Hierarchical Status Predicts Behavioral Vulnerability and Nucleus Accumbens Metabolic Profile Following Chronic Social Defeat Stress
Open accessAbstract
Extensive data highlight the existence of major differences in individuals' susceptibility to stress [1-4]. While genetic factors [5, 6] and exposure to early life stress [7, 8] are key components for such neurobehavioral diversity, intriguing observations revealed individual differences in response to stress in inbred mice [9-12]. This raised the possibility that other factors might be critical in stress vulnerability. A key challenge in the field is to identify non-invasively risk factors for vulnerability to stress. Here, we investigated whether behavioral factors, emerging from preexisting dominance hierarchies, could predict vulnerability to chronic stress [9, 13-16]. We applied a chronic social defeat stress (CSDS) model of depression in C57BL/6J mice to investigate the predictive power of hierarchical status to pinpoint which individuals will exhibit susceptibility to CSDS. Given that the high social status of dominant mice would be the one particularly challenged by CSDS, we predicted and found that dominant individuals were the ones showing a strong susceptibility profile as indicated by strong social avoidance following CSDS, while subordinate mice were not affected. Data from 1 H-NMR spectroscopy revealed that the metabolic profile in the nucleus accumbens (NAc) relates to social status and vulnerability to stress. Under basal conditions, subordinates show lower levels of energy-related metabolites compared to dominants. In subordinates, but not dominants, levels of these metabolites were increased after exposure to CSDS. To the best of our knowledge, this is the first study that identifies non-invasively the origin of behavioral risk factors predictive of stress-induced depression-like behaviors associated with metabolic changes.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Mitochondria function and energy metabolism in the NAc is implicated in social competition and vulnerability to social defeat.
“Mitochondria function and energy metabolism in the NAc was also recently implicated in social competition32,33 and vulnerability to social defeat57.”
Resilient mice have increased NAc metabolism.
“FNDC5 induces thermogenesis and elevates mitochondrial gene expression [131], and resilient mice have increased NAc metabolism [132].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [132]
Cites
Krishnan, V., Han, M.-H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., LaPlant, Q., Graham, A., Lutter, M., Lagace, D. C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.09.018 · Cited by 2,307 · cited 1× · see citing works
“Dominant and Subordinate Mice Displayed Distinct Phenotypes after CSDS Increases in state anxiety have been reported in both susceptible and resilient sub-groups after CSDS, while body weight changes were only apparent in susceptible individuals [9].”
BackgroundThe influence of social hierarchy on primate health
Sapolsky, R. M. (2005) · Science · doi:10.1126/science.1106477 · Cited by 2,113 · cited 1× · see citing works
“Our identification of dominant mice as the ones that show vulnerability to CSDS might appear counterintuitive at first glance given the broad literature indicating that subordinate individuals tend to have reduced fitness [24, 25].”
BackgroundAutomatic quantitation of localized in vivo1H spectra with LCModel
Provencher, S. W. (2001) · NMR in Biomedicine · doi:10.1002/nbm.698 · Cited by 1,640 · see citing works
A standardized protocol for repeated social defeat stress in mice
Golden, S. A., Covington, H. E., Berton, O., & Russo, S. J. (2011) · Nature Protocols · doi:10.1038/nprot.2011.361 · Cited by 1,581 · see citing works
Mechanisms of stress in the brain
McEwen, B. S., Bowles, N. P., Gray, J. D., Hill, M. N., Hunter, R. G., Karatsoreos, I. N., & Nasca, C. (2015) · Nature Neuroscience · doi:10.1038/nn.4086 · Cited by 1,386 · see citing works
Russo, S. J., Murrough, J. W., Han, M.-H., Charney, D. S., & Nestler, E. J. (2012) · Nature Neuroscience · doi:10.1038/nn.3234 · Cited by 1,206 · see citing works
Czéh, 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
GILBERT, P., & ALLAN, S. (1998) · Psychological Medicine · doi:10.1017/s0033291798006710 · Cited by 972 · see citing works
Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex
Wang, F., Zhu, J., Zhu, H., Zhang, Q., Lin, Z., & Hu, H. (2011) · Science · doi:10.1126/science.1209951 · Cited by 528 · see citing works
Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression
Bagot, R. C., Parise, E. M., Peña, C. J., Zhang, H.-X., Maze, I., Chaudhury, D., Persaud, B., Cachope, R., Bolaños-Guzmán, C. A., Cheer, J. F., et al. (2015) · Nature Communications · doi:10.1038/ncomms8062 · Cited by 491 · see citing works
Health Psychology: Why Do Some People Get Sick and Some Stay Well?
Adler, N. E., & Matthews, K. A. (1994) · Annual Review of Psychology · doi:10.1146/annurev.ps.45.020194.001305 · Cited by 489 · see citing works
ΔFosB in brain reward circuits mediates resilience to stress and antidepressant responses
Vialou, V., Robison, A. J., LaPlant, Q. C., Covington, H. E., Dietz, D. M., Ohnishi, Y. N., Mouzon, E., Rush, A. J., Watts, E. L., Wallace, D. L., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2551 · Cited by 479 · see citing works
Early life influences on life-long patterns of behavior and health
McEwen, B. S. (2003) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/mrdd.10074 · Cited by 418 · see citing works
Cramér–Rao bounds: an evaluation tool for quantitation
Cavassila, S., Deval, S., Huegen, C., ORMONDT, D. V., & Graveron‐Demilly, D. (2001) · NMR in Biomedicine · doi:10.1002/nbm.701 · Cited by 333 · see citing works
Mitochondrial function in the brain links anxiety with social subordination
Hollis, F., van der Kooij, M. A., Zanoletti, O., Lozano, L., Cantó, C., & Sandi, C. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1512653112 · Cited by 288 · see citing works
Self-citationLocalized short‐echo‐time proton MR spectroscopy with full signal‐intensity acquisition
Mlynárik, V., Gambarota, G., Hanne Frenkel, A., & Rolf Gruetter, A. (2006) · Magnetic Resonance in Medicine · doi:10.1002/mrm.21043 · Cited by 275 · see citing works
MR Spectroscopic Studies of the Brain in Psychiatric Disorders
Maddock, R. J., & Buonocore, M. H. (2011) · Current topics in behavioral neurosciences · doi:10.1007/7854_2011_197 · Cited by 266 · see citing works
The mouse that roared: neural mechanisms of social hierarchy
Wang, F., Kessels, H. W. H. G., & Hu, H. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.07.005 · Cited by 261 · see citing works
Mating Season Aggression and Fecal Testosterone Levels in Male Ring-Tailed Lemurs (Lemur catta)
Cavigelli, S. A., & Pereira, M. E. (2000) · Hormones and Behavior · doi:10.1006/hbeh.2000.1585 · Cited by 248 · see citing works
Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression
Bouvier, E., Brouillard, F., Molet, J., Claverie, D., Cabungcal, J.-H., Cresto, N., Doligez, N., Rivat, C., Do, K. Q., Bernard, C., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.144 · Cited by 248 · see citing works
From high anxiety trait to depression: a neurocognitive hypothesis
Sandi, C., & Richter‐Levin, G. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.02.004 · Cited by 227 · see citing works
Self-citationSocial factors and individual vulnerability to chronic stress exposure
Bartolomucci, A., Palanza, P., Sacerdote, P., Panerai, A. E., Sgoifo, A., Dantzer, R., & Parmigiani, S. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.06.009 · Cited by 225 · see citing works
Oliveira, R. F., Almada, V. C., & Canário, A. V. M. (1996) · Hormones and Behavior · doi:10.1006/hbeh.1996.0002 · Cited by 202 · see citing works
Ethological strategies for defence in animals and humans: Their role in some psychiatric disorders
Dixon, A. K. (1998) · British Journal of Medical Psychology · doi:10.1111/j.2044-8341.1998.tb01001.x · Cited by 198 · see citing works
Assaf, Y., & Cohen, Y. (2000) · Magnetic Resonance in Medicine · doi:10.1002/(sici)1522-2594(200002)43:2 · Cited by 184 · see citing works
Early life stress paradigms in rodents: potential animal models of depression?
Schmidt, M. V., Wang, X., & Meijer, O. C. (2010) · Psychopharmacology · doi:10.1007/s00213-010-2096-0 · Cited by 171 · see citing works
Greenberg, N. L., & Crews, D. P. (1990) · General and Comparative Endocrinology · doi:10.1016/0016-6480(90)90309-a · Cited by 170 · see citing works
Neuroanatomic differences associated with stress susceptibility and resilience
Anacker, C., Scholz, J., O’Donnell, K. J., Allemang-Grand, R., Diorio, J., Bagot, R. C., Nestler, E. J., Hen, R., Lerch, J. P., & Meaney, M. J. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.08.009 · Cited by 167 · see citing works
Monder, C., Sakai, R. R., Miroff, Y., Blanchard, D. C., & Blanchard, R. J. (1994) · Endocrinology · doi:10.1210/endo.134.3.8119159 · Cited by 129 · see citing works
Ferrari, P. F., Palanza, P., Parmigiani, S., & Rodgers, R. J. (1998) · Physiology & Behavior · doi:10.1016/s0031-9384(97)00544-1 · Cited by 124 · see citing works
Social context-dependent relationships between mouse dominance rank and plasma hormone levels
Williamson, C. M., Lee, W., Romeo, R. D., & Curley, J. P. (2017) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.12.038 · Cited by 120 · see citing works
Intermale aggression and dark/light preference in ten inbred mouse strains
Guillot, P.-V., & Chapouthier, G. (1996) · Behavioural Brain Research · doi:10.1016/0166-4328(95)00163-8 · Cited by 117 · see citing works
Henckens, M. J. A. G., Klumpers, F., Everaerd, D., Kooijman, S. C., van Wingen, G. A., & Fernández, G. (2015) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsv149 · Cited by 104 · see citing works
Corticosteroid Receptor Genetic Polymorphisms and Stress Responsivity
DeRijk, R. H., & de Kloet, E. R. (2005) · Endocrine · doi:10.1385/endo:28:3:263 · Cited by 101 · see citing works
Bosch-Bouju, C., Larrieu, T., Linders, L., Manzoni, O. J., & Layé, S. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.082 · Cited by 100 · see citing works
Castro, J. E., Diessler, S., Varea, E., Márquez, C., Larsen, M. H., Cordero, M. I., & Sandi, C. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.12.014 · Cited by 94 · see citing works
Self-citationGenetic and Phylogenetic Aspects of Mood Variation
Price, J. (1972) · International Journal of Mental Health · doi:10.1080/00207411.1972.11448570 · Cited by 92 · see citing works
Female testosterone, dominance rank, and aggression in an Ethiopian population of hybrid baboons
Beehner, J. C., Phillips‐Conroy, J. E., & Whitten, P. L. (2005) · American Journal of Primatology · doi:10.1002/ajp.20172 · Cited by 90 · see citing works
Muehlenbein, M. P., Watts, D. P., & Whitten, P. L. (2004) · American Journal of Primatology · doi:10.1002/ajp.20062 · Cited by 86 · see citing works
Duclot, F., & Kabbaj, M. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0199-13.2013 · Cited by 85 · see citing works
Barnard, C. J., Behnke, J. M., & Sewell, J. (1996) · Ethology · doi:10.1111/j.1439-0310.1996.tb01104.x · Cited by 72 · see citing works
Association between experience of aggression and anxiety in male mice
Kudryavtseva, N. N., Bondar, N. P., & Avgustinovich, D. F. (2002) · Behavioural Brain Research · doi:10.1016/s0166-4328(01)00443-0 · Cited by 65 · see citing works
Serum testosterone, agonistic behavior, and dominance in inbred strains of mice
SELMANOFF, M. K., Goldman, B. D., & Ginsburg, B. E. (1977) · Hormones and Behavior · doi:10.1016/0018-506x(77)90026-5 · Cited by 55 · see citing works
Social experience alters the response to social stress in mice
Avitsur, R., Stark, J. L., Dhabhar, F. S., Kramer, K. A., & Sheridan, J. F. (2003) · Brain Behavior and Immunity · doi:10.1016/s0889-1591(03)00034-5 · Cited by 53 · see citing works
Behavioral, hormonal and neurochemical characteristics of aggressive α-mice
Hilakivi, L. A., Lister, R. G., Duncan, M. J., Ota, M., Eskay, R. L., Mefford, I. N., & Linnoila, M. (1989) · Brain Research · doi:10.1016/0006-8993(89)90471-x · Cited by 52 · see citing works
Cunha, M. P., Martin‐de‐Saavedra, M. D., Romero, A., Egea, J., Ludka, F. K., Tasca, C. I., Farina, M., Rodrigues, A. L. S., & López, M. G. (2014) · ASN NEURO · doi:10.1177/1759091414554945 · Cited by 43 · see citing works
van der Kooij, M. A., Grosse, J., Zanoletti, O., Papilloud, A., & Sandi, C. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.10.058 · Cited by 39 · see citing works
Self-citationDefeating the fear: New insights into the neurobiology of stress susceptibility
Krishnan, V. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.05.012 · Cited by 38 · see citing works
Neurobiological mechanisms supporting experience-dependent resistance to social stress
Cooper, M. A., Clinard, C. T., & Morrison, K. E. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.01.072 · Cited by 38 · see citing works
Cordero, M. I., Just, N., Poirier, G. L., & Sandi, C. (2016) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2015.11.017 · Cited by 38 · see citing works
Self-citationEndogenous Neuroprotectants in Ammonia Toxicity in the Central Nervous System: Facts and Hypotheses
Albrecht, J., & Węgrzynowicz, M. (2005) · Metabolic Brain Disease · doi:10.1007/s11011-005-7904-6 · Cited by 30 · see citing works
Clinard, C. T., Barnes, A., Adler, S. G., & Cooper, M. A. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.09.002 · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The molecular and cellular mechanisms of depression: a focus on reward circuitry
Fox, M. E., & Lobo, M. K. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0415-3 · Cited by 232 · see citing works
Advances in understanding neural mechanisms of social dominance
Zhou, T., Sandi, C., & Hu, H. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.01.006 · Cited by 133 · see citing works
Self-citationPhenotypic variability between Social Dominance Ranks in laboratory mice
Varholick, J. A., Bailoo, J. D., Palme, R., & Würbel, H. (2018) · Scientific Reports · doi:10.1038/s41598-018-24624-4 · Cited by 53 · see citing works
Papilloud, A., Guillot de Suduiraut, I., Zanoletti, O., Grosse, J., & Sandi, C. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0215-6 · Cited by 38 · see citing works
Self-citationThe Contribution of Environmental Enrichment to Phenotypic Variation in Mice and Rats.
Kentner, A. C., Speno, A. V., Doucette, J., & Roderick, R. C. (2021) · eneuro · doi:10.1523/eneuro.0539-20.2021 · Cited by 37 · see citing works
- Authors
- Larrieu, T., Cherix, A., Duque, A., Rodrigues, J., Lei, H., Gruetter, R., & Sandi, C.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- University of Geneva (CH)
- Corresponding author
- Larrieu, Thomas
- Sandi, Carmen
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 27
- Issue
- 14
- Pages
- 2202-2210.e4
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2735615417
- Cited by
- 202
- References
- 52
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 29 · 2023: 24 · 2022: 27 · 2021: 26 · 2020: 22 · 2019: 24 · 2018: 18 · 2017: 1
- FWCI
- 9.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Swiss National Science Foundation (31003A-152614, 51NF40-158776)
- École Polytechnique Fédérale de Lausanne
- EPFL Fellows fellowship program
- Marie Curie, FP7 (291771)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- chronic social defeat stress, social dominance hierarchy, stress vulnerability, depression-like behavior, nucleus accumbens, brain metabolomics, social avoidance, energy metabolism, individual differences in stress response, C57BL/6J mice
- MeSH terms
- Animals, Male, Mice, Inbred C57BL, Nucleus Accumbens, Social Behavior, Social Dominance, Stress, Psychological, Mice, Metabolome
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
