Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Quantitative standardization of resident mouse behavior for studies of aggression and social defeat

Abstract

Territorial reactive aggression in mice is used to study the biology of aggression-related behavior and is also a critical component of procedures used to study mood disorders, such as chronic social defeat stress. However, quantifying mouse aggression in a systematic, representative, and easily adoptable way that allows direct comparison between cohorts within or between studies remains a challenge. Here, we propose a structural equation modeling approach to quantify aggression observed during the resident-intruder procedure. Using data for 658 sexually experienced CD-1 male mice generated by three research groups across three institutions over a 10-year period, we developed a higher-order confirmatory factor model wherein the combined contributions of latency to the first attack, number of attack bouts, and average attack duration on each trial day (easily observable metrics that require no specialized equipment) are used to quantify individual differences in aggression. We call our final model the Mouse Aggression Detector (MAD) model. Correlation analyses between MAD model factors estimated from multiple large datasets demonstrate generalizability of this measurement approach, and we further establish the stability of aggression scores across time within cohorts and demonstrate the utility of MAD for selecting aggressors which will generate a susceptible phenotype in social defeat experiments. Thus, this novel aggression scoring technique offers a systematic, high-throughput approach for aggressor selection in chronic social defeat stress studies and a more consistent and accurate study of mouse aggression itself.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Aggression is a composite measure for studies of aggression behavior and chronic social defeat.
Fig. 2: Aggression scores are significantly correlated across datasets.
Fig. 3: Aggression scores are stable over time and predict CSDS utility.
Fig. 4: MAD for modeling SimBA data.
Fig. 5: Three trial days are sufficient to characterize aggression.

References

  1. 1.

    Miczek KA, Faccidomo S, de Almeida RMM, Bannai M, Fish EW, Debold JF. Escalated Aggressive Behavior: New Pharmacotherapeutic Approaches and Opportunities. In: Devine J, editor Youth Violence: Scientific Approaches to Prevention. New York, NY, US: New York Academy of Sciences; 2004. p. 336–55.

  2. 2.

    Golden SA, Jin M, Shaham Y. Animal Models of (or for) Aggression Reward, Addiction, and Relapse: Behavior and Circuits. J Neurosci. 2019;39:3996–4008.

  3. 3.

    Miczek KA, de Boer SF, Haller J. Excessive aggression as model of violence: a critical evaluation of current preclinical methods. Psychopharmacology (Berl). 2013;226:445–58.

    CAS  Article  Google Scholar 

  4. 4.

    Golden SA, Heshmati M, Flanigan M, Christoffel DJ, Guise K, Pfau ML, et al. Basal forebrain projections to the lateral habenula modulate aggression reward. Nature. 2016;534:688–92.

    CAS  Article  Google Scholar 

  5. 5.

    Golden SA, Covington III HE, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nat Protoc. 2011;6:1183–91.

    CAS  Article  Google Scholar 

  6. 6.

    Krishnan V, Han M-H, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions. Cell. 2007;131:391-404.

    CAS  Article  Google Scholar 

  7. 7.

    Kudryavtseva NN, Bakshtanovskaya IV, Koryakina LA. Social model of depression in mice of C57BL/6J strain. Pharmacol Biochem Behav. 1991;38:315–20.

    CAS  Article  Google Scholar 

  8. 8.

    Hamm JA, Hoffman L. Working with Covariance: Using Higher-Order Factors in Structural Equation Modeling with Trust Constructs. In: Shockley E, Neal TMS, PytlikZillig LM, Bornstein BH, editors. Interdisciplinary Perspectives on Trust: Towards Theoretical and Methodological Integration. Cham: Springer International Publishing; 2016. p. 85–97.

  9. 9.

    Oyegbile TO, Marler CA. Winning fights elevates testosterone levels in California mice and enhances future ability to win fights. Horm Behav. 2005;48:259–67.

    CAS  Article  Google Scholar 

  10. 10.

    Golden SA, Aleyasin H, Heins R, Flanigan M, Heshmati M, Takahashi A, et al. Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice. Genes Brain Behav. 2017;16:44–55.

    CAS  Article  Google Scholar 

  11. 11.

    Jöreskog KG. A general approach to confirmatory maximum likelihood factor analysis. Psychometrika. 1969;34:183–202.

    Article  Google Scholar 

  12. 12.

    Koolhaas JM, Coppens CM, de Boer SF, Buwalda B, Meerlo P, Timmermans PJA. The Resident-intruder Paradigm: A Standardized Test for Aggression, Violence and Social Stress. J Vis Exp. 2013:e4367.

  13. 13.

    Olivier B, Young LJ. Animal Models of Aggression. In: Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. p. 1699–708.

  14. 14.

    Eagle AL, Manning CE, Williams ES, Bastle RM, Gajewski PA, Garrison A, et al. Circuit-specific hippocampal ΔFosB underlies resilience to stress-induced social avoidance. Nat Commun. 2020;11:4484.

    CAS  Article  Google Scholar 

  15. 15.

    Nilsson SRO, Goodwin NL, Choong JJ, Hwang S, Wright HR, Norville ZC, et al. Simple Behavioral Analysis (SimBA) – an open source toolkit for computer classification of complex social behaviors in experimental animals. bioRxiv. 2020:1–29.

  16. 16.

    Rosseel Y. lavaan: An R Package for Structural Equation Modeling. J Stat Softw. 2012;48:1–36.

    Article  Google Scholar 

  17. 17.

    RStudio Team. RStudio: Integrated Development for R. Boston, MA: RStudio, Inc.; 2020.

  18. 18.

    Bender AR, Raz N. Normal-appearing cerebral white matter in healthy adults: mean change over 2 years and individual differences in change. Neurobiol Aging. 2015;36:1834–48.

    Article  Google Scholar 

  19. 19.

    Hu Lt, Bentler PM. Cutoff criteria for fit indexes in covariance structure analysis: Conventional criteria versus new alternatives. Struct Equ Modeling A Multidiscip J. 1999;6:1–55.

    Article  Google Scholar 

  20. 20.

    Satorra A, Bentler PM. Ensuring Positiveness of the Scaled Difference Chi-square Test Statistic. Psychometrika. 2010;75:243–48.

    Article  Google Scholar 

  21. 21.

    Datta SR, Anderson DJ, Branson K, Perona P, Leifer A. Computational Neuroethology: A Call to Action. Neuron. 2019;104:11–24.

    CAS  Article  Google Scholar 

  22. 22.

    Goodwin NL, Nilsson SRO, Golden SA. Rage Against the Machine: Advancing the study of aggression ethology via machine learning. Psychopharmacology. 2020;237:2569–88.

    CAS  Article  Google Scholar 

  23. 23.

    de Boer SF, van der Vegt BJ, Koolhaas JM. Individual Variation in Aggression of Feral Rodent Strains: A Standard for the Genetics of Aggression and Violence? Behav Genet. 2003;33:485–501.

    Article  Google Scholar 

  24. 24.

    Newman EL, Covington HE, Suh J, Bicakci MB, Ressler KJ, DeBold JF, et al. Fighting Females: Neural and Behavioral Consequences of Social Defeat Stress in Female Mice. Biol Psychiatry. 2019;86:657–68.

    Article  Google Scholar 

  25. 25.

    Warren BL, Mazei-Robison MS, Robison AJ, Iñiguez SD. Can I Get a Witness? Using Vicarious Defeat Stress to Study Mood-Related Illnesses in Traditionally Understudied Populations. Biol Psychiatry. 2020;88:381–91.

Download references

Author information

Affiliations

Authors

Contributions

CCK, ALE, NG, SAG, and AJR conceived and interpreted experiments; CCK, ALE, IN, and NG performed experiments; KM provided critical support for experiments; CCK, HA, and ARB performed the analysis; CCK and AJR wrote the paper; all authors revised the manuscript.

Corresponding author

Correspondence to Alfred Jay Robison.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kwiatkowski, C.C., Akaeze, H., Ndlebe, I. et al. Quantitative standardization of resident mouse behavior for studies of aggression and social defeat. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01018-1

Download citation

Search

Quick links