CoChat
Sign Up
Cited by 256Stress Responses and CortisolNeurotransmitter Receptor Influence on BehaviorTryptophan and brain disorders

Establishment of a repeated social defeat stress model in female mice

Open access
Takahashi, Aki, Chung, Jia-Ru, Zhang, Song, Zhang, Hongxing, Grossman, Yael, Aleyasin, Hossein, Flanigan, Meghan E., Pfau, Madeline L. +7 more·2017·Scientific Reports
DOI 10.1038/s41598-017-12811-8PMC PMC5634448
Open this paper in CoChat — free accountOpen PDF

Abstract

Numerous studies have employed repeated social defeat stress (RSDS) to study the neurobiological mechanisms of depression in rodents. An important limitation of RSDS studies to date is that they have been conducted exclusively in male mice due to the difficulty of initiating attack behavior directed toward female mice. Here, we establish a female mouse model of RSDS by inducing male aggression toward females through chemogenetic activation of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate that females susceptible to RSDS display social avoidance, anxiety-like behavior, reduction of body weight, and elevated levels of circulating interleukin 6. In contrast, a subset of mice we term resilient only display anxiety-like behaviors after RSDS. This model allows for investigation of sex differences in the neurobiological mechanisms of defeat‒induced depression‒like behaviors. A robust female social defeat model is a critical first step in the identification and development of novel therapeutic compounds to treat depression and anxiety disorders in women.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-017-12811-8

Cites

14 of 14 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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?

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

Flagged first, then by citations

Research works printed but not linked: 39

  1. [2]Devries K Violence against women is strongly associated with suicide attempts: evidence from the WHO multi-country study on women’s health and domestic violence against women Soc. Sci. Med. 2011 73 79 86 10.1016/j.socscimed.2011.05.006 21676510 · DOI · Paper page
  2. [5]Ford DE Erlinger TP Depression and C-Reactive Protein in US Adults Arch. Intern. Med. 2004 164 1010 10.1001/archinte.164.9.1010 15136311 · DOI · Paper page
  3. [7]Kornstein SG Gender differences in chronic major and double depression J. Affect. Disord. 2000 60 1 11 10.1016/S0165-0327(99)00158-5 10940442 · DOI
  4. [10]Kendler KS Gardner CO Neale MC Prescott CA Genetic risk factors for major depression in men and women: similar or different heritabilities and same or partly distinct genes? Psychol. Med. 2001 31 605 16 11352363
  5. [11]Hodes GE Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress J. Neurosci. 2015 35 16362 16376 10.1523/JNEUROSCI.1392-15.2015 26674863 PMC4679819 · DOI · Paper page
  6. [13]Bartolomucci A Chronic psychosocial stress persistently alters autonomic function and physical activity in mice Physiol. Behav. 2003 80 57 67 10.1016/S0031-9384(03)00209-9 14568308 · DOI
  7. [14]Kudryavtseva NN Bakshtanovskaya IV Koryakina LA Social model of depression in mice of C57BL/6J strain Pharmacol. Biochem. Behav. 1991 38 315 20 10.1016/0091-3057(91)90284-9 2057501 · DOI · Paper page
  8. [15]Miczek KA Yap JJ Covington HE Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake Pharmacol. Ther. 2008 120 102 28 10.1016/j.pharmthera.2008.07.006 18789966 PMC2713609 · DOI · Paper page
  9. [16]Koolhaas JM De Boer SF De Rutter AJ Meerlo P Sgoifo A Social stress in rats and mice Acta Physiol. Scand. Suppl. 1997 640 69 72 9401610
  10. [17]Berton O Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress Science 2006 311 864 8 10.1126/science.1120972 16469931 · DOI · Paper page
  11. [19]Huhman KL Social conflict models: Can they inform us about human psychopathology? Horm. Behav. 2006 50 640 646 10.1016/j.yhbeh.2006.06.022 16870189 · DOI · Paper page
  12. [20]Kahn MW The effect of socially learned aggression or submission on the mating behavior of C57 mice J. Genet. Psychol. 1961 98 211 7 10.1080/00221325.1961.10534371 13750750 · DOI
  13. [23]Avitsur R Padgett DA Sheridan JF Social Interactions, Stress, and Immunity Neurol. Clin. 2006 24 483 491 10.1016/j.ncl.2006.03.005 16877119 · DOI
  14. [24]Chuang J-C A β3-Adrenergic-Leptin-Melanocortin Circuit Regulates Behavioral and Metabolic Changes Induced by Chronic Stress Biol. Psychiatry 2010 67 1075 1082 10.1016/j.biopsych.2009.12.003 20060958 PMC2868111 · DOI · Paper page
  15. [25]Giannarelli C Susceptibility to chronic social stress increases plaque progression, vulnerability and platelet activation Thromb. Haemost. 2017 117 816 818 10.1160/TH16-10-0817 28078352 PMC5490439 · DOI
  16. [27]Nestler EJ Hyman SE Animal models of neuropsychiatric disorders Nat. Neurosci. 2010 13 1161 1169 10.1038/nn.2647 20877280 PMC3750731 · DOI · Paper page
  17. [29]Friedman AK KCNQ channel openers reverse depressive symptoms via an active resilience mechanism Nat. Commun. 2016 7 11671 10.1038/ncomms11671 27216573 PMC4890180 · DOI · Paper page
  18. [30]Friedman AK Enhancing Depression Mechanisms in Midbrain Dopamine Neurons Achieves Homeostatic Resilience Science 2014 344 313 319 10.1126/science.1249240 24744379 PMC4334447 · DOI · Paper page
  19. [31]Siegel A Roeling TA Gregg TR Kruk MR Neuropharmacology of brain-stimulation-evoked aggression Neurosci. Biobehav. Rev. 1999 23 359 89 10.1016/S0149-7634(98)00040-2 9989425 · DOI
  20. [32]Kruk MR Current topics in behavioral neurosciences 2014 17 143 188 10.1007/7854_2014_313 24852798 · DOI
  21. [34]Lee H Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus Nature 2014 509 627 632 10.1038/nature13169 24739975 PMC4098836 · DOI · Paper page
  22. [35]Sano K Tsuda MC Musatov S Sakamoto T Ogawa S Differential effects of site-specific knockdown of estrogen receptor α in the medial amygdala, medial pre-optic area, and ventromedial nucleus of the hypothalamus on sexual and aggressive behavior of male mice Eur. J. Neurosci. 2013 37 1308 1319 10.1111/ejn.12131 23347260 · DOI
  23. [36]Golden SA Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice Genes Brain Behav. 2016 16 44 55 10.1111/gbb.12310 27457669 PMC5243174 · DOI
  24. [37]Asaba A Hattori T Mogi K Kikusui T Sexual attractiveness of male chemicals and vocalizations in mice Front. Neurosci. 2014 8 231 10.3389/fnins.2014.00231 25140125 PMC4122165 · DOI
  25. [39]Senst, L., Baimoukhametova, D., Sterley, T.-L. & Bains, J. S. Sexually dimorphic neuronal responses to social isolation. Elife5 (2016). PMC5059136 27725087
  26. [40]Ruis MA Housing familiar male wildtype rats together reduces the long-term adverse behavioural and physiological effects of social defeat Psychoneuroendocrinology 1999 24 285 300 10.1016/S0306-4530(98)00050-X 10101734 · DOI
  27. [41]LaPlant Q Role of nuclear factor kappaB in ovarian hormone-mediated stress hypersensitivity in female mice Biol. Psychiatry 2009 65 874 80 10.1016/j.biopsych.2009.01.024 19251249 PMC2746634 · DOI · Paper page
  28. [42]Dalla C Sex differences in the effects of two stress paradigms on dopaminergic neurotransmission Physiol. Behav. 2008 93 595 605 10.1016/j.physbeh.2007.10.020 18031771 · DOI
  29. [43]Chourbaji S The suitability of 129SvEv mice for studying depressive-like behaviour: both males and females develop learned helplessness Behav. Brain Res. 2010 211 105 10 10.1016/j.bbr.2010.03.019 20230860 · DOI
  30. [44]Payne AP Swanson HH Agonistic behaviour between pairs of hamsters of the same and opposite sex in a neutral observation area Behaviour 1970 36 260 9 10.1163/156853970X00402 5531509 · DOI
  31. [45]Davis ES Marler CA c-fos Changes following an aggressive encounter in female California mice: a synthesis of behavior, hormone changes and neural activity Neuroscience 2004 127 611 24 10.1016/j.neuroscience.2004.05.034 15283961 · DOI
  32. [46]Huhman KL Conditioned defeat in male and female Syrian hamsters Horm. Behav. 2003 44 293 9 10.1016/j.yhbeh.2003.05.001 14609551 · DOI · Paper page
  33. [47]Solomon MB Karom MC Huhman KL Sex and estrous cycle differences in the display of conditioned defeat in Syrian hamsters Horm. Behav. 2007 52 211 219 10.1016/j.yhbeh.2007.04.007 17555756 · DOI
  34. [49]Shimamoto, A., Debold, J. F., Holly, E. N. & Miczek, K. A. Blunted accumbal dopamine response to cocaine following chronic social stress in female rats: exploring a link between depression and drug abuse. Psychopharmacology (Berl). (2011). PMC3901580 21638221
  35. [50]Bourke CH Neigh GN Exposure to repeated maternal aggression induces depressive-like behavior and increases startle in adult female rats Behav. Brain Res. 2012 227 270 5 10.1016/j.bbr.2011.11.001 22093902 PMC3242888 · DOI
  36. [51]Ver Hoeve ES Kelly G Luz S Ghanshani S Bhatnagar S Short-term and long-term effects of repeated social defeat during adolescence or adulthood in female rats Neuroscience 2013 249 63 73 10.1016/j.neuroscience.2013.01.073 23402852 PMC3743933 · DOI
  37. [52]Haller J Fuchs E Halász J Makara GB Defeat is a major stressor in males while social instability is stressful mainly in females: towards the development of a social stress model in female rats Brain Res. Bull. 1999 50 33 9 10.1016/S0361-9230(99)00087-8 10507469 · DOI
  38. [53]Armbruster BN Li X Pausch MH Herlitze S Roth BL Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand Proc. Natl. Acad. Sci. 2007 104 5163 5168 10.1073/pnas.0700293104 17360345 PMC1829280 · DOI · Paper page
  39. [54]Roth BL DREADDs for Neuroscientists Neuron 2016 89 683 694 10.1016/j.neuron.2016.01.040 26889809 PMC4759656 · DOI · Paper page

Cited by

Sorted by citations

Authors
Takahashi, A., Chung, J.-R., Zhang, S., Zhang, H., Grossman, Y., Aleyasin, H., Flanigan, M. E., Pfau, M. L., Menard, C., Dumitriu, D., Hodes, G. E., McEwen, B. S., Nestler, E. J., Han, M.-H., & Russo, S. J.
Affiliations
  • University of Tsukuba (JP)
  • Icahn School of Medicine at Mount Sinai (US)
  • Rockefeller University (US)
Corresponding author
Russo, Scott J.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-10-09
Volume
7
Issue
1
Pages
12838-12838
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-12811-8
PMC
PMC5634448
OpenAlex
W2761181514
Cited by
256
References
14
Citations by year
2026: 23 · 2025: 30 · 2024: 25 · 2023: 33 · 2022: 30 · 2021: 39 · 2020: 22 · 2019: 27 · 2018: 25 · 2017: 2
FWCI
11.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Alliance for Research on Schizophrenia and Depression
  • York University
  • National Institutes of Health (MH096890, MH104559)
  • Japan Society for the Promotion of Science (17H04766, 15H05724)
  • National Institute of Mental Health (F31MH105217, R01MH090264, R21MH112081, P50MH096890, R01MH111918, T32MH096678, R01MH114882, F31MH111108, R01MH051399, R01MH104559, T32MH087004)
  • National Center for Complementary and Integrative Health (P50AT008661)
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
repeated social defeat stress, female mice, depression, anxiety-like behavior, social avoidance, sex differences, ventromedial hypothalamus, chemogenetic activation, male aggression, interleukin-6, weight loss, resilience, depression in women
MeSH terms
Aggression, Animals, Avoidance Learning, Behavior, Animal, Disease Models, Animal, Female, Male, Mice, Inbred C57BL, Sensation, Social Behavior, Stress, Psychological

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