Running‐induced anxiety is dependent on increases in hippocampal neurogenesis
Open accessAbstract
Exercise, specifically voluntary wheel running, is a potent stimulator of hippocampal neurogenesis in adult mice. In addition, exercise induces behavioral changes in numerous measures of anxiety in rodents. However, the physiological underpinnings of these changes are poorly understood. To investigate the role of neurogenesis in exercise‐mediated anxiety, we examined the cellular and behavioral effects of voluntary wheel running in mice with a reduction in hippocampal neurogenesis, achieved through conditional deletion of ataxia telangiectasia‐mutated and rad‐3‐related protein (ATR), a cell cycle checkpoint kinase necessary for normal levels of neurogenesis. Following hippocampal microinjection of an adeno‐associated virus expressing Cre recombinase to delete ATR, mice were exposed to 4 weeks of voluntary wheel running and subsequently evaluated for anxiety‐like behavior. Wheel running resulted in increased cell proliferation and neurogenesis, as measured by bromodeoxyuridine and doublecortin, respectively. Wheel running also resulted in heightened anxiety in the novelty‐induced hypophagia, open field and light–dark box tests. However, both the neurogenic and anxiogenic effects of wheel running were attenuated following hippocampal ATR deletion, suggesting that increased neurogenesis is an important mediator of exercise‐induced anxiety.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Previous studies have shown an increased anxiety-like phenotype in consequence of increased neurogenesis induced by voluntary wheel running.
“Moreover, previous studies have shown an increased anxiety-like phenotype in consequence of increased neurogenesis induced by voluntary wheel running.37, 38, 39”
From Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression (2017) · cites this paper as [39]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus
van Praag, H., Kempermann, G., & Gage, F. H. (1999) · Nature Neuroscience · doi:10.1038/6368 · Cited by 3,880 · see citing works
West, M. J., Slomianka, L., & Gundersen, H. J. G. (1991) · The Anatomical Record · doi:10.1002/ar.1092310411 · Cited by 2,994 · see citing works
Running enhances neurogenesis, learning, and long-term potentiation in mice
van Praag, H., Christie, B. R., Sejnowski, T. J., & Gage, F. H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.23.13427 · Cited by 2,904 · see citing works
Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation
Sahay, A., Scobie, K. N., Hill, A. S., O'Carroll, C. M., Kheirbek, M. A., Burghardt, N. S., Fenton, A. A., Dranovsky, A., & Hen, R. (2011) · Nature · doi:10.1038/nature09817 · Cited by 1,567 · see citing works
Effects of exercise training on older patients with major depression
Blumenthal, J. A., Babyak, M. A., Moore, K. A., Craighead, W. E., Herman, S., Khatri, P., Waugh, R., Napolitano, M. A., Forman, L. M., Appelbaum, M., et al. (1999) · Archives of Internal Medicine · doi:10.1001/archinte.159.19.2349 · Cited by 1,277 · see citing works
Exercise Treatment for Major Depression: Maintenance of Therapeutic Benefit at 10 Months
Babyak, M., Blumenthal, J. A., Herman, S., Khatri, P., Doraiswamy, M., Moore, K., Edward Craighead, W., Baldewicz, T. T., & Ranga Krishnan, K. (2000) · Psychosomatic Medicine · doi:10.1097/00006842-200009000-00006 · Cited by 1,063 · see citing works
Neeper, S. A., Gómez‐Pinilla, F., Choi, J., & Cotman, C. W. (1996) · Brain Research · doi:10.1016/0006-8993(96)00273-9 · Cited by 1,015 · see citing works
Farmer, J., Zhao, X., van Praag, H., Wodtke, K., Gage, F. H., & Christie, B. R. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2003.09.029 · Cited by 836 · see citing works
PHYSICAL ACTIVITY AND MENTAL HEALTH: THE ASSOCIATION BETWEEN EXERCISE AND MOOD
Peluso, M. A. M., & Andrade, L. H. (2005) · Clinics · doi:10.1590/s1807-59322005000100012 · Cited by 804 · see citing works
High impact running improves learning
Winter, B., Breitenstein, C., Mooren, F. C., Voelker, K., Fobker, M., Lechtermann, A., Krueger, K., Fromme, A., Korsukewitz, C., Flöel, A., et al. (2006) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2006.11.003 · Cited by 796 · see citing works
Ruzankina, Y., Pinzon‐Guzman, C., Asare, A., Ong, T., Pontano, L. L., Cotsarelis, G., Zediak, V. P., Velez, M., Bhandoola, A., & Brown, E. J. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.03.002 · Cited by 780 · see citing works
Neurogenesis and Exercise: Past and Future Directions
van Praag, H. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8028-z · Cited by 645 · see citing works
Kronenberg, G., Reuter, K., Steiner, B., Brandt, M. D., Jessberger, S., Yamaguchi, M., & Kempermann, G. (2003) · Journal of Comparative Neurology · doi:10.1002/cne.10945 · Cited by 640 · see citing works
Exercise and Mental Health: Many Reasons to Move
Deslandes, A., Moraes, H., Ferreira, C., Veiga, H., Silveira, H., Mouta, R., Pompeu, F. A. M. S., Coutinho, E. S. F., & Laks, J. (2009) · Neuropsychobiology · doi:10.1159/000223730 · Cited by 609 · see citing works
Adult hippocampal neurogenesis is involved in anxiety-related behaviors
Revest, J.-M., Dupret, D., Koehl, M., Funk-Reiter, C., Grosjean, N., Piazza, P.-V., & Abrous, D. N. (2009) · Molecular Psychiatry · doi:10.1038/mp.2009.15 · Cited by 549 · see citing works
Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance
Brown, E. J., & Baltimore, D. (2003) · Genes & Development · doi:10.1101/gad.1067403 · Cited by 511 · see citing works
Antidepressants recruit new neurons to improve stress response regulation
Surget, A., Tanti, A., Leonardo, E. D., Laugeray, A., Rainer, Q., Touma, C., Palme, R., Griebel, G., Ibarguen-Vargas, Y., Hen, R., et al. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.48 · Cited by 471 · see citing works
Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice
Duman, C. H., Schlesinger, L., Russell, D. S., & Duman, R. S. (2008) · Brain Research · doi:10.1016/j.brainres.2007.12.047 · Cited by 465 · see citing works
Tillerson, J. L., Caudle, W. M., Reverón, M. E., & Miller, G. W. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00096-4 · Cited by 399 · see citing works
Rhodes, J. S., van Praag, H., Jeffrey, S., Girard, I., Mitchell, G. S., Garland, T., & Gage, F. H. (2003) · Behavioral Neuroscience · doi:10.1037/0735-7044.117.5.1006 · Cited by 269 · see citing works
Paradoxical influence of hippocampal neurogenesis on working memory
Saxe, M., Malleret, G., Vronskaya, S., Mendez‐David, I., Garcia, A. D. R., Sofroniew, M. V., Kandel, E. R., & Hen, R. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611718104 · Cited by 244 · see citing works
Fuss, J., Ben Abdallah, N. M. ‐., Vogt, M. A., Touma, C., Pacifici, P. G., Palme, R., Witzemann, V., Hellweg, R., & Gass, P. (2010) · Hippocampus · doi:10.1002/hipo.20634 · Cited by 240 · see citing works
van der Borght, K., Havekes, R., Bos, T., Eggen, B. J. L., & van der Zee, E. A. (2007) · Behavioral Neuroscience · doi:10.1037/0735-7044.121.2.324 · Cited by 227 · see citing works
Exercise improves cognition and hippocampal plasticity in <i>APOE</i> ɛ4 mice
Nichol, K., Deeny, S. P., Seif, J., Camaclang, K., & Cotman, C. W. (2009) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2009.02.006 · Cited by 213 · see citing works
Van der Borght, K., Kóbor‐Nyakas, D. É., Klauke, K., Eggen, B. J. L., Nyakas, C., Van der Zee, E. A., & Meerlo, P. (2009) · Hippocampus · doi:10.1002/hipo.20545 · Cited by 210 · see citing works
Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain
Naylor, A. S., Bull, C., Nilsson, M. K. L., Zhu, C., Björk‐Eriksson, T., Eriksson, P. S., Blomgren, K., & Kuhn, H. G. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711128105 · Cited by 205 · see citing works
The effects of chronic treadmill and wheel running on behavior in rats
Burghardt, P. R., Fulk, L. J., Hand, G. A., & Wilson, M. A. (2004) · Brain Research · doi:10.1016/j.brainres.2004.05.086 · Cited by 204 · see citing works
Regular voluntary exercise reduces anxiety-related behaviour and impulsiveness in mice
Binder, E., Droste, S. K., Ohl, F., & Reul, J. M. H. M. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.04.017 · Cited by 188 · see citing works
Chaouloff, F., Durand, M., & Mormède, P. (1997) · Behavioural Brain Research · doi:10.1016/s0166-4328(96)00160-x · Cited by 174 · see citing works
Running is rewarding and antidepressive
Brené, S., Bjørnebekk, A., Åberg, E., Mathé, A. A., Olson, L., & Werme, M. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.05.015 · Cited by 172 · see citing works
Physiological and Psychological Fatigue in Extreme Conditions: Overtraining and Elite Athletes
Purvis, D. L., Gonsalves, S. G., & Deuster, P. A. (2010) · PM&R · doi:10.1016/j.pmrj.2010.03.025 · Cited by 162 · see citing works
Ataxia telangiectasia mutated is essential during adult neurogenesisPreprint
Allen, D. M., van Praag, H., Ray, J., Ohler, Z. W., Winrow, C. J., Carter, T. A., Braquet, R., Harrington, E. A., Ried, T., Brown, K. D., et al. (2001) · Genes & Development · doi:10.1101/gad.869001 · Cited by 159 · see citing works
Voluntary exercise in C57 mice is anxiolytic across several measures of anxiety
Salam, J., FOX, J., DETROY, E., GUIGNON, M., Wohl, D. A., & Falls, W. A. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.07.036 · Cited by 139 · see citing works
Clark, P. J., Brzezinska, W. J., Puchalski, E. K., Krone, D. A., & Rhodes, J. S. (2009) · Hippocampus · doi:10.1002/hipo.20543 · Cited by 138 · see citing works
Kitamura, T., Mishina, M., & Sugiyama, H. (2003) · Neuroscience Research · doi:10.1016/s0168-0102(03)00171-8 · Cited by 134 · see citing works
Frye, C. A., Edinger, K. L., & Sumida, K. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301498 · Cited by 124 · see citing works
Fuss, J., Ben Abdallah, N. M. B., Hensley, F. W., Weber, K.-J., Hellweg, R., & Gass, P. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012769 · Cited by 110 · cited 5× · see citing works
“However, the data presented herein, in addition to recent literature highlighting the prevention of running-induced anxiety by X-ray irradiation (Fuss et al. 2010a,b), strengthen the hypothesis that neurogenesis directly influences the anxiety-like behavior induced by running.”
BackgroundResultInfluentialGur, T., Conti, A. C., Holden, J., Bechtholt, A. J., Hill, T. E., Lucki, I., Malberg, J. E., & Blendy, J. A. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2051-07.2007 · Cited by 101 · see citing works
Self-citationIncreased Open Field Locomotion and Decreased Striatal GABAA Binding After Activity Wheel Running
Dishman, R. K., Dunn, A. L., Youngstedt, S. D., Davis, J. M., Burgess, M. L., Wilson, S. P., & Wilso, M. A. (1996) · Physiology & Behavior · doi:10.1016/0031-9384(96)00102-3 · Cited by 99 · see citing works
Clark, P., Kohman, R. A., Miller, D. S., Bhattacharya, T. K., Brzezinska, W. J., & Rhodes, J. S. (2011) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2010.00674.x · Cited by 94 · see citing works
Clark, P., Bhattacharya, T. K., Miller, D. S., & Rhodes, J. S. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.03.072 · Cited by 71 · see citing works
Exercise in the treatment of depression
Greer, T. L., & Trivedi, M. H. (2009) · Current Psychiatry Reports · doi:10.1007/s11920-009-0071-4 · Cited by 66 · see citing works
Correa, M., Manrique, H. M., Font, L., Escrig, M. A., & Aragón, C. M. G. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1219-3 · Cited by 59 · see citing works
Increased anxiety-related behaviour in Hint1 knockout mice
Varadarajulu, J., Lebar, M., Krishnamoorthy, G., et al. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.02.012 · Cited by 56 · see citing works
Increased depressive behaviour in mice harboring the mutant thyroid hormone receptor alpha 1
Pilhatsch, M., Winter, C., Nordström, K., Vennström, B., Bauer, M., & Juckel, G. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.05.016 · Cited by 49 · see citing works
Social Isolation Selectively Increases Anxiety in Mice without Affecting Depression-like Behavior
Kwak, C., Lee, S., & Kaang, B. (2009) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2009.13.5.357 · Cited by 34 · see citing works
Onksen, J. L., Brown, E. J., & Blendy, J. A. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.234 · Cited by 27 · see citing works
Self-citationStrenuous physical exercise adversely affects monocyte chemotaxis
Caidahl, K., Olieslagers, S., Krook, A., Rickenlund, A. M., Rickenlund, A. M., Zierath, J. R., Czepluch, F. S., Barrès, R., & Waltenberger, J. L. (2010) · Thrombosis and Haemostasis · doi:10.1160/th10-06-0363 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Adult neurogenesis, glia, and the extracellular matrix
Cope, E. C., & Gould, E. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2019.03.023 · Cited by 236 · see citing works
Otsuka, T., Nishii, A., Amemiya, S., Kubota, N., Nishijima, T., & Kita, I. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.10.055 · Cited by 86 · see citing works
Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression
Alves, N. D., Correia, J. S., Patrício, P., Mateus-Pinheiro, A., Machado-Santos, A. R., Loureiro-Campos, E., Morais, M., Bessa, J. M., Sousa, N., & Pinto, L. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.29 · Cited by 79 · see citing works
Huang, P., Dong, Z., Huang, W., Zhou, C., Zhong, W., Hu, P., Wen, G., Sun, X., Hua, H., Cao, H., et al. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.05.032 · Cited by 54 · see citing works
Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal
Turner, J. R., Wilkinson, D. S., Poole, R. L., Gould, T. J., Carlson, G. C., & Blendy, J. A. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.105 · Cited by 29 · see citing works
Self-citation
- Authors
- Onksen, J. L., Briand, L. A., Galante, R. J., Pack, A. I., & Blendy, J. A.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Blendy, J. A.
- Venue
- Genes, Brain and Behavior
- Publisher
- Wiley
- Published
- 2012-05-03
- Volume
- 11
- Issue
- 5
- Pages
- 529-538
- ISSN
- 1601-183X (ISSN-L)
- 1601-1848
- PMC
- PMC3389278
- OpenAlex
- W2015669902
- Cited by
- 29
- References
- 48
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 5 · 2016: 2 · 2015: 4 · 2014: 4 · 2013: 6 · 2012: 1
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Genes Brain & Behavior (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health
- National Institute of Mental Health (F31MH087103)
- National Institute on Drug Abuse (R01DA011649, T32DA007281)
- National Cancer Institute (P50CA143187)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- voluntary wheel running, physical activity, anxiety-like behavior, hippocampal neurogenesis, ATR, conditional gene deletion, neurogenesis, novelty-induced hypophagia, open field, light-dark box, adeno-associated virus, Cre recombinase, doublecortin, bromodeoxyuridine
- MeSH terms
- Animals, Anxiety, Behavior, Animal, Cell Count, Hippocampus, Mice, Transgenic, Neurons, Physical Conditioning, Animal, Running, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Cell Proliferation, Mice, Neurogenesis, Ataxia Telangiectasia Mutated Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
