Abstract
Numerous studies support the role of dopamine in modulating aggression1,2, but the exact neural mechanisms remain elusive. Here we show that dopaminergic cells in the ventral tegmental area (VTA) can bidirectionally modulate aggression in male mice in an experience-dependent manner. Although VTA dopaminergic cells strongly influence aggression in novice aggressors, they become ineffective in expert aggressors. Furthermore, eliminating dopamine synthesis in the VTA prevents the emergence of aggression in naive mice but leaves aggression intact in expert aggressors. VTA dopamine modulates aggression through the dorsal lateral septum (dLS), a region known for aggression control. Dopamine enables the flow of information from the hippocampus to the dLS by weakening local inhibition in novice aggressors. In expert aggressors, dLS local inhibition naturally weakens, and the ability of dopamine to modulate dLS cells diminishes. Overall, these results reveal a sophisticated role of dopamine in the rise of aggression in adult male mice.
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Data availability
Behavioural annotations, tracking, fibre photometry, slice electrophysiology and raw representative histology images can be downloaded from Zenodo (https://doi.org/10.5281/zenodo.13937311)64. Behaviour videos and additional histology images are available from the corresponding authors upon reasonable request. They are not deposited to a public database owing to their large size and the size limitation of online repositories. Illustrations of the coronal brain sections are based on images from the Allen Brain Reference Atlas (https://atlas.brain-map.org). Source data are provided with this paper.
Code availability
MATLAB codes used in this study can be downloaded from Zenodo (https://doi.org/10.5281/zenodo.13937311)64.
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Acknowledgements
We thank Y. Jiang for assisting with genotyping, T. Sippy for the insightful discussion regarding the dopamine role in humans, J. Basu and R. Yan for advice on in vitro recording experiments and W. Zhou for discussion and proofreading. Elements (mice) in Figs. 1e and 2f and Extended Data Fig. 7b,h were created with BioRender (https://biorender.com). This research was supported by NIH grants R01MH101377, R01MH124927 and U19NS107616 (D.L.), U01NS11335 (D.L. and Y.L.), U01NS12082 (Y.L.), P30-DA048736 (L.S.Z.) and R01MH133669 (N.X.T.), and by the Vulnerable Brain Project (D.L.).
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D.L. and B.D. conceived the project, designed experiments and wrote the manuscript. D.L. supervised the project. B.D. performed nearly all experiments and analysed the data. B.Z., X.D., X.C. and J.C. assisted with behavioural recording and/or analysis. L.Y. performed preliminary slice recording experiments. N.X.T. provided crucial feedback on the slice recording experiments and edited the paper. L.S.Z. provided CRISPR–SaCas9 viruses. Y.Z. and Y.L. developed GRABDA3h.
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Extended data figures and tables
Extended Data Fig. 1 Effect of chemogenetic manipulation of VTADAT cells on inter-male investigation, male sexual behaviours and locomotion.
a,b, Experimental design (a) and timeline (b) to chemogenetically manipulate VTADAT cells. c, Representative raster plots showing investigation and attack after saline or C21 treatment in mCherry, hM4Di, and hM3Dq novice aggressors. d,e, Investigation duration during the resident-intruder test (d), and the total distance travelled in the open-field arena (e) after saline or C21 treatment in mCherry, hM4Di, and hM3Dq novice aggressors. f, Representative raster plots showing investigation and attack after saline or C21 treatment in mCherry, hM4Di, and hM3Dq expert aggressors. g,h, Investigation duration during the resident-intruder test (g), and the total distance travelled in the open-field arena (h) after saline or C21 treatment in mCherry, hM4Di, and hM3Dq expert aggressors. i–m, Investigation duration (i), mount duration (j), latency to mount (k), averaged duration per intromission (l) and attack duration (m) towards female intruders after saline or C21 i.p. injections in novice aggressors. Each line represents one mouse. Bars and error bars in d,e,g,h,i–l represent mean ± SEM. Numbers inside the parentheses indicate the number of subject mice. d,e,g,h,i–m, repeated-measures (RM) two-way ANOVA followed by multiple comparison tests with Bonferroni’s correction. All tests are two-sided. All p values ≤ 0.05 are indicated. See Supplementary Table 1 for statistical details. Brain illustration in a is adapted from the Allen Brain Reference Atlas (https://atlas.brain-map.org).
Extended Data Fig. 2 Chemogenetic activation of VMHvlEsr1 cells promotes aggression in both novice and expert aggressors.
a, Experimental design to chemogenetically activate VMHvlEsr1 cells in male mice. b, Representative histology image showing hM3Dq expression (red) in the VMHvlEsr1 cells. c, The experimental timeline. d–g, The percentage of mice that attacked (d), attack duration (e), latency to attack (f) and investigation duration (g) of male intruders after saline or C21 i.p. injections in novice and expert aggressors. h–k, The percentage of mice that attacked (h), attack duration (i), latency to attack (j) and investigation duration (k) of female intruders after saline or C21 i.p. injections in novice and expert aggressors. Each line represents one mouse. Bars and error bars represent mean ± SEM. Numbers inside the parentheses indicate the number of subject mice. h, McNemar’s test; e–g, i–k, RM two-way ANOVA followed by multiple comparison tests with Bonferroni’s correction. All tests are two-sided. All p values ≤ 0.05 are indicated. See Supplementary Table 1 for statistical details. Brain illustration in a is adapted from the Allen Brain Reference Atlas (https://atlas.brain-map.org).
Extended Data Fig. 3 Chemogenetic manipulation of VTADAT cells does not change female aggression.
a, Experimental design. b, A representative histology image showing the expression of TH and hM4Di. c, Experimental timeline to chemogenetically inhibit VTADAT cells in mothers. d–h, The percentage of mice that attacked (d), attack duration (e), latency to attack (f), investigation duration (g) of a juvenile intruder and the total distance travelled in a large open arena (h) after saline or C21 treatment in aggressive lactating female mice (mothers). i, Experimental timeline to chemogenetically activate VTADAT cells in virgin and lactating females. j–n, The percentage of mice that attacked (j), attack duration (k), latency to attack (l), investigation duration (m) of a juvenile intruder and the total distance travelled in a large open arena (n) after saline or C21 treatment in virgin and aggressive lactating female mice (mothers). Each line represents one mouse. Bars and error bars represent mean ± SEM. Numbers inside the parentheses indicate the number of subject mice. d,j, McNemar’s test; f, paired Wilcoxon test; e,g,h, paired t-test; k–n, RM two-way ANOVA followed by multiple comparison tests with Bonferroni’s correction. All tests are two-sided. All p values ≤ 0.05 are indicated. See Supplementary Table 1 for statistical details. Brain illustration in a is adapted from the Allen Brain Reference Atlas (https://atlas.brain-map.org).
Extended Data Fig. 4 Effect of TH mutagenesis in VTADAT cells on inter-male investigation, male sexual behaviours and locomotion.
a,b, Experimental design (a) and timeline (b) to induce Rosa26 or TH mutagenesis in VTADAT cells. c,d, Investigation duration during each of the daily RI tests after ablating Rosa26 or TH in naïve male mice (c) and expert aggressors (d). e–h, Investigation duration (e), mount duration (f), latency to mount (g) and average duration per intromission (h) towards receptive female mice after Rosa26 or TH mutagenesis in naïve male mice (grey circle) and expert aggressors (red circle). i, Heat maps illustrating the body centre distribution of example sgRosa26- and sgTh-expressing mice during the 10-min locomotion test in a large open arena. j,k, The total travel distance (j) and the maximum velocity (k) in the open arena of the naive mice and expert aggressors with Rosa26 or sgTH mutagenesis. Each circle represents one mouse. Bars and error bars in e–h, j–k and solid lines and shades in c,d represent mean ± SEM. Numbers inside the parentheses indicate the number of subject mice. c,d, RM two-way ANOVA followed by multiple comparison tests with Bonferroni’s correction; e,g, Mann–Whitney test; f,h, unpaired t-test; j,k, ordinary two-way ANOVA followed by multiple comparison tests with Bonferroni’s correction. All tests are two-sided. All p values ≤ 0.05 are indicated. See Supplementary Table 1 for statistical details. Brain illustration in a is adapted from the Allen Brain Reference Atlas (https://atlas.brain-map.org).
Extended Data Fig. 5 dLS 6-OHDA lesion prevents the rise of aggression in naive mice but has no effect on expert aggressors.
a, Experimental design and timeline to lesion dopamine terminals at dLS and NAcs in naive wild-type male mice. b–d, Attack duration (b), latency to attack (c) and investigation duration (d) of BC male intruders during the 8-day RI tests after injecting vehicle or 6-OHDA into the NAcs or dLS of naive mice. RM two-way ANOVA followed by multiple comparison tests with Tukey’s correction. *p < 0.05, **p < 0.01, and ***p < 0.001. Statistics are for dLS-L vs. Ctrl comparisons. e, Experimental design and timeline to deplete dopamine terminals at the dLS in expert aggressors. f–h, Attack duration (f), latency to attack (g) and investigation duration (h) of BC male intruders during the 8-day RI tests after injecting vehicle or 6-OHDA into the dLS of expert aggressors. RM two-way ANOVA followed by multiple comparison tests with Bonferroni’s correction. Colour lines and shades represent mean ± SEM. Numbers inside the parentheses indicate the number of subject mice. All tests are two-sided. All p values ≤ 0.05 are indicated. See Supplementary Table 1 for statistical details. Brain illustrations in a,e are adapted from the Allen Brain Reference Atlas (https://atlas.brain-map.org).
Extended Data Fig. 6 VTADAT stimulation induces different patterns of dopamine release at the dLS and at the NAcc.
a–c, Experimental designs (a,b), and timeline (c) to stimulate the VTADAT cells and record the dopamine signal at the dLS or NAcc. d,e, PETHs of GRABDA3h signals (ΔF/F) at the dLS (d) and NAcc (e) aligned to the VTADAT light (colour) or sham light (0 mW, grey) onset. f, The mean GRABDA3h signal during the 5 s VTADAT stimulation. g, The onset of the GRABDA3h response following VTADAT stimulation. h, The latency to reach half of the GRABDA3h peak response amplitude following VTADAT stimulation. i, The half-decay time of GRABDA3h signal after VTADAT stimulation offset. j,k, PETHs of GRABDA3h signal of the dLS aligned to the VTADAT light (colour) or sham light (0 mW, grey) onset on the 1st (j) and 9th days of aggression (k). l, The mean GRABDA3h activity of the dLS on the 1st and 9th days of aggression during 5 s VTADAT stimulation or sham periods. Each circle and line represents one mouse. Lines and shades in d,e and j,k and bars and error bars in f–i and l represent mean ± SEM. Numbers inside the parentheses indicate the number of subject mice. f,h, unpaired t-test; g,i, Mann–Whitney test; l, RM two-way ANOVA followed by multiple comparison tests with Bonferroni’s correction. All tests are two-sided. All p values ≤ 0.05 are indicated. See Supplementary Table 1 for statistical details.
Extended Data Fig. 7 dLS GRABDA3h signals do not change with repeated social interactions.
a, Experimental design and fibre photometry set-up to record dopamine release at the dLS and a representative histology image. The white dashed lines indicate the fibre track. b, The experimental timeline to record dopamine release at the dLS during social interaction tests. c, Representative ΔF/F traces of GRABDA3h (black) and 405 nm control (grey) signals of dLS cells during the social interaction tests on the 1st (top) and 9th (bottom) days of testing. Red dashed lines indicate the introduction of the cupped male intruders. d,e, Average PETHs of GRABDA3h (black) and 405 nm channel (grey) signals (ΔF/F) aligned to the onset of intruder entry (d1 and e1) and investigation (d2 and e2). Red dash lines indicate the time 0 of the behaviour. f,g, The averaged ΔF/F of GRABDA3h signals (f) and 405 nm channel (g) during various behaviours on the 1st and 9th days of social interaction. h, Experimental design and timeline to record dopamine release at the dLS. i, The averaged ΔF/F of 405 nm channel during various behaviours of the RI tests on the last non-aggressive day and the 1st day of attack. j, The averaged ΔF/F of 405 nm channel during various behaviours of the RI tests on the 1st, 5th, and 9th days of aggression. Each line represents one mouse. Bars and error bars represent mean ± SEM. Numbers inside the parentheses indicate the number of subject mice. f,g,i,j, RM two-way ANOVA followed by multiple comparison tests with Bonferroni’s or Tukey’s correction. All tests are two-sided. All p values ≤ 0.05 are indicated. See Supplementary Table 1 for statistical details. Elements (mice) in b,h were created using BioRender (https://biorender.com).
Extended Data Fig. 8 Acute stimulation of VTADAT–dLS terminals or tonic activation of VTADAT–NAcs terminals does not change aggressive behaviours in novice aggressors.
a,b, Experimental design (a) and timeline (b) to determine the acute effect of VTADAT – dLS terminal stimulation on aggression. c, Behavioural raster of a representative mouse during the 20 s sham (0 mW) and light (4 mW) trials. d–f, The attack probability (d), attack duration (e) and latency to attack (f) during the 20 s light or sham stimulation periods. g, Heat maps illustrating the body centre distribution of an example mouse during the baseline and light-pairing periods when VTADAT – dLS terminals are activated in one pre-selected chamber. h, Time spent in the light-paired chamber during the 10-min baseline and 10-min light-pairing periods. i, Experimental design and timeline to quantify FOS expression after tonic stimulation of VTADAT terminals at the dLS. j, Representative images showing FOS (red) and EYFP (left, green), or ChR2 (right, green), expression in the VTA. White arrows highlight example FOS positive cells. k, The number of FOS positive cells in the VTA of EYFP and ChR2-expressing mice. l, Experimental schematics and representative histology images showing ChR2 cells in the VTA and their terminals in the NAc. The white arrows indicate the fibre tracks. m, Experimental timeline to evaluate the effect of tonic activation of VTADAT – NAcs terminals on aggression. n–q, The percentage of mice that attacked (n), attack duration (o), latency to attack (p) and investigation duration (q) of novice aggressors on sham and light-stimulated days. r, Heat maps illustrating the body centre distribution of an example mouse during the baseline and light-pairing period when VTADAT – NAcs terminals are activated in one pre-selected chamber. s, Time spent in the light-paired chamber during 10 min baseline and 10 min light-pairing periods. Each line represents one mouse. Bars and error bars represent mean ± SEM. Numbers inside the parentheses indicate the number of subject mice. d–f,h, RM two-way ANOVA followed by multiple comparison tests with Bonferroni’s correction; k, unpaired t-test; n, McNemar’s test; o,q,s, paired t-test; p, Wilcoxon matched-pairs signed-rank test. All tests are two-sided. All p values ≤ 0.05 are indicated. See Supplementary Table 1 for statistical details.
Extended Data Fig. 9 Aggression experience diminishes the dopamine-induced hyperpolarization of dLS cells.
a, Experimental timeline and schematics showing current-clamp recording of dLS cells in response to dopamine application and a representative image of the recorded lateral septum slice and a recording glass pipette. b, Left: Representative current-clamp recording traces of dLSWT cells of novice aggressors after bath application of dopamine, sumanirole (SUM), sulpiride (Sul), and sulpiride+dopamine. Right: A representative trace of a dLSWT cell of an expert aggressor after applying dopamine. c, Distribution of dLSWT cell responses to dopamine in novice and expert aggressors. d, The membrane potential change of dLSWT cells (difference between 2–3 min and -2–0 min of drug perfusion) after bath application of various drugs in novice and expert aggressors. e, The resting membrane potential (RMP) of dLSWT cells in novice and expert aggressors. Each dot represents one cell. Bars and error bars represent mean ± SEM. Numbers inside the parentheses or bars indicate the number of recorded cells. c, Fisher’s exact test; d, Ordinary one-way ANOVA followed by multiple comparison tests with Tukey’s correction and Mann–Whitney test between novice and expert aggressors; e, Mann–Whitney test. All tests are two-sided. All p values ≤ 0.05 are indicated. See Supplementary Table 1 for statistical details.
Extended Data Fig. 10 Effects of VTADAT terminal activation and aggression experience on excitatory synaptic transmission of dLS cells.
a, Schematics showing voltage-clamp recording of dLSWT cell responses to VTADAT inputs and the light stimulation protocol. b, Representative sEPSC traces of a dLS cell before (top) and after (bottom) the 5-min light stimulation. c,d, The amplitude (c) and frequency (d) of sEPSCs before and after light stimulation. e, Schematics and experimental timeline showing voltage-clamp recording of dLSDrd2 cells. f, Representative sEPSC traces of example dLSDrd2 cells from novice (top) and expert (bottom) aggressors. g,h, The amplitude (g) and frequency (h) of sEPSCs in novice and expert aggressors. i, Representative mEPSC traces of dLSDrd2 cells from novice (top) and expert (bottom) aggressors. j,k, The amplitude (j) and frequency (k) of mEPSCs in novice and expert aggressors. Each line or circle represents one cell. Bars and error bars represent mean ± SEM. Numbers inside the parentheses indicate the number of recorded cells. c,d, Friedman test followed by multiple comparison tests with Dunn’s correction. g–h,j–k, Mann–Whitney test. All tests are two-sided. All p values ≤ 0.05 are indicated. See Supplementary Table 1 for statistical details.
Supplementary information
Supplementary Note 1
Additional discussion regarding neural mechanisms underlying experience-dependent dopamine modulation of aggression and the clinical implication of our findings.
Supplementary Table 1
Detailed statistical results for all analyses shown in Figs. 1–4, and Extended Data Figs. 1–10.
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Dai, B., Zheng, B., Dai, X. et al. Experience-dependent dopamine modulation of male aggression. Nature (2025). https://doi.org/10.1038/s41586-024-08459-w
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DOI: https://doi.org/10.1038/s41586-024-08459-w
