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Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus

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Abstract

Social behaviours, such as aggression or mating, proceed through a series of appetitive and consummatory phases1 that are associated with increasing levels of arousal2. How such escalation is encoded in the brain, and linked to behavioural action selection, remains an unsolved problem in neuroscience. The ventrolateral subdivision of the murine ventromedial hypothalamus (VMHvl) contains neurons whose activity increases during male–male and male–female social encounters. Non-cell-type-specific optogenetic activation of this region elicited attack behaviour, but not mounting3. We have identified a subset of VMHvl neurons marked by the oestrogen receptor 1 (Esr1), and investigated their role in male social behaviour. Optogenetic manipulations indicated that Esr1+ (but not Esr1) neurons are sufficient to initiate attack, and that their activity is continuously required during ongoing agonistic behaviour. Surprisingly, weaker optogenetic activation of these neurons promoted mounting behaviour, rather than attack, towards both males and females, as well as sniffing and close investigation. Increasing photostimulation intensity could promote a transition from close investigation and mounting to attack, within a single social encounter. Importantly, time-resolved optogenetic inhibition experiments revealed requirements for Esr1+ neurons in both the appetitive (investigative) and the consummatory phases of social interactions. Combined optogenetic activation and calcium imaging experiments in vitro, as well as c-Fos analysis in vivo, indicated that increasing photostimulation intensity increases both the number of active neurons and the average level of activity per neuron. These data suggest that Esr1+ neurons in VMHvl control the progression of a social encounter from its appetitive through its consummatory phases, in a scalable manner that reflects the number or type of active neurons in the population.

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Figure 1: Generation and characterization of a knock-in mouse line expressing Cre recombinase in Esr1+ cells.
Figure 2: Esr1+ cells in VMHvl are necessary and sufficient for aggression.
Figure 3: Esr1+ cells in VMHvl mediate close investigation (CI) and mounting behaviours.
Figure 4: Behavioural responses shift from mounting to attack depending on photostimulation intensity and the number of activated cells in VMHvl.

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Acknowledgements

We thank C. Park for behavioural scoring, R. Robertson for behavioural scoring and MATLAB programming, L. Lo for testing Cre-mediated recombination in Esr1cre/+ male mice, C. Chiu and X. Wang for histology, M. McCardle for genotyping, J. S. Chang for technical assistance, S. Pease for generation of knock-in mice, H. Cai for training in slice electrophysiology, A. Wong for assistance with two-photon imaging, K. Deisseroth and J. Harris for AAV constructs, E. Boyden for advice on ferrule fibre fabrication, D. Lin and M. Boyle for their contributions to early stages of this project, W. Hong and R. Axel for comments on the manuscript, C. Chiu for laboratory management and G. Mancuso for administrative assistance. D.J.A. is an Investigator of the Howard Hughes Medical Institute and a Paul G. Allen Distinguished Investigator. This work was supported in part by NIH grant no. R01MH070053, and grants from the Gordon Moore Foundation and Ellison Medical Research Foundation. H.L. was supported by the NIH Pathway to Independence Award 1K99NS074077. T.E.A. was supported by NIH NRSA postdoctoral fellowship grant 1F32HD055198-01 and a Beckman Fellowship.

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Contributions

H.L. characterized Esr1cre mice, designed and performed optogenetic behavioural experiments and co-wrote the manuscript; D.-W.K. performed slice electrophysiology and imaging experiments; R.R. performed in vivo electrophysiology; T.E.A. generated the Esr1cre targeting construct and AAV vectors; A.C. carried out some behavioural experiments; L.M. and H.Z. performed in situ hybridization experiments; D.J.A. supervised experiments and co-wrote the manuscript.

Corresponding author

Correspondence to David J. Anderson.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Esr1 mRNA expression in Esr1cre/+ male and female mice.

ad, In situ hybridization for Esr1 mRNA in Esr1cre/+ male (a, b, red) and female (c, d, red) mice (Bregma −1.65 mm). b, d are the boxed areas in ac. Note that the expression of Esr1 mRNA in VMHvl (dotted outline) is higher in females than in males. eg, Immunofluorescence showing that expression of a Cre-dependent hrGFP reporter expressed from a stereotaxically injected AAV (f, green) is restricted to VMHvl, without detectable spillover expression in the nearby arcuate hypothalamic nucleus (ARH). hs, Double labelling for behaviourally-induced c-Fos (h, k, n, q, anti-c-Fos, green) and Esr1 (i, l, o, r, anti-Esr1, red) in wild-type male residents following a 30-min resident–intruder test with no (hj, n = 3), male (km, close investigation without attack, n = 4; qs, attack, n = 5) or female (np, mating, n = 5) intruders. tv, Quantification of the fraction of total (NISSL+) cells that were c-Fos+ following different behaviours (t), fraction of c-Fos+ that were Esr1+ for each behaviour (u), and fraction of NISSL+ cells that are Esr1+ (v) in VMHvl, quantified from data as illustrated in hs. *P < 0.05, ***P < 0.001, ****P < 0.0001; one-way ANOVA with Dunnett’s multiple comparisons test.

Extended Data Figure 2 In vivo electrophysiological responses of Esr1+ VMHvl neurons during photostimulation with 2, 10, and 20-ms pulses.

a, Photostimulation paradigm. Extracellular recordings were obtained from Esr1+ VMHvl neurons expressing AAV2 Cre-dependent ChR2 in solitary, awake behaving animals using a modification of a 16-wire electrode bundle micro-drive31 containing an integrated optic fibre. Following a 30-s baseline measurement, photostimulation trials were performed (473 nm, 20 Hz, blue bars) for 30 s using three different pulse-widths (2 ms, 10 ms, and 20 ms). Five trials, each 2 min in length, were recorded for each pulse-width (see c). b, Mean firing rate changes averaged across 12 multi-units (5 trials per unit) in VMHvl during 30-s photostimulation periods. 2 ms, 17.98 ± 2.35 spikes per s, 10 ms, 29.26 ± 3.67 spikes per s, and 20 ms, 28.07 ± 4.65 spikes per s. *P < 0.05, Wilcoxon rank sum test. c, Spiking responses of 12 multi-unit recording channels in VMHvl. Each raster plot represents the average of five trials per channel per pulse-width (2, 10 or 20 ms), arranged in order of response magnitude. The arrangement is the same for the three pulse widths (2 ms, 10 ms and 20 ms). df, Peri-stimulus time histograms (PSTHs) illustrating mean firing rate changes averaged over the 12 multi-units shown in c, for photostimulation trials using 20 ms (d), 10 ms (e), or 2 ms (f) light pulse-widths. Data are mean ± s.e.m. See also main Fig. 2d, which presents whole-cell patch-clamp recordings from Esr1+ neurons in VMHvl acute slice preparations, indicating that spike fidelity is close to 100% and statistically indistinguishable between 2 ms and 20 ms light pulse-widths.

Extended Data Figure 3 Photostimulation of Esr1+ VMHvl neurons expressing mCherry or Esr1 VMHvl neurons expressing ChR2 fails to evoke aggression.

a, Animals expressing Cre-dependent mCherry virus in VMHvl fail to show aggression during photostimulation. Representative raster plot showing episodes of close investigation (CI; yellow ticks), mounting (green ticks) or attack (red ticks) in an mCherry-expressing Esr1cre/+ male. No attacks are evoked towards either a castrated male (upper plot) or an intact unreceptive female (lower plot) during photostimulation trials (blue bars; 473 nm, 20 ms pulses, 20 Hz, 30 s; numbers indicate mW mm−2). b, c, Activation of the non-Esr1-expressing subpopulations of VMHvl neurons is insufficient to evoke aggression. Representative raster plots illustrating photostimulation-evoked behavioural responses towards a castrated male by a wild-type (b) or an Esr1cre/+ (c) mouse injected with the ‘Cre-out’ AAV2 containing a floxed ChR2 coding sequence (Fig. 2r). Attack (red; 3.2-6.8 mW mm−2) was elicited during photostimulation trials (blue bars) in wild-type males, indicating that the floxed ChR2 construct is effective in the absence of Cre, whereas no behaviour was evoked in Esr1cre/+ males where ChR2 is expressed in Esr1, but not in Esr1+, neurons.

Extended Data Figure 4 Latency to attack depends on the initial orientation of the resident with respect to the intruder at the time of photostimulation.

a, b, d, e, Video stills illustrating initial position and orientation (‘facing toward vs away’) of a ChR2-expressing Esr1cre/+ male (black) towards a castrated male intruder (white) at the onset of photostimulation (a, d) and at the initiation of evoked attack (b, e). c, f, trajectory plots showing the paths taken by the Esr1cre/+ males from the onset of photostimulation (red dots) to the onset of attack (red arrowheads). Cage dimensions indicated in f. g, h, Quantification of distance travelled from onset of photostimulation to attack (g) and latency to attack (h), from data in af (n = 11, **P < 0.01, Mann–Whitney U-test). Note that if the resident is initially facing away from the intruder (df), the latency to attack is longer (h) because the resident initially moves in the direction that it was facing (f) and does not attack until it encounters the intruder at close range. Data are mean ± s.e.m. n = number of animals.

Extended Data Figure 5 Photostimulation of VMHvl Esr1+ neurons in females evokes close investigation and mounting.

a, b, Representative raster plots illustrating photostimulation-evoked behaviours in Esr1cre/+ females expressing either ChR2 (a) or EGFP (b) in VMHvl towards an intact male (upper), a castrated male (middle), or an intact female (lower). Note that CI (yellow) is augmented during photostimulation in the animal expressing ChR2, but not in the animal expressing EGFP. c, d, Quantification of CI by Esr1cre/+ females expressing EGFP (blue bars; n = 4 per intruder) or ChR2 (red bars; n = 3 per intruder) during 30 s before photostimulation (open symbols) vs during 30 s photostimulation period (solid symbols). *P < 0.05, **P < 0.01, ***P < 0.001; two-way ANOVA with Tukey’s multiple comparisons test. e, Raster plot illustrating that photostimulation of Esr1cre/+ female expressing ChR2 evokes mounting (green), but failed to elicit male-like aggression. f, g, Quantification of mounting parameters by Esr1cre/+ females expressing EGFP (open bars; n = 4 per intruder) or ChR2 (black bars; n = 3 per intruder) towards the indicated intruders. Two-way ANOVA with Tukey’s multiple comparisons test, *P = 0.02 (f) and *P = 0.03 (g) without correction for multiple comparisons, but not significant when corrected (P = 0.07 (f) and P = 0.06 (g)). Data are mean ± s.e.m. n = number of animals.

Extended Data Figure 6 CI and mounting are evoked at lower photostimulation intensities than attack.

a, b, The average threshold intensity of photostimulation that evokes close investigation (CI) is similar to that required to evoke mounting (b), but significantly lower than that required to evoke attack (a). Data represent ChR2-expressing Esr1cre/+ males that exhibited CI and attack (a, n = 12 per group) or CI and mounting (b, n = 9 per group) in a given test session. **P < 0.01; Mann–Whitney U-test. Data are mean ± s.e.m. n = number of animals. c, d, Raster plot from a test session with the same resident male, showing that activation of VMHvl Esr1+ neurons elicits mounting and/or attack towards a castrated male intruder, dependent upon the intensity of photostimulation. c, A raster plot illustrating the experiment shown in Supplementary Video 6. Mounting (green) was elicited in a ChR2-expressing Esr1cre/+ male towards an unreceptive intact female during photostimulation trials (blue bars; 30 s). Note that mounting was followed by attack (red) in the high intensity photostimulation trials (3.7 mW mm−2). d, A raster plot illustrating a shift in behavioural responses from mounting to attack towards a castrated male intruder dependent upon photostimulation intensity (see Fig. 4a for the behavioural shift towards a female intruder). Note that time line is not continuous at the breakage in the line under rasters.

Extended Data Figure 7 Optogenetic silencing of VMHvl Esr1+ neurons does not affect reproductive behaviours towards females.

ad, Quantification of female-directed mating behaviours during photostimulation of Esr1cre/+ males expressing mCherry (n = 4–5) or eNpHR3.0 (n = 14–17). a, b, d, Parameters of reproductive behaviours during photostimulation trials (3 min) were normalized to those during non-stimulated periods. c, The latency from the onset of photostimulation to the first mounting. n.s., not significant; Mann–Whitney U-test. Data are mean ± s.e.m. n = number of animals.

Extended Data Figure 8 Relationship between behavioural response and photostimulation frequency.

Behaviours evoked by optogenetic activation of ChR2-expressing Esr1cre/+ males at the indicated photostimulation frequencies are plotted (5, 10, and 20 Hz). Different photostimulation intensities were applied in different episodes (coloured lines). In each episode, photostimulation frequency was varied at a fixed intensity. Only 2/14 stimulation episodes (orange) exhibited a behavioural shift from mounting to mixed to attack behaviours with increasing photostimulation frequency. Data from n = 11 animals.

Extended Data Figure 9 An example of hysteresis.

A representative raster plot illustrating a shift from mounting (0.3 mW mm−2) to attack (0.6 mW mm−2) with increasing photostimulation intensity. Note that once attack was elicited, reducing the photostimulation intensity back to 0.3 mW mm−2 no longer evoked mounting, but simply failed to elicit attack. Whether this hysteresis is intrinsic to the animal, or represents a form of conditioning, is not clear.

Extended Data Figure 10 Two alternative models to explain how activation of Esr1+ neurons in VMHvl can promote mounting and attack depending on conditions.

See Supplementary Note 2.

Supplementary information

Supplementary Information

This file contains Supplementary Notes 1-3. (PDF 155 kb)

Optogenetic activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse evokes attack towards an intact C57BL/6 female (part 1) and a castrated BALB/c male intruders (part 2).

The ChR2-expressing Esr1cre/+ male mice connected to a fiber-optic cable were photostimulated during the period indicated by either "Light on" or the LED light at the bottom right corner. (MP4 6011 kb)

Acute silencing of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse inhibits naturally occurring attack towards an intact BALB/c male intruder.

The eNpHR3.0-expressing Esr1cre/+ male mouse (black) was photostimulated during the period indicated by either "Light on" or the LED light at the bottom right corner. (MP4 642 kb)

Acute silencing of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse inhibits aggressive approach towards an intact BALB/c male intruder.

The eNpHR3.0-expressing Esr1cre/+ male mouse (black) was photostimulated during the period indicated by "Light on". (MP4 924 kb)

Optogenetic activation of VMHvl Esr1+ neurons in an Esr1cre/+ female mouse elicits close investigation towards a castrated BALB/c male intruder.

The ChR2-expressing Esr1cre/+ female mouse (black) was photostimulated during the period indicated by either "Light on" or the LED light at the bottom right corner. (MP4 1021 kb)

Optogenetic activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse evokes aggressive sniffing towards a castrated BALB/c male intruder.

The ChR2-expressing Esr1cre/+ male mouse (black) was photostimulated during the period indicated by either "Light on" or the LED light at the bottom right corner. (MP4 2562 kb)

Optogenetic activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse evokes mounting behavior towards an unreceptive intact BALB/c female intruder.

The ChR2-expressing Esr1cre/+ male mouse connected to a fiber-optic cable was photostimulated during the period indicated by either "Light on" or the LED light at the bottom right corner at indicated photostimulation intensities. (MP4 20947 kb)

Optogenetic activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse evokes mounting behavior towards a castrated BALB/c male (part 1) and an intact BALB/c male intruders (part 2).

The ChR2-expressing Esr1cre/+ male mouse (black) was photostimulated during the period indicated by either "Light on" or the LED light at the bottom right corner. (MP4 4319 kb)

Activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse shifts behavioral responses from mounting, to a mixture of mounting and attack, to attack towards an unreceptive intact BALB/c female intruder as the photostimulation intensity is increased.

The ChR2-expressing Esr1cre/+ male mouse (black) was photostimulated during the period indicated by either "Light on" or the LED light at the bottom right corner at indicated photostimulation intensities. (MP4 4741 kb)

Activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse shifts behavioral responses from mounting, to a mixed behavior of mounting and attack, to attack towards a castrated BALB/c male intruder as the photostimulation intensity is increased.

The ChR2-expressing Esr1cre/+ male mouse (black) was photostimulated during the period indicated by either "Light on" or the LED light at the bottom right corner at indicated photostimulation intensities. (MP4 3930 kb)

Optogenetic activation of VMHvl Esr1+ neurons in an Esr1cre/+ male mouse at intermediate photostimulation intensities evokes repeated, interspersed attempts at mounting and attack towards an unreceptive intact BALB/c female intruder.

The ChR2-expressing Esr1cre/+ male mouse connected to a fiber-optic cable was photostimulated during the period indicated by either "Light on" or the LED light at the bottom right corner. (MP4 1596 kb)

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Lee, H., Kim, DW., Remedios, R. et al. Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus. Nature 509, 627–632 (2014). https://doi.org/10.1038/nature13169

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