Cited by 158Neurogenesis and neuroplasticity mechanismsMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

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The effects of running and of inhibiting adult neurogenesis on learning and memory in rats.

Wojtowicz, J. Martin, Askew, Michele L., Winocur, Gordon·2008·European Journal of Neuroscience

DOI 10.1111/j.1460-9568.2008.06128.x

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Abstract

The presence of ongoing adult neurogenesis within the highly plastic hippocampal circuitry poses questions as to the relevance of new neurons to learning and memory. Correlational and causal evidence suggests that some, but not all, hippocampal tasks involve the new neurons. The evidence with regard to spatial learning in the water maze, one of the most commonly used hippocampal tasks, is contradictory. In this study we examined the effects of irradiation-induced reduction in neurogenesis on spatial learning and another standard hippocampal task, contextual fear conditioning, in rats that experienced normal cage conditions or voluntary running. The results indicate that reduced neurogenesis had little effect on spatial learning but severely impaired contextual fear conditioning. It was suggested that compensatory mechanisms within the hippocampus may have contributed selectively to sparing of spatial function. Performance on the fear conditioning task was weakly related to enhanced neurogenesis or running. The results improve our understanding of the functional role of adult neurogenesis in behaving animals.

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From pattern to purpose: how comparative studies contribute to understanding the function of adult neurogenesis
Barker, J. M., Boonstra, R., & Wojtowicz, J. M. (2011) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2011.07823.x · Cited by 74
“…or even improvements, in performance on certain ‘hippocampus-dependent’ tasks after irradiation or genetic ablation of adult neurogenesis in the hippocampus (Shors et al., 2002; Snyder et al., 2005; Leuner et al., 2006; Saxe et al., 2006, 2007; Scharfman & Hen, 2007; Wojtowicz et al., 2008).”
Background
Loss of hippocampal neurogenesis, increased novelty-induced activity, decreased home cage activity, and impaired reversal learning one year after irradiation of the young mouse brain
Kalm, M., Karlsson, N., Nilsson, M. K. L., & Blomgren, K. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.01.006 · Cited by 75
“Morris water maze, fear conditioning and open field (Naylor et al., 2008; Raber et al., 2011; Rola et al., 2004; Wojtowicz et al., 2008).”
NMDA receptor regulates migration of newly generated neurons in the adult hippocampus via Disrupted‐In‐Schizophrenia 1 (DISC1)
Namba, T., Ming, G., Song, H., Waga, C., Enomoto, A., Kaibuchi, K., Kohsaka, S., & Uchino, S. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07282.x · Cited by 70
Induction of c-Fos, Zif268, and Arc from acute bouts of voluntary wheel running in new and pre-existing adult mouse hippocampal granule neurons
Clark, P., Bhattacharya, T. K., Miller, D. S., & Rhodes, J. S. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.03.072 · Cited by 75
“Recent studies using irradiation to reduce neurogenesis from running did not report any impairments in wheel running or motor task performance, so new neurons may not be critical for sensory or motor processing (Clark et al., 2008; Wojtowicz et al., 2008).”
Functional and mechanistic exploration of an adult neurogenesis‐promoting small molecule
Petřík, D., Jiang, Y., Birnbaum, S. G., Powell, C. M., Kim, M., Hsieh, J., & Eisch, A. J. (2012) · The FASEB Journal · doi:10.1096/fj.11-201426 · Cited by 70
When is adult hippocampal neurogenesis necessary for learning? Evidence from animal research
Castilla‐Ortega, E., Pedraza, C., Estivill‐Torrús, G., & Santín, L. J. (2011) · Reviews in the Neurosciences · doi:10.1515/rns.2011.027 · Cited by 69
“…that achieved a better performance also possessed more new hippocampal neurons [water maze (Ambrogini et al. , 2000 ; Drapeau et al. , 2003 ; Sisti et al. , 2007 ), contextual fear conditioning (Wojtowicz et al. , 2008 ) and trace conditioning (Leuner et al. , 2004 ; Dalla et al. , 2007 , 2009 )].”
BackgroundInfluential
Time-dependent involvement of adult-born dentate granule cells in behavior
Kim, W. R., Christian, K. M., Ming, G., & Song, H. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.07.012 · Cited by 67
The Ever-Changing Morphology of Hippocampal Granule Neurons in Physiology and Pathology
Llorens-Martı́n, M., Rábano, A., & Ávila, J. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00526 · Cited by 64
“Furthermore, such exposure impairs hippocampal-dependent learning (Wojtowicz et al., 2008; Hernandez-Rabaza et al., 2009).”
Central Nervous System Effects of Whole-Body Proton Irradiation
Sweet, T. B., Panda, N., Hein, A. M., Das, S. L., Hurley, S. D., Olschowka, J. A., Williams, J. P., & O’Banion, M. K. (2014) · Radiation Research · doi:10.1667/rr13699.1 · Cited by 64
New neurons generated from running are broadly recruited into neuronal activation associated with three different hippocampus‐involved tasks
Clark, P., Bhattacharya, T. K., Miller, D. S., Kohman, R. A., DeYoung, E. K., & Rhodes, J. S. (2012) · Hippocampus · doi:10.1002/hipo.22020 · Cited by 53
“Literature directly assessing the contribution of exerciseinduced neurogenesis to cognitive performance is scarce (Wojtowicz et al., 2008; Wong-Goodrich et al., 2010; Winocur et al., 2011).”
Background
Decreased cytogenesis in the granule cell layer of the hippocampus and impaired place learning after irradiation of the young mouse brain evaluated using the IntelliCage platform
Barlind, A., Karlsson, N., Björk‐Eriksson, T., Isgaard, J., & Blomgren, K. (2009) · Experimental Brain Research · doi:10.1007/s00221-009-2095-8 · Cited by 49
“This might oVer an explanation to why mice generally perform less consistently than rats in active avoidance test protocols such as the MWM. Mice are known to perform more consistently in exploration-based memory tests, for example (D’Hooge and De Deyn 2001).”
BackgroundInfluential
Nuclear deterrents: Intrinsic regulators of IL-1β-induced effects on hippocampal neurogenesis
Ó’Léime, C. S., Cryan, J. F., & Nolan, Y. M. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.07.153 · Cited by 53
Homeostatic regulation of adult hippocampal neurogenesis in aging rats: long-term effects of early exercise
Merkley, C. M., Jian, C., Mosa, A. J., Tan, Y., & Wojtowicz, J. M. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00174 · Cited by 49
Stimulant Reduction Intervention using Dosed Exercise (STRIDE) - CTN 0037: Study protocol for a randomized controlled trial
Trivedi, M. H., Greer, T. L., Grannemann, B. D., Church, T. S., Somoza, E. C., Blair, S. N., Szapocznik, J., Stoutenberg, M., Rethorst, C. D., Warden, D., et al. (2011) · Trials · doi:10.1186/1745-6215-12-206 · Cited by 50
“Similar results have been found for exercise-induced hippocampal neurogenesis and improvements in spatial memory in rats and mice [33-35].”
Result
Synaptogenesis in adult‐generated hippocampal granule cells is affected by behavioral experiences
Ambrogini, P., Cuppini, R., Lattanzi, D., Ciuffoli, S., Frontini, A., & Fanelli, M. (2009) · Hippocampus · doi:10.1002/hipo.20679 · Cited by 48
“Adult neurogenesis is involved in some kinds of hippocampus-dependent learning (Shors et al., 2001, 2002; Madsen et al., 2003; Winocur et al., 2006; Wojtowicz et al., 2008).”
Background
Neurogenesis, Exercise, and Cognitive Late Effects of Pediatric Radiotherapy
Rodgers, S. P., Treviño, M., Zawaski, J. A., Gaber, M. W., & Leasure, J. L. (2013) · Neural Plasticity · doi:10.1155/2013/698528 · Cited by 47
Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze
Merritt, J. R., & Rhodes, J. S. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.11.030 · Cited by 46
Targeting Adult Neurogenesis to Optimize Hippocampal Circuits in Aging
McAvoy, K. M., & Sahay, A. (2017) · Neurotherapeutics · doi:10.1007/s13311-017-0539-6 · Cited by 45
“Studies using the MWM have found that ablation of adult-born DGCs impairs spatial memory only when the target location of the hidden platform is reversed [143, 144].”
Background
The Alzheimer's disease drug memantine increases the number of radial glia‐like progenitor cells in adult hippocampus
Namba, T., Maekawa, M., Yuasa, S., Kohsaka, S., & Uchino, S. (2008) · Glia · doi:10.1002/glia.20831 · Cited by 46
“, 2004) and cognitive functions, including learning and memory (Becker and Wojtowicz, 2007; Kee et al., 2007; Wojtowicz et al., 2008).”
Background
Comparative neuroscience of stimulant-induced memory dysfunction: role for neurogenesis in the adult hippocampus
Canales, J. J. (2010) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e32833e16b6 · Cited by 41
“Similarly, irradiation in rats had no effects on spatial learning (Wojtowicz et al., 2008).”
Background
Voluntary wheel running enhances contextual but not trace fear conditioning
Kohman, R. A., Clark, P., DeYoung, E. K., Bhattacharya, T. K., Venghaus, C. E., & Rhodes, J. S. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.08.031 · Cited by 40
Exercise but not (–)-epigallocatechin-3-gallate or β-alanine enhances physical fitness, brain plasticity, and behavioral performance in mice
Bhattacharya, T. K., Pence, B. D., Ossyra, J. M., Gibbons, T. E., Perez, S., McCusker, R. H., Kelley, K. W., Johnson, R. W., Woods, J. A., & Rhodes, J. S. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.03.023 · Cited by 40
“While exercise improves behavioral performance across multiple domains of cognition, one of the most robust effects of exercise on any hippocampal-involved behavioral measure is contextual fear conditioning [22,24–26].”
Transgenic mouse models for studying adult neurogenesis
Semerci, F., & Maletić‐Savatić, M. (2016) · Frontiers in Biology · doi:10.1007/s11515-016-1405-3 · Cited by 43
Neural Activity Patterns Underlying Spatial Coding in the Hippocampus
Sosa, M., Gillespie, A. K., & Frank, L. M. (2016) · Current topics in behavioral neurosciences · doi:10.1007/7854_2016_462 · Cited by 43
“The regular addition of new neurons to DG circuitry has major implications for network activity in the region (Ge et al. 2008; Schmidt-Hieber et al. 2004) and for behavior dependent on the DG (Dupret et al. 2008; Garthe et al. 2009; Jessberger et al. 2009; Shors et al. 2001; Wojtowicz et al. 2008).”
Background
Running in laboratory and wild rodents: Differences in context sensitivity and plasticity of hippocampal neurogenesis
Klaus, F., & Amrein, I. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.04.027 · Cited by 40
Chronic retinoic acid treatment suppresses adult hippocampal neurogenesis, in close correlation with depressive-like behavior
Hu, P., Wang, Y., Liu, J., Meng, F., Qi, X., Chen, L., van Dam, A., Joëls, M., Lucassen, P. J., & Zhou, J. (2016) · Hippocampus · doi:10.1002/hipo.22574 · Cited by 41
“In humans, accutane is a comparable compound and its oral doses of 0.5– 2.0 mg/kg per day were also linked to depressive symptoms before (Hazen et al., 1983; Wysowski et al., 2001; Bremner et al., 2012).”
BackgroundInfluential
Learning and Activity after Irradiation of the Young Mouse Brain Analyzed in Adulthood Using Unbiased Monitoring in a Home Cage Environment
Karlsson, N., Kalm, M., Nilsson, M. K. L., Mallard, C. E., Björk‐Eriksson, T., & Blomgren, K. (2010) · Radiation Research · doi:10.1667/rr2231.1 · Cited by 38
Neurogenesis and pattern separation: time for a divorce
Becker, S. (2016) · Wiley Interdisciplinary Reviews Cognitive Science · doi:10.1002/wcs.1427 · Cited by 43
Deficient Plasticity in the Hippocampus and the Spiral of Addiction: Focus on Adult Neurogenesis
Canales, J. J. (2012) · Current topics in behavioral neurosciences · doi:10.1007/7854_2012_230 · Cited by 37
“2006), and irradiation in rats had no effect on spatial learning (Wojtowicz et al. 2008).”
Background
Exposure to N-Ethyl-N-Nitrosourea in Adult Mice Alters Structural and Functional Integrity of Neurogenic Sites
Capilla‐González, V., Gil‐Perotín, S., Ferragud, A., Bonet‐Ponce, L., Canales, J. J., & García‐Verdugo, J. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029891 · Cited by 34
“Morris Water Maze [55,56], and T-Maze tasks [57].”
Method
The future of cognitive neurorehabilitation
Stuss, D. T. (2011) · Neuropsychological Rehabilitation · doi:10.1080/09602011.2011.605590 · Cited by 34
Adult neurogenesis mediates forgetting of multiple types of memory in the rat
Scott, G. A., Terstege, D. J., Roebuck, A. J., Gorzo, K. A., Vu, A. P., Howland, J. G., & Epp, J. R. (2021) · Molecular Brain · doi:10.1186/s13041-021-00808-4 · Cited by 33
“Neurogenesis was substantially increased by voluntary exercise, replicating a large body of previous findings [4, 7, 8, 12, 18, 19, 23].”
MethodResultInfluential
Translating the impact of exercise on cognition: Methodological issues in animal research
Hatchard, T., Ting, J., & Messier, C. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.06.043 · Cited by 33
Factors affecting graded and ungraded memory loss following hippocampal lesions
Winocur, G., Moscovitch, M., & Sekeres, M. J. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.10.001 · Cited by 33
Castration and training in a spatial task alter the number of immature neurons in the hippocampus of male mice
Benice, T. S., & Raber, J. (2010) · Brain Research · doi:10.1016/j.brainres.2010.03.028 · Cited by 31
“, 2006), but not all (Wojtowicz et al., 2008), using irradiation to suppress new neuron production have reported disruption in spatial learning and memory in the reference memory version of the Morris water maze.”
Background
Long-term running alleviates some behavioral and molecular abnormalities in Down syndrome mouse model Ts65Dn
Kida, E., Rabe, A., Walus, M., Albertini, G., & Golabek, A. A. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.11.022 · Cited by 31
“, 2003); reduction in neurogenesis by irradiation had little effect on the spatial learning in rats (Wojtowicz et al., 2008); and running improved the performance of Ts65Dn mice in the Morris water maze, but did not rescue altered neurogenesis in these animals (Llorens-Martín et al.”
Background
Hippocampal neurogenesis in food‐storing red squirrels: the impact of age and spatial behavior
Johnson, K. M., Boonstra, R., & Wojtowicz, J. M. (2010) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2010.00589.x · Cited by 30
“Detailed laboratory studies provide support for subtle contribution of new neurons in flexible learning strategies and in contextual learning (Garthe et al. 2009; Wojtowicz et al. 2008).”
Long-term cognitive, emotional and neurogenic alterations induced by alcohol and methamphetamine exposure in adolescent rats
Loxton, D., & Canales, J. J. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.11.003 · Cited by 30
“This is consistent with the observation that inhibition of adult hippocampal neurogenesis does not generally impact on this type of memory (Hernandez-Rabaza et al., 2009, Wojtowicz et al., 2008), except when the long-term retention of a spatial location is required (Jessberger et al., 2009).”
A role for adult hippocampal neurogenesis at multiple time scales: A study of recent and remote memory in humans.
Déry, N., Goldstein, A., & Becker, S. (2015) · Behavioral Neuroscience · doi:10.1037/bne0000073 · Cited by 33
Using causal models to distinguish between neurogenesis-dependent and -independent effects on behaviour
Lazic, S. E. (2011) · Journal of The Royal Society Interface · doi:10.1098/rsif.2011.0510 · Cited by 27
Dose-related effects of chronic resveratrol administration on neurogenesis, angiogenesis, and corticosterone secretion are associated with improved spatial memory retention following global cerebral ischemia
Girbovan, C., Kent, P., Merali, Z., & Plamondon, H. (2015) · Nutritional Neuroscience · doi:10.1179/1476830515y.0000000020 · Cited by 27
Effects of chronic exercise and treatment with the antipsychotic drug olanzapine on hippocampal volume in adult female rats.
Barr, A. M., Wu, C. H., Wong, C., Hercher, C., Töpfer, E., Boyda, H. N., Procyshyn, R. M., Honer, W. G., & Beasley, C. L. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.10.010 · Cited by 26
Cyclin D2 knockout mice with depleted adult neurogenesis learn Barnes maze task.
Urbach, A., Robakiewicz, I., Baum, E., Kaczmarek, L., Witte, O. W., & Filipkowski, R. K. (2012) · Behavioral Neuroscience · doi:10.1037/a0031222 · Cited by 24
Regulation of behaviour by the nuclear receptor TLX
O’Leary, J. D., O’Leary, O. F., Cryan, J. F., & Nolan, Y. M. (2016) · Genes Brain & Behavior · doi:10.1111/gbb.12357 · Cited by 24
“It should be noted however that controversy remains regarding the role of adult hippocampal neurogenesis in spatial learning (Arruda-Carvalho et al. 2011; Ben Abdallah et al. 2013; Clelland et al. 2009; Drapeau et al. 2003; Saxe et al. 2006; Snyder et al. 2005; Wojtowicz et al. 2008).”
Background

Authors: Wojtowicz, J. M., Askew, M. L., & Winocur, G.
Affiliations: University of Toronto (CA)
Corresponding author: Wojtowicz, J. Martin
ORCID: Winocur, Gordon
Venue: European Journal of Neuroscience
Publisher: Wiley
Published: 2008-03
Volume: 27
Issue: 6
Pages: 1494-1502
ISSN: 0953-816X (ISSN-L)
1460-9568
DOI: 10.1111/j.1460-9568.2008.06128.x
OpenAlex: W2169145097
Cited by: 158
References: 45
Citations by year: 2026: 1 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 1 · 2017: 9 · 2016: 16 · 2015: 15 · 2014: 12 · 2013: 10 · 2012: 10
FWCI: 6.05
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 17 d)
Locations: European Journal of Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: University of Toronto
National Institutes of Health
Canadian Institutes of Health Research
Natural Sciences and Engineering Research Council of Canada
Topics: Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: adult neurogenesis, voluntary running, hippocampus, spatial learning, contextual fear conditioning, compensatory mechanisms, learning and memory, hippocampal plasticity
MeSH terms: Animals, Cell Differentiation, Cobalt Radioisotopes, Fear, Hippocampus, Learning, Male, Memory, Physical Conditioning, Animal, Random Allocation, Rats, Long-Evans, Rats

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The effects of running and of inhibiting adult neurogenesis on learning and memory in rats.

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