Research Article

History of winning remodels thalamo-PFC circuit to reinforce social dominance

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Science  14 Jul 2017:
Vol. 357, Issue 6347, pp. 162-168
DOI: 10.1126/science.aak9726

The brain circuits of a winner

Social dominance in mice depends on their history of winning in social contests. Zhou et al. found that this effect is mediated by neuronal projections from the thalamus to a brain region called the dorsomedial prefrontal cortex. Selective manipulation of synapses driven by this input revealed a causal relationship between circuit activity and mental effort–based dominance behavior. Thus, synapses in this pathway store the memory of previous winning or losing history.

Science, this issue p. 162

Abstract

Mental strength and history of winning play an important role in the determination of social dominance. However, the neural circuits mediating these intrinsic and extrinsic factors have remained unclear. Working in mice, we identified a dorsomedial prefrontal cortex (dmPFC) neural population showing “effort”-related firing during moment-to-moment competition in the dominance tube test. Activation or inhibition of the dmPFC induces instant winning or losing, respectively. In vivo optogenetic-based long-term potentiation and depression experiments establish that the mediodorsal thalamic input to the dmPFC mediates long-lasting changes in the social dominance status that are affected by history of winning. The same neural circuit also underlies transfer of dominance between different social contests. These results provide a framework for understanding the circuit basis of adaptive and pathological social behaviors.

In most social species, reaching the top of the social hierarchy is strongly affected by mental strength or personality traits (including courage, perseverance, and motivational drive), as well as a previous history of winning (16). The formation of a dominance hierarchy can result from a reinforcing mechanism known as the “winner effect,” where animals increase their probability of victory after prior winning (711). The dorsomedial prefrontal cortex (dmPFC) has been implicated in the chronic regulation of social dominance (1218). However, the acute requirement of the dmPFC during ongoing social competition and the upstream neural circuits that regulate dmPFC activity in dominance behaviors have been essentially unknown. It has also been unclear whether the winner effect can be generalized—in other words, whether dominance acquired in one type of competition can transfer to another behavioral type.

Winner mice display more pushes and resistances in the dominance tube test

To investigate social competition in laboratory mice, we applied the dominance tube test (19), which is highly transitive and stable and correlates well with other dominance measures (6). The behavior in the tube test was video-monitored and categorized as push initiation, push-back, resistance, retreat, or stillness (Fig. 1, A and B; fig. S1A; movie S1; and methods). Analysis of 72 tube test trials revealed that winner mice initiated significantly more pushes, and with a longer duration per push, than loser mice (Fig. 1C). When being pushed, winner mice also showed more and longer push-backs and resistances and fewer retreats (Fig. 1, D to F). For a cage of four male weight-matched C57BL/6J mice, we derived a linear dominance rank order based on total numbers of wins against cagemates in pairwise tube tests (18) (fig. S1B). Opponents with closer rank distances spent a longer time and generated more pushes (fig. S1, C and D) in the tube.

Fig. 1 dmPFC neurons are activated during effortful behaviors in the dominance tube test.

(A) Schematic of “effortful” (push initiation, push-back, and resistance) and passive (stillness and retreat) behavior patterns of two mice confronting each other in the tube test. The arrows indicate the direction of body movement. (B) Sample behavior annotations for a pair of mice in a tube test trial. (C and D) Number and mean duration of pushes initiated (C) and push-backs (D). The number of trials is indicated in each bar. Mann-Whitney U test. (E and F) Percentage of time that mice resisted (E) or retreated (F) while being pushed. Mann-Whitney U test. (G) Tetrode recording in the dmPFC of mice during the tube test (top) and three well-isolated single units (yellow, red, and blue clusters; bottom). PC, principal component. (H) Sample raster plots of a pPyr neuron during five losing tube test trials. Different behavioral epochs are indicated by colored shading. Inset, mean firing rate (FR) for different behavioral epochs. Kruskal-Wallis test. (I and J) Mean firing rate of all pPyr (n = 160) (I) and pIN (n = 13) (J) units during different behavioral epochs. One-way repeated measures ANOVA (analysis of variance). (K) Scatter plots of the firing rates of all pPyr units during push (left), resistance (middle), and retreat (right) behavioral epochs, plotted against firing rates during the stillness epoch. Colored circles indicate neurons that showed significant differences in firing rates. Most of the circles are distributed underneath the y = x diagonal line in the push and resistance plots, but not in the retreat plot. Pie graphs show the percentage of pPyr neurons that had significantly higher, significantly lower, or unchanged firing rates during the respective epochs, relative to stillness. Wilcoxon signed-rank test. (L) Venn diagram of overlap between subpopulations with increased activity during push, resistance, and retreat behaviors. (M) Linear regression analysis of the change index (CI; see methods) of push and resistance behaviors for the 11 neurons that showed significantly increased activity during both states. Dashed lines indicate 95% confidence intervals. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; n.s., not significant. Error bars, SEM.

dmPFC neurons activated in effortful behavioral epochs during social contests

We performed single-unit recordings in freely behaving mice while they engaged in the tube test (Fig. 1G). Using 16-channel tetrodes targeting dmPFC [including the anterior part of the anterior cingulate (ACC) and the prelimbic (PL) part of the PFC (fig. S2, A and B)], we successfully recorded 342 well-isolated neurons in 22 mice, including 306 putative pyramidal (pPyr, 89.5%) and 36 putative fast-spiking interneuron (pIN) cells (fig. S2, C and D; criteria for single-unit isolation and cell-type classification are given in the methods). We aligned spiking activity with epochs of pushing (including push initiation and push-back), resistance, retreat, and stillness (Fig. 1H and methods). The average firing rate of recorded pPyr units was significantly higher during the “effortful” (push and resistance) behavioral epochs, but not the passive (retreat) behavioral epochs, than during stillness (Fig. 1, H and I, and movie S2). In contrast, the average firing rate of pIN units increased insignificantly during the retreat epoch (Fig. 1J). A notable fraction of the pPyr units showed increased firing rates during push (11.4%, 31 of 271 units) and resistance (10.1%, 25 of 247 units) behaviors, significantly more than the fraction that showed decreased firing rates (1.1% for pushing, P < 0.0001, Z test; 2% for resistance, P = 0.002, Z test; Fig. 1K and fig. S2E). One-third of neurons (11 of 31) with increased activity during push behavior also showed an increase in firing rate during resistance, which was significantly higher than the chance level (P < 0.0001, Z test; Fig. 1L). These 11 neurons showed highly correlated increases in activity during push and resistance behaviors [linear regression analysis, coefficient of determination (R2) = 0.82, slope = 0.90, P < 0.001; Fig. 1M]. Although both pushing and resistance require effort, they differ in that the former involves body movement, whereas the latter does not. Thus, regardless of whether the animal is in motion, these two different behavioral states tend to recruit the same subset of dmPFC neurons.

DREADD inhibition of dmPFC reduces effortful behaviors and causes losing

Given that dmPFC neuronal activity is differentially modulated when animals make an effort during competition, we next tested whether dmPFC neural activity is required for dominance in the tube test. We applied the DREADD (designer receptors exclusively activated by designer drugs) method to inactivate dmPFC neurons, using an adeno-associated virus (AAV2) expressing the engineered Gi-coupled hM4D receptor (20) (Fig. 2A and fig. S3, A and B). Whole-cell recordings of neurons from acutely isolated dmPFC brain slices confirmed that clozapine-N-oxide (CNO, 5 μM) suppressed hM4D-expressing dmPFC neuron activity (Fig. 2B), causing a significantly increased spike threshold and decreased spike number under current step injections (Fig. 2, C and D). We then intraperitoneally (i.p.) injected CNO (5 mg per kilogram of body weight) into a subset of mice (each from a different four-mouse group), which had hM4D expressed bilaterally in the dmPFC and had stable tube test ranks (persisting for at least three continuous daily trials before the manipulation; Fig. 2E). This treatment induced a decline in tube test ranks of the injected mice, starting at 1 to 1.5 hours and peaking at 6 to 8 hours after injection (Fig. 2, E to G and fig. S3C). There were significantly fewer and shorter initiated pushes and push-backs, and more retreats, after CNO injection (Fig. 2, H and I). At 24 hours after CNO injection, most mice returned to their original rank position (Fig. 2, E to G), consistent with the reversal of the effect on cell physiology after CNO washout (Fig. 2B).

Fig. 2 DREADD inhibition of dmPFC neurons causes losing and decreases effortful behaviors in the tube test.

(A) AAV-hSyn-hM4D construct and viral injection site in the dmPFC, including the PL region and part of the ACC. Scale bar, 50 μm. IRES, internal ribosome entry site; WPRE, woodchuck hepatitis virus posttranscriptional regulatory element; pA, poly(A); MO, medial orbital cortex. (B) Current-voltage relationship of a representative dmPFC neuron recorded before, during, and after 5 μM CNO perfusion. Raw traces show individual voltage responses to a series of 600-ms current pulses from 0 to 120 pA with 20-pA steps. Red traces indicate the minimal current to induce action potentials. (C) The minimal injected current to induce action potential (APs) is increased by CNO. Paired t test, n = 10. (D) Number of induced action potentials at different current steps. Paired t test, n = 10. (E) Tube test results for a cage of hM4D-expressing mice before and after i.p. injection of CNO into the rank-1 mouse at time 0. hr, hour. (F) Summary of rank changes in hM4D-expressing mice after i.p. injection of CNO. Each line represents one animal. (G) Average rank change after CNO or saline injection. Wilcoxon matched-pairs signed-rank test. (H) Behavioral annotation of two tube test trials between the same pair of mice before and after CNO injection. (I) Comparison of behavioral performance of same mice injected with saline solution or CNO. Mann-Whitney U-test. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars, SEM.

Optogenetic activation of dmPFC induces instantaneous winning in the tube test

Using optogenetics, we next tested whether dmPFC activation is sufficient to quickly induce dominance behavior in social competition. AAV2 virus expressing light-sensitive channelrhodopsin (ChR2) (21) under the control of the ubiquitously expressed CAG promoter (AAV-CAG-ChR2-tdTomato) was stereotactically injected into the right dmPFC of the ranked mice and expressed for 4 weeks, and an optic fiber was implanted directly above the injection site (Fig. 3, A and B; fig. S4; and methods). dmPFC neurons show both phasic and tonic firing patterns (22). We thus first used a 100-Hz phasic protocol (9.9 ms per pulse, four pulses per second; fig. S5A) with 473-nm laser stimulation, which significantly increased the expression of the immediate early gene c-Fos in the illuminated side of the dmPFC (P < 0.05; Fig. 3B). Whole-cell recordings in dmPFC brain slices showed that both a 100-Hz phasic protocol and a 5-Hz tonic protocol (fig. S5B) efficiently activated dmPFC neurons (Fig. 3, C and D), and this was also verified by in vivo optrode recordings of the single-unit responses from virally injected animals (Fig. 3, E and F).

Fig. 3 Optogenetic activation of dmPFC Pyr neurons induces instant winning and more effortful behaviors in the tube test.

(A) Schematic illustrating the CAG::ChR2 viral construct, viral injection site, and optic fiber placement (indicated by the white arrowhead). Scale bar, 100 μm. (B) c-Fos expression induced by photostimulation (NeuN, neuron nuclei). Scale bar, 50 μm. Student’s t test. (C and D) Current-clamp traces from an in vitro slice recording of a ChR2-expressing neuron illuminated by 100-Hz phasic (C) or 5-Hz tonic (D) light stimulation. Scale bars in (C), 100 ms (horizontal) and 20 mV (vertical); in (D), 1 s and 40 mV. (E and F) Raster plots (top), peristimulus time histogram (middle), and waveform (inset; scale bars, 500 μs and 50 μV) from an in vivo optrode recording of a single neuron responding to 100-Hz phasic (E) and 5-Hz tonic (F) light stimulation. The Z-scored single-unit firing rates of multiple neurons are shown in the bottom panels. (G) Daily tube test results for a cage of mice injected with CAG::ChR2 virus before and after acute dmPFC photostimulation of the rank-3 mouse at day 0. (H and I) Summary of dmPFC photostimulation–induced rank change in mice injected with CAG::ChR2 (H) or Ubi::eGFP (I) virus. Each line represents one animal. (J) Rank change in the tube test under different stimulation conditions. Light stimulation was delivered throughout the tube test at day 0. Wilcoxon matched-pairs signed-rank test. Except as noted, CAG-ChR2 mice were used. (K) Comparison of the behavioral performances of same mice during light-off and light-on trials. Mann-Whitney U test. (L) A greater rise in rank position requires a stronger laser intensity. Wilcoxon signed-rank test. (M) Left, schematic illustrating mPFC subregions. The dmPFC contains both anterior ACC and the PL region. IL, infralimbic; pACC, posterior ACC. Right, rank change in the tube test after optogenetic activation of different mPFC subregions. Wilcoxon matched-pairs signed-rank test. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars, SEM.

In tube tests with pairs of mice, we delivered the 100-Hz phasic light protocol to one of the mice to activate its dmPFC immediately before it entered the tube to confront its opponent, and we kept the light on throughout the test, which lasted, on average, 12.8 ± 1.3 s (n = 93; Fig. 3G). This instantaneously induced winning against previously dominant opponents with a 90% success rate (Fig. 3, G and H; fig. S5C, J and K; and movie S3), without affecting the motor performance or anxiety level (fig. S6). The same photostimulation protocol did not affect the tube test rank of mice injected with AAV-Ubi-eGFP virus (eGFP, enhanced green fluorescent protein) in the dmPFC (Fig. 3I and fig. S5F). The 5-Hz tonic stimulation protocol had a similar success rate (80%) in elevating the rank of stimulated mice (Fig. 3J and fig. S5, D, J, and K).

Under photostimulation, the originally subordinate mice not only resisted pushes from the opponents for a longer duration, but also pushed more (Fig. 3K). The laser intensity required to dominate the opponents correlated with the rank distance that the mouse needed to move: A rank increase of three (rank 4 moving to rank 1) required laser intensity that was 3.2-fold that required for a rank increase of two (rank 4 to rank 2 or rank 3 to rank 1) and 7.1-fold that required for a rank increase of one (rank 4 to rank 3, rank 3 to rank 2, or rank 2 to rank 1), demonstrating a dosage-dependent relationship between the level of dmPFC activation and the amount of effort required (Fig. 3L).

Importantly, dmPFC photoactivation did not change muscle strength, as assessed by measuring grip strength during the light-on and -off periods (fig. S7A). Most (98%, n = 103) photostimulated tube test wins occurred within less than 1 min, suggesting that testosterone, a conventionally slow-acting hormone, is unlikely to have played a role in this quick process. To confirm this, we measured the levels of testosterone at 1 min and 1.5 hours after photostimulation and found them to be indistinguishable from the baseline and unstimulated control levels (fig. S7B). To test whether the increased dominance is manifested by a heightened level of basal aggression, we subjected mice to the resident-intruder assay (23), during which we intermittently turned the 473-nm light (5 Hz, 10 ms) on and off in 1-min epochs with a switched sequence. The test mice showed low basal aggression levels and no significant difference between the light-on and -off periods in aggressive behaviors (including attacks and chases; fig. S7, C to F, and movie S4). Furthermore, the dmPFC-photostimulated mice also showed a normal preference toward novel mice in the social memory test (fig. S7, G and H).

With localized injection, we mapped the effective site to a dmPFC site containing both the anterior part of the ACC and the PL region (Figs. 2A and 3A and fig. S4). A more dorsal and posterior part of the ACC (Fig. 3M and fig. S8, A and B) and a ventral mPFC site mostly containing the infralimbic cortex (Fig. 3M and fig. S8, C and D) were not effective in stimulating winning behavior (Fig. 3M and fig. S5, G and H). For cell-type specificity, we used a CaMKII (calcium- and calmodulin-dependent protein kinase II) promoter to drive ChR2 only in dmPFC Pyr neurons, and we found that it was sufficient to elevate tube test rank (Fig. 3J and fig. S5, I to K).

Synaptic strength in the MDT-dmPFC circuit underlies the winner effect in the tube test

Performance in the tube test diverged on the second day after photostimulation: Some mice returned to their original rank, whereas others maintained their newly elevated rank (Fig. 3H and 4A). Comparison of their experiences revealed that these mice differed in the number of winning trials on the stimulation day: Mice receiving more than six photostimulated wins all maintained their new rank, whereas most mice receiving fewer than five photostimulated wins returned to their original rank (Fig. 4A). This sustained rank elevation was not caused by a secondary effect through the experience of nonstimulated rival mice (fig. S9). Thus, repeated stimulated winning led to sustained dominance without further photostimulation, reflecting the winner effect. Systematic injection of MK801 (0.15 mg/kg, i.p.) eliminated the sustained winning induced by six photostimulated wins, suggesting that an NMDAR (N-methyl-d-aspartate receptor)–dependent plasticity mechanism may mediate this long-lasting increase in dominance (Fig. 4B and fig. S10A).

Fig. 4 Synaptic strength of the MDT-dmPFC circuit underlies the winner effect in the tube test.

(A) Mice either maintain their new rank or return to their original rank position after dmPFC photostimulation, depending on the number of stimulated-win trials. Z test, n = 13 and 11 mice that underwent two to five and six to 20 stimulation trials, respectively. d, day. (B) I.p. injection of MK801, but not saline solution, at 30 min before six photostimulated wins abolished sustained winning on subsequent days. Left, Wilcoxon signed-rank test; right, Z test. (C) Optogenetic LTP or LTD experiment in the MDT-dmPFC pathway. Top, schematic of viral injection and opotrode recording sites. Bottom left, representative coronal section showing the injection site of AAV-oCHIEF-tdTomato in MDT. Bottom right, representative coronal dmPFC section showing distribution of tdTomato+ axons projected from the MDT. LHb, lateral habenular; MHb, medial habenular; MDC, mediodorsal thalamus, central; MDM, mediodorsal thalamus, medial; MDL, mediodorsal thalamus, lateral. Blue, Hoechst; red, tdTomato. Scale bars, 25 μm (top right) and 500 μm (bottom right). (D) Average slopes of in vivo light-evoked fEPSPs (average of six responses) in the dmPFC (normalized to baseline) before and after six wins induced by photostimulation of MDT-dmPFC terminals. Insets, representative fEPSP trace before and after six wins. Paired t test. (E and G) Average slopes of in vivo light-evoked fEPSPs (average of six responses) in the dmPFC (normalized to baseline) before and after LFS (E) or HFS (G). Insets, representative fEPSP traces before and after LFS (E) and HFS (G). (F) LFS reverses the sustained rank increase resulting from six wins induced by MDT-dmPFC photostimulation. Left, Wilcoxon signed-rank test; right, Z test. (H) HFS induction directly causes sustained winning in the tube test. Left, Wilcoxon signed-rank test; right, Z test. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars, SEM.

We next searched for the neural circuit pathway that supports this behavioral plasticity mechanism. The mPFC receives prominent projections from the mediodorsal thalamus (MDT) (24), and the MDT-dmPFC circuit shows synaptic weakening during repeated defeat–induced social avoidance (25). We thus hypothesized that this same pathway may undergo long-lasting synaptic strengthening after repeated winning. If that is the case, we should be able to (i) detect enhanced synaptic strength in the MDT-dmPFC pathway after repeated winning, (ii) eliminate the sustained winning by introducing long-term depression (LTD) to reverse the synaptic strengthening in the MDT-mPFC circuit, and (iii) directly cause sustained winning by inducing long-term potentiation (LTP) in the MDT-mPFC synapses without any tube test competition. We expressed oCHIEF, a variant of ChR2 that can faithfully respond to 100-Hz stimulation (fig. S11A) (26, 27), in the MDT (fig. S12, A to C) and implanted an optrode (for electrophysiology recording) or an optic fiber (for behavioral manipulation) in the dmPFC (Fig. 4C; fig. S12, D and E; and methods). Optical activation of the MDT axonal terminals in the dmPFC (5 Hz, 10 ms) induced instantaneous winning in the tube test (fig. S12F).

To measure synaptic responses of the MDT-dmPFC pathway in free-moving mice, we recorded field response in the dmPFC evoked by photostimulation of the oCHIEF-expressing MDT-dmPFC axonal terminals. Brief pulses of blue light were delivered at 0.05 Hz through the optical fiber, and fEPSPs (field excitatory postsynaptic potentials) were used to measure the MDT-dmPFC synaptic efficacy (fig. S11, B and C) (27). After a stable baseline was acquired for at least 3 days, we photostimulated the MDT-dmPFC axonal terminals to induce repeated winning six times and measured the fEPSPs on the following days. Accompanying the rank elevation, the fEPSP of the MDT-dmPFC pathway was significantly increased on the following 2 days after repeated winning, reflecting strengthening of the MDT-dmPFC synapses (Fig. 4D).

Next, by applying low-frequency stimulation (LFS), an optical LTD protocol (900 pulses of 2-ms light stimulation delivered at 1 Hz; fig. S11D) (27, 28), at the MDT-dmPFC terminals, we were able to induce LTD in the MDT-dmPFC synapses (Fig. 4E) and eliminate the sustained winning effect after six stimulated wins (Fig. 4F and fig. S10B). Conversely, delivery of high-frequency stimulation (HFS), an optical LTP protocol (fig. S11A and methods) (28), at the MDT-dmPFC terminals significantly potentiated MDT-dmPFC transmission in vivo (Fig. 4G). Application of this in vivo LTP protocol to freely moving mice in the home cage caused significant, long-lasting tube test rank increases (Fig. 4H and fig. S10C).

Transferrable winner effect from the tube test to the warm spot competition

We next asked whether dominance acquired in the tube tests can transfer to other forms of dominance behavior. We subjected mice to an independent measure of social hierarchy, the warm spot test, in which four cagemate C57 mice competed for a warm corner in a cage with an ice-cold floor (Fig. 5A). The amount of time that each mouse occupied the warm spot correlated with its tube test rank (Fig. 5, B to D, and movie S5), cross-validating that these two assays share dominance as a common core variable. Activation of dmPFC neurons by using AAV2 expressing the engineered Gq-coupled hM3D receptor (20) increased the occupation time and rank in the warm spot test at 2 hours, but not 2 days, after CNO injection (1 mg/kg, i.p.) (Fig. 5, E and F).

Fig. 5 Transferrable dominance from the tube test to the warm spot competition.

(A) Schematic of the warm spot test. Four mice compete for a warm corner in a cage with an ice-cold floor. (B) Cumulative time in the warm spot of four cagemate mice of different tube test rank. Inset, total time in the warm spot in the 20-min test. (C) Correlation between time in the warm spot and tube test rank. Pearson’s correlation test, P = 0.046. (D) Contingency table showing the correlation between rank in the tube test and rank in the warm spot test. The number of animals in each category is displayed. (E and F) Time in the warm spot (top) and rank in the warm spot test (bottom) for mice expressing hM3D in the dmPFC at 1 day before, 2 hours after, and 2 days after i.p. injection of CNO (E) or saline solution (F). Data for each mouse are shown in gray; averages are shown in red and blue; n = 6. (G) Schematic of the experimental procedure. After basal ranks were assessed in the tube test and warm spot test, dmPFC photostimulation was applied to subordinate mice during the tube test to induce winning in 10 successive trials; mice were confirmed to maintain the elevated tube test rank in the absence of photostimulation and then subjected to the warm spot test. The red asterisk marks the mouse being manipulated. (H) Time in the warm spot (left) and rank (right) in the warm spot test were elevated 2 hours after repeated winning in the tube test. Wilcoxon matched-pairs signed rank test, n = 6. (I) Rank increase in the warm spot test is specific to mice with a sustained rank increase in the tube test. Mann-Whitney U test. (J) Reciprocal reinforcement of winning in different contests leads to establishment of dominance hierarchy. *P < 0.05; **P < 0.01. Error bars, SEM.

We then tested whether sustained winning in the tube test resulting from repeated dmPFC stimulation could lead to increased rank in the warm spot test. After we subjected mice that were previously subordinate in both tests to 10 photostimulated tube test wins, their occupation times and ranks in the warm spot test were significantly elevated compared with their performances before the tube test (P = 0.016 for occupation time, P = 0.016 for rank, Wilcoxon signed-rank test; Fig. 5, G to I), even though these mice were not directly stimulated in the warm spot context.

Discussion

Collectively, these results provide strong evidence that activation of the dmPFC is both necessary and sufficient to quickly induce winning in social competitions. Specifically, by optogenetically isolating a synaptic input from the MDT to the dmPFC, we could selectively manipulate synapses driven by this input and establish a causal relationship between the activity of the MDT-dmPFC circuit and dominance behavior. dmPFC activation does not seem to boost dominance by enhancing basal aggression level or physical strength (fig. S7), but rather by initiating and maintaining more effortful behaviors in social competition (Fig. 3K). The mPFC has been implicated in cost-benefit analysis and effort-based decision-making (1416, 2932). We propose that these mPFC-based cognitive processes may provide a neurobiological foundation for dominance-associated personality traits, such as perseverance or competitive drive.

One important parameter for the cost-benefit computation in a social confrontation is the history of winning. With the in vivo optogenetic LTP and LTD experiments, we provide evidence that synapses in the MDT-dmPFC pathway may encode winning history. Whereas earlier work on the winner effect in fish was mostly focused on hormonal changes after repeated winning (33), our results reveal that the synaptic plasticity mechanism in the MDT-dmPFC circuit plays a key role in the winner effect in mammals. Moreover, we discovered a generalized form of the winner effect, where dominance transfers from one contest type to another through a shared neural circuit mechanism. Previous studies of the winner effect were restricted to the impact of winning on the same behavior paradigm (33). However, given that animals are dealing with different forms of competition in setting up the social hierarchy, the generalized winner effect that we describe here is of high evolutionary importance—for example, it may allow a monkey that succeeds in fighting for bananas earlier to occupy a more comfortable resting spot later. Such reciprocal reinforcement between winning in different behavioral paradigms would help to accelerate the establishment of a stable dominance hierarchy (Fig. 5J). It may also have important implications in cognitive training for competitive games. Considering that an excess or lack of dominance drive is associated with many personality disorders and mental problems, our results might shed light on the treatment of these psychiatric diseases.

Supplementary Materials

www.sciencemag.org/content/357/6347/162/suppl/DC1

Materials and Methods

Figs. S1 to S12

Table S1

References (3451)

Movies S1 to S5

References and Notes

  1. Acknowledgments: We thank Q. Li, H. Kessels, H. Li, and W. Li for critical comments on the manuscript; D. Anderson for stimulating discussions that led to the idea of the warm spot test; J. Zhu and K. Yuan for assistance in experiments; K. Deisseroth and Z. Qiu for AAV-ChR2 constructs; B. Roth for AAV-hM4D and AAV-hM3D constructs; C. Li and X. Gu for advice on analysis of tetrode recording data; and X. Xu for Matlab code for behavior annotation. This work was supported by grants from the Ministry of Science and Technology of China (2011CBA00400 and 2016YFA0501000), the National Natural Science Foundation of China (91432108, 31225010, and 81527901), and the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02030004) to H.H. All the data necessary to understand and assess the conclusions of this manuscript are available in the supplementary materials. Computer codes are archived at www.dropbox.com/sh/7pthozsrzj4vxr0/AACMaW9a8_5ITDumIJw_6Z_pa?dl=0. T.Z. and H.Z. conducted most optogenetic and behavioral experiments and designed the experiments with H.H. T.Z. performed in vivo tetrode recording with the help of Y.C. and Z.Y. and conducted optogenetic LTP and LTD experiments. Z.F. performed the warm spot test and dominance transfer experiments. F.W. and H.L. participated in tube test and viral injection experiments. L.Z., L.L., Y.Z., and Z.W. participated in analysis of in vivo tetrode recordings. H.H. conceived the project and wrote the manuscript with the help of T.Z. and H.Z.
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