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Transformations of neural representations in a social behaviour network

Nature volume 608, pages 741–749 (2022)Cite this article

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Abstract

Mating and aggression are innate social behaviours that are controlled by subcortical circuits in the extended amygdala and hypothalamus1,2,3,4. The bed nucleus of the stria terminalis (BNSTpr) is a node that receives input encoding sex-specific olfactory cues from the medial amygdala5,6, and which in turn projects to hypothalamic nuclei that control mating7,8,9 (medial preoptic area (MPOA)) and aggression9,10,11,12,13,14 (ventromedial hypothalamus, ventrolateral subdivision (VMHvl)), respectively15. Previous studies have demonstrated that male aromatase-positive BNSTpr neurons are required for mounting and attack, and may identify conspecific sex according to their overall level of activity16. However, neural representations in BNSTpr, their function and their transformations in the hypothalamus have not been characterized. Here we performed calcium imaging17,18 of male BNSTprEsr1 neurons during social behaviours. We identify distinct populations of female- versus male-tuned neurons in BNSTpr, with the former outnumbering the latter by around two to one, similar to the medial amygdala and MPOA but opposite to VMHvl, in which male-tuned neurons predominate6,9,19. Chemogenetic silencing of BNSTprEsr1 neurons while imaging MPOAEsr1 or VMHvlEsr1 neurons in behaving animals showed, unexpectedly, that the male-dominant sex-tuning bias in VMHvl was inverted to female-dominant whereas a switch from sniff- to mount-selective neurons during mating was attenuated in MPOA. Our data also indicate that BNSTprEsr1 neurons are not essential for conspecific sex identification. Rather, they control the transition from appetitive to consummatory phases of male social behaviours by shaping sex- and behaviour-specific neural representations in the hypothalamus.

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Fig. 1: BNSTprEsr1 neurons are necessary for the transition from appetitive to consummatory social behaviours in sexually experienced male mice.
Fig. 2: BNSTprEsr1 neurons represent intruder sex via a cell-identity code.
Fig. 3: BNSTpr is required for male-biased intruder sex representations in VMHvl.
Fig. 4: Differential effect of BNSTpr silencing on sex representations in VMHvl and MPOA shown by sequential imaging of identified units.
Fig. 5: Differential effect of BNSTpr silencing on behaviour representations in MPOA and VMHvl shown by unilateral ChemoScope imaging.

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Data availability

The data on which this study is based are available on reasonable request.

Code availability

The custom MATLAB and Python codes used to analyse the data in this study are available on request.

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Acknowledgements

We thank A. Kennedy and A. Nair for advice on miniscope data analysis; M. Hui and C. Kim for assistance with animal surgery and behaviour experiments; M. Zelikowsky for advice on statistical analysis; W. Hong for pilot experiments performed on BNSTpr; X. Da, J. Chang and X. Wang for histology; Y. Huang for genotyping; Caltech OLAR staff for animal care; J. Costanza for mouse colony management; M. Schnitzer, A. Vinograd and B. Weissbourd for constructive comments on the manuscript; C. Chiu for laboratory management; G. Mancuso for administrative assistance; and members of the Anderson laboratory for helpful comments on this project. This paper was supported by NIH grant nos. MH070053, MH112593 and NS123916 and by the Simons Collaboration on the Global Brain. D.J.A. is an investigator of the Howard Hughes Medical Institute.

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  1. Tomomi Karigo

    Present address: Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA

Authors and Affiliations

  1. Division of Biology and Biological Engineering 140-80, TianQiao and Chrissy Chen Institute for Neuroscience, California Institute of Technology, Pasadena, CA, USA

    Bin Yang, Tomomi Karigo & David J. Anderson

  2. Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA

    Bin Yang, Tomomi Karigo & David J. Anderson

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Contributions

B.Y. performed experiments, analysed data and prepared figures. T.K. performed retrograde tracing experiments. B.Y. and D.J.A. designed the study and wrote the paper.

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Correspondence to David J. Anderson.

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Extended data figures and tables

Extended Data Fig. 1 Chemogenetic and optogenetic silencing of BNSTprEsr1 neurons disrupts aggression and mating.

a, Illustration of hM4d (Gi)-mediated silencing in bilateral BNSTprEsr1 neurons. b, Example behavior raster plot from 1 animal across 4 recording sessions. c, Percent of BNSTprEsr1 neurons that express mCherry. Values are plotted as mean ± SEM, n = 6 mice. d–m, Measurements performed before (pre-CNO: saline injection, gray points) vs. after (CNO injection, maroon points) chemogenetic silencing of BNSTpr, of time spent sniffing male intruders (d), number of attack bouts toward male intruders (e), time spent attacking male intruders (f), time spent sniffing female intruders (g), number of mount bouts toward female intruders (h), time spent mounting female intruders (i), time spent mounting male intruders (j), time spent attacking female (k), and time spent attacking male (l), time spent mounting female (m) in mCherry/CNO only controls (l, m) per 30-minute session. 100µl containing either saline (pre-CNO) or 7.5mg/kg CNO was given i.p. 60 min prior to start of behavior tests. n, Illustration of bilateral optogenetic silencing in BNSTpr. o, t, Mean probability of sniff behavior occurring relative to onset of optogenetic silencing. p, u, Duration of sniffing toward male (p) or female (u) intruders. q, v, Duration of attack (q) toward male intruders or mount (v) toward female intruders as a percentage of the duration of optogenetic silencing. “Sham” controls were the same animals during a 10s “sham stimulation,” i.e., without light. r, w, Percent of time spent interacting with male or female urine (r), or male or female conspecifics separated by a meshed barrier (w) before and during (r) or before, during and after (w) optogenetic silencing of BNSTpr. Optogenetic silencing conditions: 470nm @ ~1 mW/mm2 for 10 s (o, p, q, t, u, v). 470nm @ ~1 mW/mm2 for 10 min (r, s, w, x) Statistics: For Chemogenetic inhibition, two-sided Wilcoxon signed-rank test (d–m). Values are plotted as total time or total bouts per 30-minute session per animal. n = 7 mice (d–k), n = 4 mice (l, m). For Optogenetic inhibition during interactions with male or female conspecifics (o, p, q, t, u, v), two-sided Kolmogorov-Smirnov test (o, t), two-sided Wilcoxon signed-rank test (p, q, u, v). Male-male trials (o, p, q), n = 131 stim and 125 sham trials pooled from 10 mice. Male-female trials mice (t, u, v), n = 181 stim and 170 sham trials pooled from 10 mice. For Optogenetic inhibition during urine preference (r) and “pencil cup” (mesh barrier) (w) tests, two-way ANOVA with Bonferroni correction, n = 6 mice. Values are plotted as mean ± SEM. ****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.05. The mouse brain images in this figure (a, n) have been reproduced from ref. 41.

Extended Data Fig. 2 Optogenetic silencing of BNSTprEsr1 terminals in MPOA or VMHvl during male-male/ male-female interactions.

a, c, Diagram illustrating BNST terminal silencing in MPOA (a) or VMHvl (c). b, d, Representative images showing cre-dependent Halo-EYFP cell body expression in BNSTpr and axonal expression in MPOA (b) and VMHvl (d). Similar expression patterns were observed in all 14 animals tested (b, d). e, h, k, n, Raster plots showing distribution of social behaviors relative to optogenetic silencing of BNSTpr terminal in MPOA (e, k) or VMHvl (h, n). f, i, l, o, Average probability of behavior occurring relative to onset of optogenetic silencing. g, j, m, p, Duration of attack (g, j) or mount (m, p) as a percentage of the 5-second optogenetic silencing. Statistics: two-sided Kolmogorov-Smirnov test (f, i, l, o), values are plotted as mean ± SEM. Two-sided Wilcoxon signed-rank test (g, j, m, p). ****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.05. n = 7 mice for each silenced region. The mouse brain images in this figure (a, c) have been reproduced from ref. 41.

Extended Data Fig. 3 Performance of 0.85 mm Ø prism coupled GRIN lens compared to 0.6 mm Ø GRIN lens for imaging BNSTpr.

a, b, d, e, Illustrations showing GRIN lens placement in BNSTpr from top (a, d) and side (b, e) views. a–c, Illustrations or data from animals implanted with prism lenses. d–f, Data from animals implanted with conventional cylindrical GRIN lenses. c, f, Mean pixel correlation during 1 example imaging session. g, Cumulative fraction of number of units captured per imaging session normalized to the diameter of the GRIN lens. h, Cumulative fraction of the peak to noise ratio (PNR) of all units imaged using either a 0.6mm grin lens or a 0.85mm prism-coupled grin lens. i, Raster plots of MeApd, BNSTpr, MPOA and VMHvl Esr1+ neuronal activity during male-male or male-female unrestrained social interactions. For comparative purposes, all frames containing each behavior scored (indicated below plot) during a 30 min social interaction were concatenated and binned into 10s intervals; Averaged z-scored responses of each unit across all bins are shown. Tables below show the average variance (R2) in population activity that can be explained by intruder sex or by male and female-directed consummatory behavior and the ratio of female-preferring to male-preferring neurons in each imaged region. The mouse brain image in this figure (i) has been reproduced from ref. 41.

Extended Data Fig. 4 Miniscope imaging analysis of BNSTpr neurons.

a, Example raster plot of population responses to 5 repeated presentations of dangled male, female or toy intruders from a cohort of 9 individual animals (cohort 1, n = 6, cohort 2, n = 9). b, continuously recorded raw ∆F/F traces of 20 example neurons from 1 recording session. c, Average z-scored responses of BNSTpr neurons per animal (n = 15 mice) during 8 annotated behaviors/conditions. d, Percent of units per animal (n = 15 mice) whose average response is >2σ baseline measured prior to intruder introduction. e, Histograms of male- / female-preferring units determined by choice probability from single-unit responses to dangled intruders. f, Venn diagram of units that are male- or female- sniff preferring (top), or attack- or mount- preferring (bottom) (determined by choice probability) during free interactions with, or sniffing of dangled, male or female intruders. g–l, Comparison of BNSTprEsr1 (g, h, i) and BNSTprAB (j, k, l) population responses to dangled presentation of male or female intruders. g, j, Illustration of BNSTprEsr1 (g) and BNSTprAB (j) miniscope imaging using a conventional 0.6mm GRIN lens. h, k, Average z-scores of single-unit responses relative to the start of sniff during 5 repeated dangling presentations of male or female intruders. i, l, percent of male vs female preferring units in BNSTpr. n = 15 mice. The mouse brain images in this figure (g, j) have been reproduced from ref. 41.

Extended Data Fig. 5 ChemoScope imaging of MPOA and VMHvl across multiple days.

a, f, k, Diagram showing the position of 0.6mm GRIN lens in relation to MPOA, BNSTpr and VMHvl. b–e, Sagittal histology sections showing the expression of jGCaMP7f in MPOA (b, c), hM4Di-mCherry in BNSTpr (b, e), and lack of cell body expression of hM4Di-mCherry in MPOA (d). g–j, Coronal histology sections showing the expression of jGCaMP7f in MPOA (g, h), hM4Di-mCherry in BNSTpr (g, j), and lack of cell body expression of hM4Di-mCherry in MPOA (i). l–o, Coronal histology sections showing the expression of jGCaMP7f VMHvl (l, m), hM4Di-mCherry in BNSTpr (o), and lack of cell body expression of hM4Di-mCherry in VMHvl (n). Similar expression patterns were observed in 14 mice tested (7 mice for each imaged region). p, r, example raster plots of average single-unit responses to 5 trials of dangled male or female intruders in MPOA (p) and VMHvl (r) across multiple imaging sessions (sessions are 2-3 days apart). Units are sorted based on their eigenvalues in the first principal component of the population activity vector. q, s, percent of units that are male or female preferring across 2 days of imaging in MPOA (q) and VMHvl (s), in saline-injected animals. n = 7 mice from each imaged region.

Extended Data Fig. 6 ChemoScope imaging of MPOA and VMHvl.

a–p, Cumulative fractions showing average single unit responses to dangled male and female intruders from initially (i.e., in saline-injected animals) male preferring (a–d), female preferring (e–h), co-active (i–l) and not active (m–p) units in MPOA (a, b, e, f, i, j, m, n) and VMHvl (c, d, g, h, k, l, o, p). q, average responses to dangled male or female intruders in MPOA (left panel) and VMHvl (right panel). r–t, mean response difference between dangled female and male intruders (r), percentage of male vs female preferring units (s) and the ratio of female- to male-preferring units (t) before and after the application of CNO, in MPOA or VMHvl. Statistics: two-sided Kolmogorov-Smirnov test (a–q), values are plotted as mean ± SEM. Two-sided Wilcoxon signed-rank test (r–t). ****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.05. n = 7 mice from each imaged region.

Extended Data Fig. 7 Tracking changes to MPOA and VMHvl single-unit responses before and after silencing BNSTpr.

a, b, Spatial maps showing distribution of male- or female preferring units before (gray) and after (maroon) chemogenetic silencing of BNSTpr in MPOA(a) or VMHvl (b). c, d, response profiles of initially (i.e., in saline-injected animals/pre-CNO) male- or female preferring units after BNSTpr silencing, in MPOA (c) and VMHvl (d). (e–s) 2d scatter plots and bar plots showing average single-unit responses to dangled male and female intruders from tracked units in MPOA and VMHvl, sorted as indicated.

Extended Data Fig. 8 Effect of BNSTpr silencing on VMHvl behavior representations and female / male preference.

a, Raster plot of all recorded units from 1 example animal over 3 imaging sessions. Units are sorted separately for each recorded session based on their responses during male and female interactions. b, c, e–h, Cumulative fractions (b, e, g) and bar graphs (c, f, h) of VMHvl single-unit responses to initially (i.e., in saline-injected animals/pre-CNO) sniff active (b, c) or attack active (e–h) cells during attack before CNO (i.e., saline-injected/pre-CNO) (e, f), or before and after CNO (b, c, g, h). g, h, mCherry/CNO only controls. d, percent sniff active cells in VMHvl before (i.e., saline-injected/pre-CNO) and after CNO. Statistics: two-sided Kolmogorov-Smirnov test (b, e, g), values are plotted as mean ± SEM, two-sided Wilcoxon signed-rank test (c, d, f, h). ****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.05. n = 7 mice.

Extended Data Fig. 9 Retrograde tracing and imaging of BNSTpr projection neurons.

a, d, Diagram showing retrograde tracing of BNSTpr projection neurons. b, e, Example images showing MPOA or VMHvl projecting neurons expressing mScarlet or mNeongreen. c, Average number of back-labeled BNSTpr neurons per animal. n = 7 mice. f, Percent of VGAT+ projection neurons that are Esr1+. n = 3 mice per injected region. Values are plotted as mean ± SEM (c, f). g, j, Diagram showing miniscope imaging of VMHvl-projecting (n = 2 mice) or MPOA-projecting (n = 2 mice) BNSTpr neurons. h, k, Average z-scores of single-unit responses relative to the start of sniff during 5 repeated dangling presentations of male or female intruders (n = 2 mice per injected region). i, l, Percent of male- or female-preferring units (n = 2 mice per injected region). The mouse brain images in this figure (a, b, g, j) have been reproduced with permission from ref. 41.

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Yang, B., Karigo, T. & Anderson, D.J. Transformations of neural representations in a social behaviour network. Nature 608, 741–749 (2022). https://doi.org/10.1038/s41586-022-05057-6

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