sec, while a new identical pair of object was placed in the field (IJ). The rat returned to the field for sample trial 2 until it explored one of the objects for at least 25 sec. After a 120 sec delay, rats were then tested with a familiar (GH) object and a novel pair of two unique objects (KL, easy condition), or a novel combination of previously seen objects (HI, hard). Quantitative analyses of the ZOR (C) and SOR (D) reveal different effects obtained from these protocols. While 6-month-old (white bars) and 12-month-old (light grey) animals generally perform well under all conditions, 24-month old animals (dark grey) show recognition memory deficits only in SOR, while their performance in ZOR is relatively intact (data are mean ± SEM, * = p < 0.05 vs 12 months, ‡ = p < 0.05 vs. 24 months, § = p <0.05 vs. easy trials in the same age group).
Analysis of path lengths (A) in the Morris water maze (MWM) shows that when the platform was hidden, 6-month-old rats (white diamonds) swam shorter paths to reach the hidden platform than either 12-month-old (light gray square) 24-month-old (dark gray triangle) rats by day 2 of training. By day 4, 12-month-old rats also outperformed 24-month old ones. During trials in which the platform was visible (B), all 3 age groups had significantly different path lengths on day one, and this difference became much smaller by day 2 such that only 6-month-old and 24-month-old rats shows a significant difference. During the probe trial (C), both 6-month-old (white) and 12-month-old (light grey) rats spent significantly more time than aged rats (dark grey) in the quadrant that previously held the platform (target) than the opposite quadrant. Regression shows that spatial memory performance does not predict the performance of individual animals in zero-delay object recognition (ZOR, D). However, spatial memory significantly predicts SOR performance (E) in individual animals (all data are mean ± SEM; * = p < 0.05, 12 vs 24-moth-old; † = p < 0.05, 6-month-old vs 24-month-old; ‡ = p < 0.05, 6-month-old and 24-month-old; § p < 0.05, vs opposite quadrant in the same age group).
Ennaceur A, Delacour J (1988). A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res, 31: 47-59.
Willig F, Palacios A, Monmaur P, M’Harzi M, Laurent J, Delacour J (1987). Short-term memory, exploration and locomotor activity in aged rats. Neurobiol Aging, 8: 393-402.
Bartolini L, Casamenti F, Pepeu G (1996). Aniracetam restores object recognition impaired by age, scopolamine, and nucleus basalis lesions. Pharmacol Biochem Behav, 53: 277-283.
Da Silva Costa-Aze V, Dauphin F, Boulouard M (2011). Serotonin 5-HT6 receptor blockade reverses the age-related deficits of recognition memory and working memory in mice. Behav Brain Res, 222: 134-140.
Vannucchi MG, Scali C, Kopf SR, Pepeu G, Casamenti F (1997). Selective muscarinic antagonists differentially affect in vivo acetylcholine release and memory performances of young and aged rats. Neurosci, 79: 837-846.
Pitsikas N, Rigamonti AE, Cella SG, Sakellaridis N, Muller EE (2005). The nitric oxide donor molsidomine antagonizes age-related memory deficits in the rat. Neurobiol Aging, 26: 259-264.
Burke SN, Wallace JL, Hartzell AL, Nematollahi S, Plange K, Barnes CA (2011). Age-associated deficits in pattern separation functions of the perirhinal cortex: a cross-species consensus. Behav Neurosci, 125, 836-847.
Leite MR, Wilhelm EA, Jesse CR, Brandão R, Nogueira CW (2011). Protective effect of caffeine and a selective A2A receptor antagonist on impairment of memory and oxidative stress of aged rats. Exp Gerontol, 46: 309-315.
Scali C, Casamenti F, Pazzagli M, Bartolini L, Pepeu G (1994). Nerve growth factor increases extracellular acetylcholine levels in the parietal cortex and hippocampus of aged rats and restores object recognition. Neurosci Lett, 170: 117-120.
Scali C, Giovannini MG, Bartolini L, Prosperi C, Hinz V, Schmidt B, Pepeu G (1997). Effect of metrifonate on extracellular brain acetylcholine and object recognition in aged rats. Eur J Pharmacol, 325: 173-180.
Scali C, Giovannini MG, Prosperi C, Bartolini L, Pepeu G (1997). Tacrine administration enhances extracellular acetylcholine in vivo and restores the cognitive impairment in aged rats. Pharmacol Res, 36: 463-469.
Pietá Dias C, Martins de Lima MN, Presti-Torres J, Dornelles A, Garcia VA, Siciliani Scalco F, Rewsaat Guimarães M, Constantino L, Budni P, Dal-Pizzol F, Schröder N (2007). Memantine reduces oxidative damage and enhances long-term recognition memory in aged rats. Neurosci, 146: 1719-1725.
Burke SN, Wallace JL, Nematollahi S, Uprety AR, Barnes CA (2010). Pattern separation deficits may contribute to age-associated recognition impairments. Behav Neurosci, 124, 559-573
de Lima MN, Laranja DC, Caldana F, Bromberg E, Roesler R, Schröder N (2005). Reversal of age-related deficits in object recognition memory in rats with l-deprenyl. Exp Gerontol, 40: 506-511.
Aggleton JP, Blindt HS, Candy JM (1989). Working memory in aged rats. Behav Neurosci, 103: 975-983.
Bergado JA, Almaguer W, Rojas Y, Capdevila V, Frey JU (2011). Spatial and emotional memory in aged rats: a behavioral-statistical analysis. Neurosci, 172: 256-269.
Cavoy A, Delacour J (1993). Spatial but not object recognition is impaired by aging in rats. Physiol Behav, 53: 527-530.
Murray EA, Bussey TJ, Saksida LM (2007). Visual perception and memory: a new view of medial temporal lobe function in primates and rodents. Annu Rev Neurosci, 30: 99-122.
Graham KS, Scahill VL, Hornberger M, Barense MD, Lee AC, Bussey TJ, Saksida LM (2006). Abnormal categorization and perceptual learning in patients with hippocampal damage. J Neurosci, 26: 7547-7554.
Baxter MG, Murray EA (2001). Impairments in visual discrimination learning and recognition memory produced by neurotoxic lesions of rhinal cortex in rhesus monkeys. Eur J Neurosci, 13: 1228-1238.
Clark RE, West AN, Zola SM, Squire LR (2001). Rats with lesions of the hippocampus are impaired on the delayed nonmatching-to-sample task. Hippocampus, 11: 176-186.
Broadbent NJ, Squire LR, Clark RE (2004). Spatial memory, recognition memory, and the hippocampus. Proc Natl Acad Sci USA, 101: 14515-14520.
Zola SM, Squire LR (2001). Relationship between magnitude of damage to the hippocampus and impaired recognition memory in monkeys. Hippocampus, 11: 92-98.
Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA (2011). A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci, 12: 585-601.
Alvarez P, Zola-Morgan S, Squire LR (1995). Damage limited to the hippocampal region produces long-lasting memory impairment in monkeys. J Neurosci, 15: 3796-3807.
Murray EA, Mishkin M (1998). Object recognition and location memory in monkeys with excitotoxic lesions of the amygdala and hippocampus. J Neurosci, 18: 6568-6582.
Bartko SJ, Winters BD, Cowell RA (2007). Perirhinal cortex resolves feature ambiguity in configural object recognition and perceptual oddity tasks. Learn Mem, 14: 821-832.
Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982). Place navigation impaired in rats with hippocampal lesions. Nature, 297: 681-683.
Marrone DF, Ramirez-Amaya V, Barnes CA (2012). Neurons generated in senescence maintain capacity for functional integration. Hippocampus, 22: 1134-1142.
Marrone DF, Satvat E, Shaner MJ, Worley PF, Barnes CA (2012). Attenuated long-term Arc expression in the aged fascia dentata. Neurobiol Aging, 33: 979-990.
Gerrard JL, Burke SN, McNaughton BL, Barnes CA (2008). Sequence reactivation in the hippocampus is impaired in aged rats. J Neurosci, 28: 7883-7890.
Baxter MG, Gallagher M (1996). Neurobiological substrates of behavioral decline: models and data analytic strategies for individual differences in aging. Neurobiol Aging, 17: 491-495.
Gheidi A, Azzopardi E, Adams AA, Marrone DF (2013). Experience-dependent persistent expression of zif268 during rest is preserved in the aged dentate gyrus. BMC Neurosci, 14: 100.
Barnes CA (1979). Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol, 93: 74-104.
Cohen SJ, Stackman RW (2015). Assessing rodent hippocampal involvement in the novel object recognition task: A review. Behav Brain Res, 285:105-117.
Curtis CE, D’Esposito M (2003). Persistent activity in the prefrontal cortex during working memory. Trends Cogn Sci, 7: 415-423.
Bizon JL, Foster TC, Alexander GE, Glisky EL (2012). Characterizing cognitive aging of working memory and executive function in animal models. Front Aging Neurosci, 4:19.
Hales JB, Broadbent NJ, Velu PD, Squire LR, Clark RE (2015). Hippocampus, perirhinal cortex, and complex visual discriminations in rats and humans. Learn Mem, 22: 83-91.
Koen JD, Yonelinas AP (2014). The effects of healthy aging, amnestic mild cognitive impairment, and Alzheimer’s disease on recollection and familiarity: a meta-analytic review. Neuropsychol Rev, 24: 332-354.
Mandler G (1980). Recognizing: The judgement of prior occurrence. Psychol Rev, 87: 252-271.
Brown MW, Aggleton JP (2001). Recognition memory: what are the roles of the perirhinal cortex and hippocampus? Nature Rev Neurosci, 2: 51-61.