Abstract
Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders1 and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli2. Nuclei within the ventromedial hypothalamus3,4,5, extended amygdala6 and limbic7 circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour8. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF–lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF–lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF–lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF–lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.
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Acknowledgements
This research was supported by US National Institutes of Health grants R01 MH090264, P50 MH096890 and P50 AT008661-01 (S.J.R.), R01 MH092306 (M.H.H.), T32 MH087004 (M.L.P., M.H. and M.F.), T32 MH096678 (M.L.P.), F30 MH100835 (M.H.), F31 MH105217 (M.L.P.), National Institute of General Medical Sciences 1FI2GM117583-01 (S.A.G.) and the Natural National Science Foundation of China 81200862 (H.Z.). We would like to thank K. Miczek and Y. Shaham for their input.
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S.A.G. and S.J.R. designed and wrote the manuscript. S.A.G., D.J.C., M.H., C.M., J.J.W., M.L.P., N.R. H.A., G.E.H., M.F., D.B., L.K., J.T. and B.K. collected behavioural and immunohistochemistry data and aided in data analysis. H.Z., M.-H.H., D.C., K.G. and M.L.S. designed, carried out and analysed electrophysiological experiments.
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Reviewer Information Nature thanks O. Hikosaka and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
Extended Data Figure 1 Social behaviours exhibited by resident CD-1 and intruder C57 mice during aggression screening.
a, Experimental schematic of aggression screening procedure used in a subset (40 residents and 40 intruders) of mice to quantify social behaviours. b–e, Bouts of attacks (F2,156 = 13.10, two-way ANOVA ***P < 0.0001; post-hoc test ***P < 0.001; n = 40 per group) (b), pursuits (c), withdrawals (F2,156 = 5.745, two-way repeated measures ANOVA **P < 0.001; post-hoc test ***P < 0.001; n = 40 per group) (d) and non-aggressive social approaches (e). f–h, Duration of attacks (F2,156 = 7.069, two-way repeated measures ANOVA **P < 0.001; post-hoc test ***P < 0.001; n = 40 per group) (f), pursuits (g), withdrawals (h) and non-aggressive social approaches (e). All data are presented as mean ± s.e.m.
Extended Data Figure 2 Detailed ethological analysis of AGG aggression-related behaviours.
a, Experimental schematic of aggression screening procedure used in a sample (448 mice total; 138 NON and 310 AGG) of mice. b, Histogram of attack latency frequency using 10-s bins. c–e, Mean distribution across screening sessions (left) and individual screening sessions (right) for latency to aggression (F2,1338 = 49.37, two-way repeated measures ANOVA P < 0.001; post-hoc test, *P < 0.001; n = 138–310) (c), number of attack bouts (F2,1338 = 21.03, two-way repeated measures ANOVA P < 0.001; post-hoc test, *P < 0.001; n = 138–310) (d) and mean attack duration (F2,1338 = 11.96, two-way repeated measures ANOVA P < 0.001; post-hoc test, *P < 0.001; n = 138–310) (e). f, g, Correlation of mean latency to initial aggression with mean attack bouts (r = −0.78, P < 0.0001) (f) and mean duration of attack bouts (r = −0.40, P < 0.0001) (g). Distribution plots are presented as the median with interquartile range and normality determined by D’Agostino–Pearson, Shapiro–Wilk and Kolmogorov–Smirnov normality tests (P < 0.0001). Summary data are represented as mean ± s.e.m.
Extended Data Figure 3 Aggression CPP behaviour.
a, Experimental schematic of aggression CPP procedure. b, c, Individual duration spent in the intruder-paired context for AGG (t7 = 3.106, *P < 0.05; two-tailed paired t-test, n = 8 per group) (b) and NON (t7 = 2.918, *P < 0.05; two-tailed paired t-test, n = 8 per group) (c). d, Duration spent in the middle neutral chamber during pre-test and test sessions. e, Experimental schematic of sensory CPP procedure. f, g, Individual duration spent in the intruder-paired context for AGG (f) and NON (g). h, Duration spent in the middle neutral chamber during pre-test and test sessions. Summary data are represented as mean ± s.e.m.
Extended Data Figure 4 BF–lHb circuit tracing and GABAergic cell-type specificity.
a, Schematic of viral tracing strategy. b, Representative BF viral infection with AAV2-hSyn-eYFP. Scale bar: 500 μm. c, Histological analysis of viral infection with AAV2-hSyn-eYFP (F3,11 = 223.0, one-way ANOVA ***P < 0.0001, post-hoc test, ***P < 0.0001; n = 3 mice, 3 slices per mouse) across adjacent anatomical regions. d, e, Whole-cell electrophysiological recordings (d) and representative traces of lHb neurons photostimulated with AAV2-hSyn-ChR2.0 in the absence or presence of bath-applied GABAA receptor antagonist gabazine (2 μm; F2,7 = 220, one-way ANOVA P < 0.05; post-hoc test, ***P < 0.001, n = 4, 2, 2 cells from 2 mice) (e). f, Optically evoked IPSC response delay (n = 21 oIPSC events, 2 mice). g, Representative images of eYFPBF→lHb terminal colocalization between vesicular GABA transporter (top), and not vesicular glutamate transporter 1 (bottom). Scale bars: 10 μm; white arrows indicate colocalization within insets. MS, medial septum; pLS, posterior lateral septum. Summary data are represented as mean ± s.e.m.
Extended Data Figure 5 Multiunit anaesthetized optrode recordings.
a, Schematic of in vivo anaesthetized multi-unit optrode recording procedure (left) and representative optrode placement in lHb (right; scale bar: 200 μm). b, c, Heatmaps of normalized firing rates for lHb neurons in response to BF terminal stimulation with ChR2BF→lHb (b) or NpHR3BF→lHb (c) and averaged spike wave-form shown below for pre-stimulation, stimulation and post-stimulation epochs. d, Percentage of cells by firing response (top) and average normalized lHb firing rate (bottom) after BF–lHb terminal stimulation with ChR2BF→lHb for all identified cells (F2,134 = 8.249, one-way repeated-measure ANOVA P < 0.001; post-hoc test, *P < 0.05; n = 68 cells from 3 mice) and cells that significantly decreased firing during the stimulation epoch (F7,105 = 8.868, one-way repeated-measure ANOVA P < 0.0001; post-hoc test, *P < 0.05; n = 16/68 cells from 3 mice). e, Percentage of cells by firing response (top) and average normalized lHb firing rate (bottom) after BF–lHb terminal stimulation with NpHR3BF→lHb for all identified cells (F2,128 = 10.32, one-way repeated-measure ANOVA P < 0.0001; post-hoc test, *P < 0.05; n = 65/65 cells from 3 mice) and cells that significantly increased firing during the stimulation epoch (F7,203 = 17.58, one-way repeated-measure ANOVA P < 0.0001; post-hoc test, *P < 0.05; n = 30/65 cells from 3 mice). mHb, medial habenula. Summary data are represented as mean ± s.e.m.
Extended Data Figure 6 BF–lHb AAV infection and CPP locomotor behaviour.
a, Schematic of BF coronal slice (left), alongside representative AAV-ChR2-eYFP (top) and AAV-NpHR3.0-eYFP (bottom) infections. Scale bar: 500 μm. b, Schematic of lHb coronal slice (left), alongside representative images of BF terminal infection by AAV-ChR2-eYFP (middle top) and AAV-NpHR3.0-eYFP (middle bottom) within the lHb. Scale bar: 200 μm. Representative close-ups of terminal regions shown in insets on right. Scale bar: 50 μm. All representative images counterstained with DAPI. c, d, Histological analysis of BF infection in NON (c) and AGG (d) mice. e, f, Histological analysis of habenular viral infection in NON (e) and AGG mice (f). g–j, Total distance travelled (g, h) and mean velocity (i, j) between NON and AGG during the CPP pre-test and test phase. All data are presented as mean ± s.e.m., and are not significant as determined by two-way ANOVA, P < 0.05. dStr, dorsal striatum; mHb, medial habenula; MS, medial septum; pLS, posterior lateral septum.
Extended Data Figure 7 Direct lHb stimulation bi-directionally modulates aggression reward.
a, Schematic of viral infection strategy. b, c, Representative images of lHb cell body infection in NON (b) and AGG (c). Scale bar: 200 μm. d, Histological analysis of lHb viral infection. e, Representative CPP traces of NON. NON::NpHRlHb cell body infection mimics the physiological effect of NON::ChR2BF→lHb terminal stimulation. f, Normalized CPP score (t15 = 2.834, *P < 0.05; two-tailed unpaired t-test, n = 8–9 per group) and subtracted CPP score (t15 = 3.058, **P < 0.01; two-tailed unpaired t-test, n = 8–9 per group) in NON::eYFPlHb and NON::NpHRlHb. g, Individual duration spent in the intruder-paired context for NON::eYFPlHb (t9 = 0.9129, P > 0.05; two-tailed paired t-test, n = 10 per group) and NON::NpHRlHb (t9 = 2.344, *P < 0.05; two-tailed paired t-test, n = 10 per group). h, Representative CPP traces of AGG::eYFPlHb and AGG::ChR2lHb. i, Normalized CPP score (t18 = 2.692, *P < 0.05; two-tailed unpaired t-test, n = 9–11 per group) and subtracted CPP score (t18 = 4.203, ***P < 0.01; two-tailed unpaired t-test, n = 9–11 per group) for the intruder-paired context in AGG::eYFPlHb and AGG::ChR2lHb. j, Individual duration spent in the intruder-paired context for AGG::eYFPlHb mice (t10 = 3.212, **P < 0.01; two-tailed paired t-test, n = 9 per group) and AGG::ChR2lHb mice (t8 = 1.348, P < 0.05; two-tailed paired t-test, n = 11 per group). Summary data are represented as mean ± s.e.m. dStr, dorsal striatum; mHb, medial habenula.
Extended Data Figure 8 BF–lHb stimulation modulates cocaine CPP.
a, Experimental timeline of general anxiety and cocaine CPP testing. b–e, BF–lHb stimulation during open field testing (b, c) and elevated plus maze testing (d, e). f, Subthreshold cocaine (10 mg kg−1, intraperitoneal) CPP procedure with BF–lHb stimulation during CPP test (t9 = 2.403, P < 0.05; two-tailed unpaired t-test, n = 5–6 per group).
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Golden, S., Heshmati, M., Flanigan, M. et al. Basal forebrain projections to the lateral habenula modulate aggression reward. Nature 534, 688–692 (2016). https://doi.org/10.1038/nature18601
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DOI: https://doi.org/10.1038/nature18601
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