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Sexually dimorphic oxytocin circuits drive intragroup social conflict and aggression in wild house mice

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Abstract

In nature, both males and females engage in competitive aggressive interactions to resolve social conflicts, yet the behavioral principles guiding such interactions and their underlying neural mechanisms remain poorly understood. Through circuit manipulations in wild mice, we unveil oxytocin-expressing (OT+) neurons in the hypothalamic paraventricular nucleus (PVN) as a neural hub governing behavior in dyadic and intragroup social conflicts, influencing the degree of behavioral sexual dimorphism. We demonstrate that OT+ PVN neurons are essential and sufficient in promoting aggression and dominance hierarchies, predominantly in females. Furthermore, pharmacogenetic activation of these neurons induces a change in the ‘personality’ traits of the mice within groups, in a sex-dependent manner. Finally, we identify an innervation from these OT neurons to the ventral tegmental area that drives dyadic aggression, in a sex-specific manner. Our data suggest that competitive aggression in naturalistic settings is mediated by a sexually dimorphic OT network connected with reward-related circuitry.

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Fig. 1: OT+ PVN neurons are activated during dyadic aggressive interactions.
Fig. 2: OT+ PVN neurons promote dyadic adult- and pup-directed aggression in wild females.
Fig. 3: OT+ PVN neurons regulate intragroup dynamics and behavioral personalities in males and females.
Fig. 4: Sexual dimorphism in the anatomy and activity of OT+ PVN circuitry.
Fig. 5: Activation of PVN–VTA oxytocinergic circuit promotes aggression in males and females.

Data availability

Brain areas were determined according to their anatomy using the Franklin and Paxinos Brain Atlas (third edition)73. Source data are provided with this paper.

Code availability

Code associated with this publication can be found in our GitHub repository at https://github.com/LabTaliKimchi.

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Acknowledgements

We thank G. Brodsky for her assistance with the graphics and N. Stettner, O. Amram, S. Ovadia, O. Meir and B. Siani from the Weizmann Veterinary Department for their great assistance with animal breeding and care. We thank U. Alon and A. Mayo from the Weizmann Institute for their assistance with the behavioral personality analysis. We would also like to thank S. Devore and all members of the Kimchi Lab at the Weizmann Institute for their helpful comments on the manuscript. This work was supported by the Israeli Science Foundation (grant 2141/21) and the European Research Council (grant agreement 856487) to T.K. S.W. is supported by the Deutsch-Israelische Projektkooperation (DIP) (grant SH 752/2-1).

Author information

Authors and Affiliations

  1. Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel

    Yizhak Sofer, Noga Zilkha, Elena Gimpel, Silvia Gabriela Chuartzman & Tali Kimchi

  2. Sagol Department of Neurobiology, the Integrated Brain and Behavior Research Center, University of Haifa, Haifa, Israel

    Shlomo Wagner

Authors
  1. Yizhak Sofer
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  2. Noga Zilkha
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  3. Elena Gimpel
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  4. Shlomo Wagner
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  6. Tali Kimchi
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Contributions

Y.S., N.Z. and T.K. conceived and designed this study. Y.S. performed all experiments. N.Z. contributed to the ablation experiments. Y.S., N.Z., S.G.C. and E.G. analyzed all data. E.G. contributed to behavioral analysis. S.G.C. wrote all the codes. S.W. provided viruses and OT:Cre lab mice. Y.S., N.Z., E.G., S.G.C., S.W. and T.K. wrote, reviewed and edited the manuscript. T.K. funded and supervised all aspects of the study.

Corresponding author

Correspondence to Tali Kimchi.

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Nature Neuroscience thanks Ioana Carcea and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Only a full physical aggressive encounter induces an increase in the number of OT+/cFos+ PVN neurons of wild females.

a, Schematic illustration of the three experimental groups. b, Number of OT+/cFos+ PVN neurons in non-social control, socially restricted and aggressive females. nall groups = 5 in b. All statistical tests were two-tailed. One-way ANOVA with Tukey post hoc in b. Data are presented as mean ± SEM. *P ≤ 0.05. See Supplementary Data for more detailed statistics.

Source data

Extended Data Fig. 2 OT+ SON neurons are not activated during aggressive interactions in wild-derived mice.

a, Representative images of coronal brain sections of the SON showing expression of OT+ (orange) and cFos+ (green) in control (top) and socially exposed (bottom) females. b, Number of OT+/cFos+ SON neurons in control and social mice of both sexes. ncontrol females = 4, ncontrol males = 4, nsocial females = 5, nsocial males = 8. All statistical tests were two-tailed. Unpaired t test in b. Data are presented as mean ± SEM. Scale bars, 100 μm; zoomed image, 10 μm. See Supplementary Data for more detailed statistics.

Source data

Extended Data Fig. 3 Wild-backcrossed (BX) OT:Cre mice present similar behavioral and physiological phenotypes to wild mice, differently from lab mice.

a–c, Total aggression toward same-sex unfamiliar intruders. d, Self-grooming behavior in the presence of an adult intruder. e–g, Total aggression toward unfamiliar pups. h, Locomotion behavior in the open-field test. i,j, Parental behavior toward unfamiliar pups. k,l, Anxiety-related behavior in the open-field test. m,n, Social investigation of unfamiliar adults. o,p, Wildness behavior in the open-field test. q, OT mRNA in the hypothalamus. r, Number of OT+ PVN neurons. s, OT plasma levels. t, Corticosterone plasma levels. nlab females = 5 in a–c,e–g,i,j,r,t, 12 in d,m,n, 6 in h,k,l,o,p, 7 in q and 9 in s. nwild females = 5 in a–c, 11 in d,m,n, 10 in e–g,i,j, 6 in h,k,l,o–q, 4 in r and 8 in s,t. nwild-BX females = 5 in a–c,e–g,i,j, 13 in d,m,n, 7 in h,k,l,o–q, 3 in r, 8 in s and 6 in t. nlab males = 8 in a,s, 9 in b–p,r,t, 7 in q and 8 in s. nwild males = 8 in a,r–t, 9 in b–g,i,j,m and 7 in h,k,l,o,q. nwild-BX males = 9 in a–j,l–p,t, 8 in k,s and 7 in q,r. All statistical tests were two-tailed. Kruskal–Wallis in a–n, Fisher exact in o,p. One-way ANOVA with Tukey post hoc in q–t. Data are presented as mean ± SEM. #P<0.1, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. See Supplementary Data for more detailed statistics.

Source data

Extended Data Fig. 4 Ablation of OT+ PVN neurons is specific and decreases female aggression, without affecting locomotion or anxiety-related behaviors.

a, Schematic illustrations of the injection procedure (left) and representative images of OT+ (orange) and AVP+ (cyan) in the PVN of control and OT+ ablated wild-BX mice, following unilateral injection of AAV-DIO-taCasp3-TEVp (right). b,c, Quantification of AVP+ PVN (b) and OT+ SON (c) neurons of control and ablated mice. d–m, Adult-directed (d–h) and pup-directed (i–m) behavior of control and ablated mice of both sexes. Total aggressive animals (d,i), duration (e,j), events (f,k) and latency (g,l) to total aggressive behaviors; and duration of sniffing (h,m). n–p, Anxiety-related behaviors (n,o) and locomotion (p) during an open-field test. q, Plasma corticosterone levels. ncontrol = 6 in b, 5 in c and 31 in q. nablation = 7 in b,c and 29 in q. ncontrol females = 16 in d,e, 17 in f,m–p, 14 in g and 18 in i–l. nablation females = 24 in d,e,h,l–p, 23 in f,i–k and 25 in g. ncontrol males = 19 in d–f,h–j,p and 20 in g,k–o. nablation males = 20 in d–f,o,p, 21 in g–j,l–n and 19 in k. All statistical tests were two-tailed. Unpaired t test in b,c,q; Fisher exact in d,i; Mann–Whitney in e–h,j–p. Data are presented as mean ± SEM. #P < 0.1, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. Scale bars, 100 μm. See Supplementary Data for more detailed statistics.

Source data

Extended Data Fig. 5 Activation of OT+ PVN neurons is specific and increases female aggression without affecting locomotion or anxiety-related behaviors.

a, A representative image of mCherry (cyan) and OT+ (orange) staining in the PVN of AAV-hSyn-DIO-hM3D-mCherry bilaterally injected mice. b, Venn diagram (left) and percentage (right) of OT+ neurons co-expressing mCherry+ in the PVN. c, Number of OT+/cFos+ neurons in the SON of control and activated mice. d–m, Adult-directed (d–h) and pup-directed (i–m) behavior of control and activated mice of both sexes. Total aggressive animals (d,i), duration (e,j), events (f,k) and latency (g,l) to total aggressive behaviors; and duration of sniffing (h,m). n–p, Anxiety-related behaviors (n,o) and locomotion (p) during an open-field test. q, Plasma corticosterone levels. ncontrol = 5 in c and 30 in q. nactivation = 7 in c and 27 in q. ncontrol females = 16 in d–f,i–k,n and 17 in g,h,l,m,o,p. nactivation females = 13 in d–f,h,j,k,m–p and 14 in g,i,l. ncontrol males = 18 in d–f,h,k,n,o, 19 in g,i,j,l and 17 in l,p. nactivation males = 15 in d,e,k–o and 16 in f–j,p. All statistical tests were two-tailed. Unpaired t test in c,q; Fisher exact in d,i; Mann–Whitney in e–h,j–p. Data are presented as mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. Scale bars, 100 μm. See Supplementary Data for more detailed statistics.

Source data

Extended Data Fig. 6 Daily Glicko scores and quantification of selected variables in groups of control and ablated wild-BX mice of both sexes.

a–d, Daily Glicko scores (that is, dynamic social dominance ranking) of each experimental group of 5 mice (‘arena’), in female (a,b) and male (c,d), control (a,c) and ablated (b,d) mice. e–j, Representative social and locomotion variables in the semi-natural experiment: walking time (e), hiding time (f), arena time (g), distance pairs (h), chasing time (i) and being-chased time (j). nall groups = 15 in a–j. Data are presented as mean ± SEM.

Source data

Extended Data Fig. 7 Daily Glicko scores and quantification of arena variables in groups of control and activated wild-BX mice of both sexes.

a–d, Daily Glicko scores (that is, dynamic social dominance ranking) of each experimental group of 5 mice (‘arena’), in female (a,b) and male (c,d), control (a,c) and manipulated (b,d) mice. e–j, Representative social and locomotion variables in the arena: walking time (e), hiding time (f), arena time (g), distance pairs (h), chasing time (i) and being-chased time (j). k, Number of chasing events of activated females and males as percentage of their respective controls during the arena experiment. nall groups = 15 in a–k. All statistical tests were two-tailed. Repeated-measures ANOVA with Tukey post hoc in k. Data are presented as mean ± SEM. *P ≤ 0.05, **P ≤ 0.01. See Supplementary Data for more detailed statistics.

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Extended Data Fig. 8 OT+ PVN neurons play a role in regulating behavioral personalities within groups of wild mice, in a sex and ranking-associated manner.

a, Full array of behavioral variables and their correlations with the proximity to each archetype, in the activation cohorts (activation and controls, in males and females). Variables with the highest positive correlation are the ones that are most enriched near each archetype. Only significant correlations are presented. b,c, Correlation of the individual social rank (that is, last day Glicko score) and the distance from each archetype (A, B, P and I), presented for control (top) and activated (bottom) females (b) and males (c). Panels with a significant correlation are highlighted. nall groups = 15 in b. All statistical tests were two-tailed. Spearman’s correlation in b. See Supplementary Data for more detailed statistics.

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Extended Data Fig. 9 OT+ PVN neurons innervate dopaminergic circuitry in a sexually dimorphic manner.

a,b, Quantification of OT+ PVN anterograde projections to various brain regions of wild-BX mice following the semi-natural experiment: representative images of non-dopaminergic regions showing OT+ PVN fibers (white; a), and fiber density of females and males in non-dopaminergic brain regions (b). c, Quantification of TH+ neurons in dopaminergic brain regions of males and females. d, Summary of anatomical differences in OT+ PVN fibers and number of TH+ neurons between males and females. Significant differences are highlighted. e, Quantification of OT+/cFos+ neurons in the PVN of control and activated females and males, following C21 i.p. injection. f, Schematic illustration of the changes in neuronal activity of OT+–TH+ circuits following OT+ PVN activation. Activation of OT+ PVN neurons abolishes sex differences in the AVPe and A14 and leads to a female-biased sex difference in the VTA. nfemales = 9, nmales = 8 in b. nfemales = 11 in A14, 12 in AVPe, 10 in PAG, SN,VTA, nmales = 12 in A14,PAG,VTA, 13 in AVPe, 11 in SN in c. ncontrol females = 10, nactivation females = 10, ncontrol males = 15, nactivation males = 15 in e. All statistical tests were two-tailed. Repeated-measures ANOVA with Tukey post hoc in b; unpaired t test with FDR correction in c; two-way ANOVA with Tukey post hoc in e. Data are presented as mean ± SEM. **P ≤ 0.01, ***P ≤ 0.001. Scale bars, 100 μm. See Supplementary Data for more detailed statistics. Acb, accumbens nucleus; LPO, lateral preoptic area; LS, lateral septal nucleus; MPA, medial preoptic area; MPO, medial preoptic nucleus; SHy, septohypothalamic nucleus; BNST, bed nucleus of the stria terminalis; VDB, nucleus of the vertical limb of the diagonal band; VLPO, ventrolateral preoptic nucleus.

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Extended Data Fig. 10 Detailed behavioral analysis of specific parameters in OT-manipulated mice.

a–g, Detailed analysis of specific aggressive behaviors in males and females. Quantification of duration (left), number (middle) and latency (right) in control (aCSF) and activated (C21) mice; launch attack (a), lateral threat (b), tug (c), chase (d), clinch attack (e), bite (f) and sniffing (g). nfemale = 8, nmale = 10. All statistical tests were two-tailed. Wilcoxon matched-pairs signed-rank test. Data are presented as mean. #P < 0.1, *P ≤ 0.05. See Supplementary Data for more detailed statistics.

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Supplementary information

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Supplementary Video 1

Representative video clips of aggressive and nonaggressive behavioral parameters.

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Sofer, Y., Zilkha, N., Gimpel, E. et al. Sexually dimorphic oxytocin circuits drive intragroup social conflict and aggression in wild house mice. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01685-5

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