A reduced number of hippocampal granule cells does not associate with an anhedonia-like phenotype in a rat chronic mild stress model of depression
Open accessAbstract
Several clinical and preclinical studies have indicated that hippocampal shrinkage and decreased neurogenesis are implicated in the pathology of depression. Recent animal studies have shown, however, that the development of depression-related symptoms may take place through neurogenesis-independent pathways. To evaluate whether the stress-induced morphological changes in the hippocampal formation are causally related to the development of anhedonia-like symptoms, we combined the chronic mild stress (CMS) rat model of depression with stereological estimations of the number of proliferating progenitors, the total number of granule cells, and the volume of the ventral hippocampal formation (VHF). First, we found that stress-susceptible and stress-resilient animals, as categorized according to the behavioral read-out, both have a decrease in hippocampal cell proliferation. Our results also indicated that the anhedonia-like state in CMS rats develops prior to maximal suppression of cell proliferation, but correlates with a reduction in the total number of granule cells in the VHF. Furthermore, recovery from depression-related symptoms correlated with re-establishment of proliferation rates, but not with the total number of granule cells. Notably, decreases in the number of granule cells occurred independently of the induction of an anhedonia-like phenotype. There were no stress-induced changes in the volume of the VHF. We conclude that cell proliferation and a reduction in the total number of granule cells in the VHF are triggered by chronic stress, but do not associate with development of an anhedonia-like state in rats.
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?
In a chronic mild stress model, both stress-resilient rats and susceptible rats showing a depressive phenotype had lower hippocampal cell proliferation.
“This study found that both resilient rats and susceptible rats exhibiting a depressive phenotype were characterized by reduced hippocampal cell proliferation.”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [46]
In susceptible rats, depressive behaviors appeared before hippocampal cell proliferation declined.
“amongst the susceptible rats, the development of depressive behaviors occurred prior to reductions in hippocampal cell proliferation (46).”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [46]
The study indicates that hippocampal changes arise from stress and are probably independent of whether a major depressive episode develops.
“Instead, this study suggests that hippocampal changes result from stress and are likely independent of MDE development.”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [46]
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
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., et al. (2003) · Science · doi:10.1126/science.1083328 · Cited by 4,321 · 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
Self-citationGUNDERSEN, H. J. G., BENDTSEN, T. F., KORBO, L., MARCUSSEN, N., MØLLER, A., NIELSEN, K., NYENGAARD, J. R., PAKKENBERG, B., SØRENSEN, F. B., VESTERBY, A., et al. (1988) · APMIS · doi:10.1111/j.1699-0463.1988.tb05320.x · Cited by 2,929 · see citing works
Self-citationCausal Relationship Between Stressful Life Events and the Onset of Major Depression
Kendler, K. S., Karkowski, L. M., & Prescott, C. A. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.6.837 · Cited by 2,486 · cited 1× · see citing works
“Chronic stress has been causally related to the development and the progression of depressive disorders (Kendler et al. 1999, 2001).”
BackgroundWillner, P., Towell, A., Sampson, D., Sophokleous, S., & Muscat, R. (1987) · Psychopharmacology · doi:10.1007/bf00187257 · Cited by 1,993 · see citing works
Willner, P. (1997) · Psychopharmacology · doi:10.1007/s002130050456 · Cited by 1,832 · see citing works
Hippocampal Volume Reduction in Major Depression
Bremner, J. D., Narayan, M., Anderson, E. R., Staib, L. H., Miller, H. L., & Charney, D. S. (2000) · American Journal of Psychiatry · doi:10.1176/ajp.157.1.115 · Cited by 1,670 · see citing works
Willner, P. (2005) · Neuropsychobiology · doi:10.1159/000087097 · Cited by 1,605 · see citing works
Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus
Cameron, H. A., & Mckay, R. D. G. (2001) · Journal of Comparative Neurology · doi:10.1002/cne.1040 · Cited by 1,585 · see citing works
The efficiency of systematic sampling in stereology—reconsidered
GUNDERSEN, H. J. G., JENSEN, E. B. V., KIÊU, K., & NIELSEN, J. (1999) · Journal of Microscopy · doi:10.1046/j.1365-2818.1999.00457.x · Cited by 1,317 · see citing works
Untreated Depression and Hippocampal Volume Loss
Sheline, Y. I., Gado, M. H., & Kraemer, H. C. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.8.1516 · Cited by 1,180 · see citing works
Chronic mild stress-induced anhedonia: A realistic animal model of depression
Willner, P., Muscat, R., & Papp, M. (1992) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(05)80194-0 · Cited by 1,160 · cited 2× · see citing works
“The chronic mild stress (CMS) model is a wellvalidated animal model of major depression (Willner et al. 1992; Willner 1997, 2005).”
BackgroundCzéh, B., Michaelis, T., Watanabe, T., Frahm, J., de Biurrun, G., van Kampen, M., Bartolomucci, A., & Fuchs, E. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.211427898 · Cited by 1,090 · see citing works
Malberg, J. E., & Duman, R. S. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300234 · Cited by 815 · see citing works
Neural stem cell proliferation is decreased in schizophrenia, but not in depression
Reif, A., Fritzen, S., Finger, M., Strobel, A., Lauer, M., Schmitt, A., & Lesch, K.-P. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001791 · Cited by 630 · see citing works
Depression: a case of neuronal life and death?
Duman, R. S. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.02.033 · Cited by 612 · see citing works
Surget, A., Saxe, M., Leman, S., Ibarguen-Vargas, Y., Chalon, S., Griebel, G., Hen, R., & Belzung, C. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.02.022 · Cited by 556 · see citing works
Papp, M., Willner, P., & Muscat, R. (1991) · Psychopharmacology · doi:10.1007/bf02244188 · Cited by 542 · see citing works
Vermetten, E., Vythilingam, M., Southwick, S. M., Charney, D. S., & Bremner, J. D. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00634-6 · Cited by 487 · see citing works
Kendler, K. S., Thornton, L. M., & Gardner, C. O. (2001) · American Journal of Psychiatry · doi:10.1176/appi.ajp.158.4.582 · Cited by 480 · see citing works
Antidepressant-Induced Neurogenesis in the Hippocampus of Adult Nonhuman Primates
Perera, T. D., Coplan, J. D., Lisanby, S. H., Lipira, C. M., Arif, M., Carpio, C., Spitzer, G., Santarelli, L., Scharf, B., Hen, R., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0237-07.2007 · Cited by 461 · see citing works
Depression-Related Variation in Brain Morphology Over 3 Years: Effects of Stress?
Frodl, T. S., Koutsouleris, N., Bottlender, R., Born, C., Jäger, M., Scupin, I., Reiser, M., Möller, H.-J., & Meisenzahl, E. M. (2008) · Archives of General Psychiatry · doi:10.1001/archpsyc.65.10.1156 · Cited by 359 · see citing works
Jayatissa, M. N., Bisgaard, C. F., Tingström, A., Papp, M., & Wiborg, O. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301041 · Cited by 348 · see citing works
Self-citationMurray, F., Smith, D., & Hutson, P. H. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.01.014 · Cited by 334 · see citing works
D’Aquila, P. S., Brain, P. F., & Willner, P. (1994) · Physiology & Behavior · doi:10.1016/0031-9384(94)90316-6 · Cited by 324 · see citing works
Alonso, R., Griebel, G., Pavone, G., Stemmelin, J., Fur, G. L., & Soubrié, P. (2003) · Molecular Psychiatry · doi:10.1038/sj.mp.4001464 · Cited by 319 · see citing works
Holick, K. A., Lee, D. C., Hen, R., & Dulawa, S. C. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301399 · Cited by 313 · see citing works
Alterations of neuroplasticity in depression: the hippocampus and beyond
Fuchs, E., Czéh, B., Kole, M. H. P., Michaelis, T., & Lucassen, P. J. (2004) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2004.09.002 · Cited by 271 · see citing works
Moreau, J., Jenck, F., Martin, J. R., Mortas, P., & Haefely, W. E. (1992) · European Neuropsychopharmacology · doi:10.1016/0924-977x(92)90035-7 · Cited by 250 · see citing works
Slomianka, L., & West, M. J. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.06.086 · Cited by 236 · see citing works
Self-citationVollmayr, B., Simonis, C., Weber, S., Gass, P., & Henn, F. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00527-4 · Cited by 229 · see citing works
Zhou, Q., Hu, Y., Hua, Y., Hu, M., Luo, C., Han, X., Zhu, X., Wang, B., Xu, J., & Zhu, D. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04914.x · Cited by 225 · see citing works
Bergström, A., Jayatissa, M. N., Mørk, A., & Wiborg, O. (2007) · Brain Research · doi:10.1016/j.brainres.2007.12.025 · Cited by 195 · see citing works
Self-citationChanges in sleep architecture following chronic mild stress
Cheeta, S., Ruigt, G. S. F., Proosdij, J. N. V., & Willner, P. (1997) · Biological Psychiatry · doi:10.1016/s0006-3223(96)00058-3 · Cited by 175 · see citing works
Fabricius, K., Wörtwein, G., & Pakkenberg, B. (2008) · Brain Structure and Function · doi:10.1007/s00429-007-0169-6 · Cited by 165 · see citing works
Functional implications of decreases in neurogenesis following chronic mild stress in mice
Mineur, Y. S., Belzung, C., & Crusio, W. E. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.09.045 · Cited by 159 · see citing works
Chronic mild stress affects sucrose intake and sleep in rats
Grønli, J., Murison, R. C. C., Bjorvatn, B., Sørensen, E., Portas, C. M., & Ursin, R. (2003) · Behavioural Brain Research · doi:10.1016/s0166-4328(03)00252-3 · Cited by 158 · see citing works
van der Hart, M. G. C., Czéh, B., de Biurrun, G., Michaelis, T., Watanabe, T., Natt, O., Frahm, J., & Fuchs, E. (2002) · Molecular Psychiatry · doi:10.1038/sj.mp.4001130 · Cited by 158 · see citing works
Silva, R., Mesquita, A. R., Bessa, J. M., Sousa, J. C., Sotiropoulos, I., Leão, P., Almeida, O. F. X., & Sousa, N. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.12.026 · Cited by 157 · see citing works
Effects of vagus nerve stimulation on rat hippocampal progenitor proliferation
Revesz, D., Tjernstrom, M., Ben-Menachem, E., & Thorlin, T. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.08.012 · Cited by 126 · see citing works
Bergström, A., Jayatissa, M. N., Thykjær, T., & Wiborg, O. (2007) · Journal of Molecular Neuroscience · doi:10.1007/s12031-007-0065-9 · Cited by 123 · see citing works
Self-citationHippocampal volume and 2-year outcome in depression
Kronmüller, K.-T., Pantel, J., Köhler, S., Victor, D., Giesel, F., Magnotta, V. A., Mundt, C., Essig, M., & Schröder, J. (2008) · British Journal of Psychiatry · doi:10.1192/bjp.bp.107.040378 · Cited by 107 · see citing works
Bisgaard, C. F., Jayatissa, M. N., Enghild, J. J., Sánchez, C., Artemychyn, R., & Wiborg, O. (2007) · Journal of Molecular Neuroscience · doi:10.1007/s12031-007-0025-4 · Cited by 93 · see citing works
Self-citationJayatissa, M. N., Bisgaard, C. F., West, M. J., & Wiborg, O. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.11.009 · Cited by 92 · see citing works
Self-citationWang, S., Zhang, Z., Guo, Y., Teng, G., & Chen, B. (2007) · Behavioural Brain Research · doi:10.1016/j.bbr.2007.11.028 · Cited by 84 · see citing works
Impaired fear memory and decreased hippocampal neurogenesis following olfactory bulbectomy in rats
Jaako-Movits, K., & Zharkovsky, A. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04481.x · Cited by 76 · see citing works
Fuchs, E., h, B. C., & gge, G. F. (2004) · Behavioural Pharmacology · doi:10.1097/00008877-200409000-00003 · Cited by 70 · see citing works
Bondolfi, G., Chautems, C., Rochat, B., Bertschy, G., & Baumann, P. (1996) · Psychopharmacology · doi:10.1007/s002130050152 · Cited by 66 · see citing works
Czéh, B., Pudovkina, O., van der Hart, M. G. C., Simon, M., Heilbronner, U., Michaelis, T., Watanabe, T., Frahm, J., & Fuchs, E. (2005) · Psychopharmacology · doi:10.1007/s00213-005-2184-8 · Cited by 33 · see citing works
Life events and hippocampal volume in first-episode major depression
Kronmüller, K., Pantel, J., Götz, B., Köhler, S., Victor, D., Mundt, C., Magnotta, V. A., Giesel, F., Essig, M., & Schröder, J. (2008) · Journal of Affective Disorders · doi:10.1016/j.jad.2008.01.022 · Cited by 32 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The chronic mild stress (CMS) model of depression: History, evaluation and usage
Willner, P. (2017) · Neurobiology of Stress · doi:10.1016/j.ynstr.2016.08.002 · Cited by 959 · see citing works
Belleau, E. L., Treadway, M. T., & Pizzagalli, D. A. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.09.031 · Cited by 550 · see citing works
Depression and Hippocampal Neurogenesis: A Road to Remission?
Eisch, A. J., & Petrik, D. (2012) · Science · doi:10.1126/science.1222941 · Cited by 516 · see citing works
The neurobiology of depression and antidepressant action
Willner, P., Scheel-Krüger, J., & Belzung, C. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.12.007 · Cited by 519 · see citing works
Kubera, M., Obuchowicz, E., Goehler, L., Brzeszcz, J., & Maes, M. (2011) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.08.026 · Cited by 443 · see citing works
Jesulola, E., Micalos, P., & Baguley, I. J. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.12.025 · Cited by 379 · see citing works
Stress and Loss of Adult Neurogenesis Differentially Reduce Hippocampal Volume
Schoenfeld, T. J., McCausland, H. C., Morris, H. D., Padmanaban, V., & Cameron, H. A. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.05.013 · Cited by 260 · see citing works
Petrik, D., Lagace, D. C., & Eisch, A. J. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.09.003 · Cited by 241 · see citing works
Garza, J. C., Guo, M., Zhang, W., & Lu, X.-Y. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.161 · Cited by 209 · see citing works
Delgado y Palacios, R., Campo, A., Henningsen, K., Verhoye, M., Poot, D., Dijkstra, J., Van Audekerke, J., Benveniste, H., Sijbers, J., Wiborg, O., et al. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.05.014 · Cited by 113 · see citing works
Self-citationTGF-β/Smad Signalling in Neurogenesis: Implications for Neuropsychiatric Diseases
Hiew, L.-F., Poon, C.-H., You, H.-Z., & Lim, L.-W. (2021) · Cells · doi:10.3390/cells10061382 · Cited by 71 · see citing works
Understanding the effects of chronic benzodiazepine use in depression: a focus on neuropharmacology
Lim, B., Sproule, B. A., Zahra, Z., Sunderji, N., Kennedy, S. H., & Rizvi, S. J. (2020) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000316 · Cited by 50 · see citing works
- Authors
- Jayatissa, M. N., Henningsen, K., Nikolajsen, G., West, M. J., & Wiborg, O.
- Affiliations
- Aarhus University Hospital (DK)
- Aarhus University (DK)
- Corresponding author
- Wiborg, Ove
- Venue
- Stress
- Publisher
- Informa UK Limited
- Published
- 2009-11-23
- Volume
- 13
- Issue
- 2
- Pages
- 95-105
- ISSN
- 1025-3890 (ISSN-L)
- 1607-8888
- OpenAlex
- W1978226315
- Cited by
- 69
- References
- 51
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 2 · 2019: 1 · 2018: 5 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 3 · 2013: 1 · 2012: 8
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Stress (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Lundbeckfonden
- H. Lundbeck A/S
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- hippocampal granule cells, anhedonia, chronic mild stress, depression, hippocampal neurogenesis, cell proliferation, stress resilience, stress vulnerability, recovery from depression
- MeSH terms
- Animals, Cell Count, Depression, Hippocampus, Male, Neurons, Stress, Psychological, Rats, Wistar, Cell Proliferation, Rats, Neurogenesis
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
