Metabolic Brain Disease

, 24:643 | Cite as

Effect of exercise on learning and memory in a rat model of developmental stress

  • Laurian Grace
  • Sarah Hescham
  • Lauriston A. Kellaway
  • Kishor Bugarith
  • Vivienne A. Russell
Original Paper


Adverse life events occurring in early development can result in long-term effects on behavioural, physiological and cognitive processes. In particular, perinatal stressors impair neurogenesis in the hippocampus which consequently impairs memory formation. Exercise has previously been shown to have antidepressant effects and to increase cognitive functioning by increasing neurogenesis and neurotrophins in the hippocampus. The current study examined the effects of maternal separation, which has been shown to model anxiety in animals, and the effects of exercise on learning and memory. Forty-five male Sprague-Dawley rats were divided into four groups, maternally separated / non-runners, maternally separated / runners, non-separated / runners and non-separated / non-runners. Maternal separation occurred from postnatal day 2 (P2) to 14 (P14) for 3 h per day. Exercised rats were given voluntary access to individual running wheels attached to their cages from P29 to P49. Behavioural testing (Morris water maze (MWM) and object recognition tests) took place from P49 to P63. Maternally separated rats showed no significant difference in anxiety levels in the elevated plus maze and the open field compared to the normally reared controls. However, rats that were allowed voluntary access to running wheels showed increased levels of anxiety in the elevated plus maze and in the open field. Maternal separation did not have any effect on memory performance in the MWM or the object recognition tasks. Exercise increased spatial learning and memory in the MWM with the exercised rats displaying a decreased latency in locating the hidden platform than the non-exercised rats. The exercised rats spent significantly less time exploring the most recently encountered object in the temporal order task in comparison to the non-exercised controls, therefore showing improved temporal recognition memory. All groups performed the same on the other recognition tasks, with all rats showing intact memory performance. Results indicate that maternal separation had little effect on the rats whereas exercise enhanced both spatial and recognition memory.


Maternal separation Stress Exercise Learning and memory 


  1. Aisa B, Tordera R, Lasheras B, Del Rio J, Ramirez MJ (2007) Cognitive impairment associated to HPA axis hyperactivity after maternal separation. Psychoneuroendocrinology 32:256–266CrossRefPubMedGoogle Scholar
  2. Andersen SL, Teicher MH (2004) Delayed effects of early stress on hippocampal development. Neuropsychopharmacology 29:1988–1993CrossRefPubMedGoogle Scholar
  3. Barker GRI, Bird F, Alexander V, Warburton EC (2007) Recognition memory for objects, place, and temporal order: a disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex. J Neurosci 27:2948–2957CrossRefPubMedGoogle Scholar
  4. Bertaina-Anglade V, Enjuanes E, Morillon D, la Rochelle D (2006) The object recognition task in rats and mice: a simple and rapid model in safety pharmacology to detect amnesic properties of a new chemical entity. J Pharmacol Toxicol Methods 54:99–105CrossRefPubMedGoogle Scholar
  5. Bevins RA, Besheer J (2006) Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study ‘recognition memory’. Nature Protocols 1:1306–1311CrossRefPubMedGoogle Scholar
  6. Binder E, Droste SK, Ohl F, Reul JM (2004) Regular voluntary exercise reduces anxiety-related behaviour and impulsiveness in mice. Behav Brain Res 155:197–206CrossRefPubMedGoogle Scholar
  7. Clark PJ, Brzezinska WJ, Thomas MW, Ryzhenko NA, Toshkov SA, Rhodes JS (2008) Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice. Neuroscience 155:1048–1058CrossRefPubMedGoogle Scholar
  8. Clements KM, Saunders AJ, Robertson BA, Wainwright PE (2007) Spontaneously hypertensive, Wistar Kyoto and Sprague–Dawley rats differ in their use of place and response strategies in the water radial arm maze. Neurobiol Learn Mem 87:285–294CrossRefPubMedGoogle Scholar
  9. Coleman MA, Garland T, Marler CA, Newton SS, Swallow JG, Carter PA (1998) Glucocorticoid response to forced exercise in laboratory house mice (Mus domesticus). Physiol Behav 63:279–285CrossRefPubMedGoogle Scholar
  10. Daniels WMU, Pietersen CY, Carstens ME, Stein DJ (2004) Maternal separation in rats leads to anxiety-like behavior and a blunted ACTH response and altered neurotransmitter levels in response to a subsequent stressor. Metab Brain Dis 19:1/2Google Scholar
  11. Duman CH, Schlesinger L, Russell DS, Duman RS (2008) Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice. Brain Res 1199:148–158PubMedGoogle Scholar
  12. Faure J, Uys JDK, Marais L, Stein DJ, Daniels WMU (2007) Early maternal separation alters the response to traumitization: resulting in increased levels of hippocampal neurotrophic factors. Metab Brain Dis 22:183–195CrossRefPubMedGoogle Scholar
  13. Gareau MG, Jury J, Perdue MH (2007) Neonatal maternal separation of rat pups results in abnormal cholinergic regulation of epithelial permeability. Am J Physiol Gastrointest Liver Physiol 293:198–203CrossRefGoogle Scholar
  14. Gomez-Pinilla F, Vaynman S (2005) A “deficient environment” in prenatal life may compromise systems important for cognitive function by affecting BDNF in the hippocampus. Exp Neurol 192:235–243CrossRefPubMedGoogle Scholar
  15. Griesbach GS, Hovda DA, Molteni R, Wu A, Gomez-Pinnilla F (2004) Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function. Neuroscience 125:129–139CrossRefPubMedGoogle Scholar
  16. Gruss M, Braun K, Frey JU, Korz V (2008) Maternal separation during a specific postnatal time window prevents reinforcement of the hippocampal long-term potentiation in adolescent rats. Neuroscience 152:1–7CrossRefPubMedGoogle Scholar
  17. Horvath KM, Harkany T, Mulder J, Koolhaas JM, Luiten PG, Meerlo P (2004) Neonatal handling increases sensitivity to acute neurodegeneration in adult rats. J Neurobiol 60:463–472CrossRefPubMedGoogle Scholar
  18. Howells FM, Russell VA, Mabandla MV, Kellaway LA (2005) Stress reduces the neuroprotective effect of exercise in a rat model for Parkinson’s disease. Behav Brain Res 165:210–220CrossRefPubMedGoogle Scholar
  19. Hunsaker MR, Lee B, Kesner RP (2008) Evaluating the temporal context of episodic memory: the role of CA3 and CA1. Behav Brain Res 188:310–315CrossRefPubMedGoogle Scholar
  20. Kalinichev M, Easterling KW, Plotsky PM, Holtzman SG (2002) Long-lasting changes in stress-induced corticosterone response and anxiety-like behaviors as a consequence of neonatal maternal separation in Long-Evans rats. Pharmacol Biochem Behav 73:131–140CrossRefPubMedGoogle Scholar
  21. Kandel ER, Shwartz JH, Jessell TM (2006) Principals of neural science. McGraw-Hill, United StatesGoogle Scholar
  22. Kathol RG, Jaeckle RS, Lopez JF, Meller WH (1989) Pathophsiology of HPA axis abnormalities in patients with major depression: an update. Am J Psychiatry 146:311–317PubMedGoogle Scholar
  23. Knuth ED, Etgen AM (2007) Long-term behavioral consequences of brief, repeated neonatal isolation. Brain Res 1128:139–147CrossRefPubMedGoogle Scholar
  24. Lee I (2005) The role of hippocampal subregions in detecting spatial novelty. Behav Neurosci 119:145–153CrossRefPubMedGoogle Scholar
  25. Liu D, Diorio J, Day JC, Francis DD, Meaney MJ (2000) Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat Neurosci 3:799–806CrossRefPubMedGoogle Scholar
  26. Macri S, Chiarotti F, Wurbel H (2008) Maternal separation and maternal care act independently on the development of HPA responses in male rats. Behav Brain Res 191:227–234CrossRefPubMedGoogle Scholar
  27. Madruga C, Xavier LL, Achaval M, Sanvitto GL, Lucion AB (2006) Early handling, but not maternal separation, decreases emotional responses in two paradigms of fear without changes in mesolimbic dopamine. Behav Brain Res 166:241–246CrossRefPubMedGoogle Scholar
  28. Marais L, van Rensburg SJ, van Zyl JM, Stein DJ, Daniels WMU (2008) Maternal separation of rat pups increases the risk of developing depressive-like behavior after subsequent chronic stress by altering corticosterone and neurotrophin levels in the hippocampus. Neurosci Res 61:106–112CrossRefPubMedGoogle Scholar
  29. Marmendal M, Erkisson CJP, Fahlke C (2006) Early deprivation increases exploration and locomotion in adult male Wistar offspring. Pharmacol Biochem Behav 85:535–544CrossRefPubMedGoogle Scholar
  30. Mello PB, Benetti F, Cammarota M, Izquierdo I (2008) Effects of acute and chronic physical exercise and stress on different types of memory in rats. Anais da Academia Brasilera de Ciencias 80:301–309Google Scholar
  31. Mesquita AR, Pego JM, Summaveille T, Maciel P, Almeida OFX, Sousa N (2007) Neurodevelopment milestone abnormalities in rats exposed to stress in early life. Neuroscience 147:1022–1033CrossRefPubMedGoogle Scholar
  32. Pickering C, Gustafsson L, Cebere A, Nylander I, Liljequist S (2006) Repeated maternal separation of male Wistar rats alters glutamate receptor expression in the hippocampus but not the prefrontal cortex. Brain Res 1099:101–108CrossRefPubMedGoogle Scholar
  33. Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33CrossRefPubMedGoogle Scholar
  34. Roceri M, Hendricks W, Racagni G, Ellenbroek BA, Riva MA (2002) Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry 7:609–616CrossRefPubMedGoogle Scholar
  35. Stranahan AM, Khalil D, Gould E (2006) Social isolation delays the positive effects of running on adult neurogenesis. Nat Neurosci 9:526–533CrossRefPubMedGoogle Scholar
  36. Stranahan AM, Khalil D, Gould E (2007) Running induces widespread structural alterations in the hippocampus and the entorhinal cortex. Hippocampus 17:1017–1022CrossRefPubMedGoogle Scholar
  37. Tang AC, Reeb BC, Romeo RD, McEwen BS (2003) Modification of social memory, hypothalamic-pituitary-adrenal axis, and brain asymmetry by neonatal novelty exposure. J Neurosci 23:8254–8260PubMedGoogle Scholar
  38. Vallee M, Mayo W, Dellu F, Le Moal M, Simon H, Maccari S (1997) Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J Neurosci 7:2626–2636Google Scholar
  39. Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J NeuroSci 20:2580–2590CrossRefPubMedGoogle Scholar
  40. Vaynman S, Ying Z, Gomez-Pinilla F (2007) The select action of hippocampal calcium calmodulin protein kinase II in mediating exercise-enhanced cognitive function. Neuroscience 144:825–833CrossRefPubMedGoogle Scholar
  41. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nature Protocols 1:848–858CrossRefPubMedGoogle Scholar
  42. Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nature Protocols 2:322–328CrossRefPubMedGoogle Scholar
  43. Widenfalk J, Olson L, Thoren P (1999) Deprived of habitual running, rats down-regualte BDNF and TrkB messages in the brain. Neurosci Res 34:125–132CrossRefPubMedGoogle Scholar
  44. Wigger A, Neumann ID (1999) Gender-Dependent alterations in behavioral and neuroendocrine responses to emotional stress in adult rats. Physiol Behav 66:293–302CrossRefPubMedGoogle Scholar
  45. Ying Z, Roy RR, Zhong H, Zdunowski S, Edgerton VR, Gomez-Pinilla F (2008) BDNF—exercise interactions in the recovery of symmetrical stepping after a cervical hemisection in rats. Neuroscience 155:1070–1078CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Laurian Grace
    • 1
  • Sarah Hescham
    • 1
  • Lauriston A. Kellaway
    • 1
  • Kishor Bugarith
    • 1
  • Vivienne A. Russell
    • 1
  1. 1.Department of Human BiologyUniversity of Cape TownObservatorySouth Africa

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