Prefrontal cortical control of a brainstem social behavior circuit

Article metrics

Abstract

The prefrontal cortex helps adjust an organism's behavior to its environment. In particular, numerous studies have implicated the prefrontal cortex in the control of social behavior, but the neural circuits that mediate these effects remain unknown. Here we investigated behavioral adaptation to social defeat in mice and uncovered a critical contribution of neural projections from the medial prefrontal cortex to the dorsal periaqueductal gray, a brainstem area vital for defensive responses. Social defeat caused a weakening of functional connectivity between these two areas, and selective inhibition of these projections mimicked the behavioral effects of social defeat. These findings define a specific neural projection by which the prefrontal cortex can control and adapt social behavior.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Layer 5 excitatory neurons in mPFC make direct projections to dPAG.
Figure 2: Induction of social avoidance by social defeat.
Figure 3: Inhibition of mPFC–dPAG projections mimics social defeat.
Figure 4: Social defeat weakens mPFC–dPAG functional connectivity.
Figure 5: Evolution of synaptic field potentials in sensory and defeated mice across testing days.
Figure 6: Cell-specific retrograde tracing and ChR2-assisted circuit mapping identifies targets of PFC projections in PAG.
Figure 7: Selective inhibition of Vglut2+ neurons in dPAG increases social approach.

Change history

  • 11 January 2017

    In the version of this article initially published online, the annotation above the ChR2 bars in Figure 6k appeared as NNN instead of ***. Also, the third author's name was given as Zina Perova; the correct name is Zinaida Perova. The errors have been corrected in the print, PDF and HTML versions of this article.

References

  1. 1

    Arnsten, A.F. Stress signalling pathways that impair prefrontal cortex structure and function. Nat. Rev. Neurosci. 10, 410–422 (2009).

  2. 2

    Takahashi, A., Nagayasu, K., Nishitani, N., Kaneko, S. & Koide, T. Control of intermale aggression by medial prefrontal cortex activation in the mouse. PLoS One 9, e94657 (2014).

  3. 3

    Carrier, N. & Kabbaj, M. Sex differences in social interaction behaviors in rats are mediated by extracellular signal-regulated kinase 2 expression in the medial prefrontal cortex. Neuroscience 212, 86–92 (2012).

  4. 4

    Wang, F. et al. Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex. Science 334, 693–697 (2011).

  5. 5

    Covington, H.E. III et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J. Neurosci. 30, 16082–16090 (2010).

  6. 6

    Challis, C., Beck, S.G. & Berton, O. Optogenetic modulation of descending prefrontocortical inputs to the dorsal raphe bidirectionally bias socioaffective choices after social defeat. Front. Behav. Neurosci. 8, 43 (2014).

  7. 7

    Goodson, J.L. The vertebrate social behavior network: evolutionary themes and variations. Horm. Behav. 48, 11–22 (2005).

  8. 8

    Warden, M.R. et al. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492, 428–432 (2012).

  9. 9

    Bossert, J.M. et al. Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking. J. Neurosci. 32, 4982–4991 (2012).

  10. 10

    Faturi, C.B., Rangel, M.J. Jr., Baldo, M.V. & Canteras, N.S. Functional mapping of the circuits involved in the expression of contextual fear responses in socially defeated animals. Brain Struct. Funct. 219, 931–946 (2014).

  11. 11

    Mobbs, D. et al. From threat to fear: the neural organization of defensive fear systems in humans. J. Neurosci. 29, 12236–12243 (2009).

  12. 12

    Silva, B.A. et al. Independent hypothalamic circuits for social and predator fear. Nat. Neurosci. 16, 1731–1733 (2013).

  13. 13

    Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).

  14. 14

    Price, J.S. & Sloman, L. The evolutionary model of psychiatric disorder. Arch. Gen. Psychiatry 41, 211 (1984).

  15. 15

    Allen, N.B. & Badcock, P.B. Darwinian models of depression: a review of evolutionary accounts of mood and mood disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 815–826 (2006).

  16. 16

    Ottenbreit, N.D. & Dobson, K.S. Avoidance and depression: the construction of the cognitive-behavioral avoidance scale. Behav. Res. Ther. 42, 293–313 (2004).

  17. 17

    Anand, A. et al. Antidepressant effect on connectivity of the mood-regulating circuit: an FMRI study. Neuropsychopharmacol. 30, 1334–1344 (2005).

  18. 18

    Gabbott, P.L., Warner, T.A., Jays, P.R., Salway, P. & Busby, S.J. Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J. Comp. Neurol. 492, 145–177 (2005).

  19. 19

    Floyd, N.S., Price, J.L., Ferry, A.T., Keay, K.A. & Bandler, R. Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat. J. Comp. Neurol. 422, 556–578 (2000).

  20. 20

    Lee, A.T., Vogt, D., Rubenstein, J.L. & Sohal, V.S. A class of GABAergic neurons in the prefrontal cortex sends long-range projections to the nucleus accumbens and elicits acute avoidance behavior. J. Neurosci. 34, 11519–11525 (2014).

  21. 21

    Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).

  22. 22

    Wei, J., Bai, W., Liu, T. & Tian, X. Functional connectivity changes during a working memory task in rat via NMF analysis. Front. Behav. Neurosci. 9, 2 (2015).

  23. 23

    Shiroma, P.R. et al. Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression. Intl. J. Neuropsychopharmacol. 17, 1805–1813 (2014).

  24. 24

    Vauterin, C. & Bazot, M. A double-blind controlled trial of amineptine versus trimipramine in depression. Curr. Med. Res. Opin. 6, 101–106 (1979).

  25. 25

    Armbruster, B.N., Li, X., Pausch, M.H., Herlitze, S. & Roth, B.L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl. Acad. Sci. USA 104, 5163–5168 (2007).

  26. 26

    Motta, S.C. et al. Dissecting the brain's fear system reveals the hypothalamus is critical for responding in subordinate conspecific intruders. Proc. Natl. Acad. Sci. USA 106, 4870–4875 (2009).

  27. 27

    Fitzgerald, P.B., Laird, A.R., Maller, J. & Daskalakis, Z.J. A meta-analytic study of changes in brain activation in depression. Hum. Brain Mapp. 29, 683–695 (2008).

  28. 28

    Seminowicz, D.A. et al. Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 22, 409–418 (2004).

  29. 29

    Mayberg, H.S. et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am. J. Psychiatry 156, 675–682 (1999).

  30. 30

    Likhtik, E., Stujenske, J.M., Topiwala, M.A., Harris, A.Z. & Gordon, J.A. Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nat. Neurosci. 17, 106–113 (2014).

  31. 31

    Northoff, G. & Sibille, E. Why are cortical GABA neurons relevant to internal focus in depression? A cross-level model linking cellular, biochemical and neural network findings. Mol. Psychiatry 19, 966–977 (2014).

  32. 32

    Wall, N.R., Wickersham, I.R., Cetin, A., De La Parra, M. & Callaway, E.M. Monosynaptic circuit tracing in vivo through Cre-dependent targeting and complementation of modified rabies virus. Proc. Natl. Acad. Sci. USA 107, 21848–21853 (2010).

  33. 33

    Vianna, D.M. & Brandão, M.L. Anatomical connections of the periaqueductal gray: specific neural substrates for different kinds of fear. Braz. J. Med. Biol. Res. 36, 557–566 (2003).

  34. 34

    Spruston, N. Pyramidal neurons: dendritic structure and synaptic integration. Nat. Rev. Neurosci. 9, 206–221 (2008).

  35. 35

    Petreanu, L., Huber, D., Sobczyk, A. & Svoboda, K. Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections. Nat. Neurosci. 10, 663–668 (2007).

  36. 36

    Haubensak, W. et al. Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature 468, 270–276 (2010).

  37. 37

    Tovote, P. et al. Midbrain circuits for defensive behaviour. Nature 534, 206–212 (2016).

  38. 38

    McCarthy, M.M., Pfaff, D.W. & Schwartz-Giblin, S. Midbrain central gray GABAA receptor activation enhances, and blockade reduces, sexual behavior in the female rat. Exp. Brain Res. 86, 108–116 (1991).

  39. 39

    Mota-Ortiz, S.R., Sukikara, M.H., Felicio, L.F. & Canteras, N.S. Afferent connections to the rostrolateral part of the periaqueductal gray: a critical region influencing the motivation drive to hunt and forage. Neural Plast. 2009, 612698 (2009).

  40. 40

    Lonstein, J.S. & Stern, J.M. Role of the midbrain periaqueductal gray in maternal nurturance and aggression: c-fos and electrolytic lesion studies in lactating rats. J. Neurosci. 17, 3364–3378 (1997).

  41. 41

    Kvitsiani, D. et al. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex. Nature 498, 363–366 (2013).

  42. 42

    Karlsson, M.P., Tervo, D.G. & Karpova, A.Y. Network resets in medial prefrontal cortex mark the onset of behavioral uncertainty. Science 338, 135–139 (2012).

  43. 43

    Behrens, T.E., Woolrich, M.W., Walton, M.E. & Rushworth, M.F. Learning the value of information in an uncertain world. Nat. Neurosci. 10, 1214–1221 (2007).

  44. 44

    Lisboa, S.F., Camargo, L.H., Magesto, A.C., Resstel, L.B. & Guimaraes, F.S. Cannabinoid modulation of predator fear: involvement of the dorsolateral periaqueductal gray. Intl. J. Neuropsychopharmacolog. 17, 1193–1206 (2014).

  45. 45

    Dielenberg, R.A., Leman, S. & Carrive, P. Effect of dorsal periaqueductal gray lesions on cardiovascular and behavioral responses to cat odor exposure in rats. Behav. Brain Res. 153, 487–496 (2004).

  46. 46

    Mobbs, D. et al. When fear is near: threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science 317, 1079–1083 (2007).

  47. 47

    Duman, R.S., Aghajanian, G.K., Sanacora, G. & Krystal, J.H. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat. Med. 22, 238–249 (2016).

  48. 48

    Christoffel, D.J. et al. Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nat. Neurosci. 18, 962–964 (2015).

  49. 49

    An, X., Bandler, R., Ongür, D. & Price, J.L. Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in macaque monkeys. J. Comp. Neurol. 401, 455–479 (1998).

  50. 50

    Amano, K. et al. Endorphins and pain relief. Further observations on electrical stimulation of the lateral part of the periaqueductal gray matter during rostral mesencephalic reticulotomy for pain relief. Appl. Neurophysiol. 45, 123–135 (1982).

  51. 51

    Tsankova, N.M. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat. Neurosci. 9, 519–525 (2006).

  52. 52

    Borgius, L., Restrepo, C.E., Leao, R.N., Saleh, N. & Kiehn, O. A transgenic mouse line for molecular genetic analysis of excitatory glutamatergic neurons. Mol. Cell. Neurosci. 45, 245–257 (2010).

  53. 53

    Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000).

  54. 54

    Silva, B.A. et al. Independent hypothalamic circuits for social and predator fear. Nat. Neurosci. 16, 1731–1733 (2013).

  55. 55

    Paxinos, G. & Franklin, K.B.J. The Mouse Brain in Stereotaxic Coordinates (Academic Press, San Diego, 2001).

  56. 56

    Vyssotski, A.L. et al. EEG responses to visual landmarks in flying pigeons. Curr. Biol. 19, 1159–1166 (2009).

  57. 57

    Vyssotski, A.L. et al. Miniature neurologgers for flying pigeons: multichannel EEG and action and field potentials in combination with GPS recording. J. Neurophysiol. 95, 1263–1273 (2006).

  58. 58

    Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).

  59. 59

    Suzuki, Y., Kiyokage, E., Sohn, J., Hioki, H. & Toida, K. Structural basis for serotonergic regulation of neural circuits in the mouse olfactory bulb. J. Comp. Neurol. 523, 262–280 (2015).

  60. 60

    Szulwach, K.E. et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J. Cell Biol. 189, 127–141 (2010).

  61. 61

    Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).

  62. 62

    Hsu, S.M. & Raine, L. Protein A, avidin, and biotin in immunohistochemistry. J. Histochem. Cytochem. 29, 1349–1353 (1981).

  63. 63

    Field, J. et al. Purification of a RAS-responsive adenylyl cyclase complex from Saccharomyces cerevisiae by use of an epitope addition method. Mol. Cell. Biol. 8, 2159–2165 (1988).

  64. 64

    Nishiguchi, K.M. et al. Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179. Nat. Commun. 6, 6006 (2015).

  65. 65

    Kubista, M., Akerman, B. & Nordén, B. Characterization of interaction between DNA and 4′,6-diamidino-2-phenylindole by optical spectroscopy. Biochemistry 26, 4545–4553 (1987).

  66. 66

    Zhan, Y. Theta frequency prefrontal-hippocampal driving relationship during free exploration in mice. Neuroscience 300, 554–565 (2015).

  67. 67

    Vialou, V. et al. DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat. Neurosci. 13, 745–752 (2010).

  68. 68

    Mitra, P. & Bokil, H. Observed Brain Dynamics (Oxford University Press, Oxford; New York, 2008).

Download references

Acknowledgements

We thank F. Zonfrillo for animal husbandry and P. Heppenstall (Mouse Biology Unit, EMBL) for providing the Vglut2::Cre mouse line. Funding was provided by EMBL (C.T.G., T.B.F.), the ERC Advanced Grant “Corefear” (C.T.G.), the Swiss National Science Foundation Advanced Fellows Program (T.B.F.), the Wellcome Trust/Royal Society Henry Dale Fellowship (098400/Z/12/Z, T.B.) a Medical Research Council (MRC) grant MC-UP-1201/1 (T.B.), Marie Sklodowska-Curie grant no. 659842 (Z.P.), the University of Zurich, Forschungskredit (A.L.V.) and the One Hundred Talents Program of CAS and funding from the Shenzhen city government (JCYJ20140901003938992 and KQCX2015033117354153) (Y.Z.).

Author information

T.B.F. designed, performed and analyzed all experiments, except the retrograde tracer experiments, which were designed, performed and analyzed by L.M.; the in vitro electrophysiology experiments, which were designed, performed and analyzed by Z.P. and T.B.; the monosynaptic rabies experiment, which was designed, performed and analyzed by B.A.S.; the evoked field potential experiments, which were designed, performed and analyzed by M.E.M.; the Granger causality and power analyses, which were carried out by Y.Z.; and some behavioral experiments and imaging, which were performed and analyzed by A.K., V.V., L.G., A.H. and S.P. The AAV-Syn::Venus-2A-HAhM4D virus was packaged and tested by V.G. and A.I. The wireless recording device was built by A.L.V. The project was conceived and the manuscript written by T.B.F and C.T.G., with critical input from T.B.

Correspondence to Cornelius T Gross.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Social, anxiety-like and depressive-like behaviors in defeated and control mice.

(a) Social avoidance (n=9; day, F[6,8] = 5.81, p = 0.0001) and (b) number of attacks (n=8) across social defeat sessions during the period in which the intruder was prevented from attacking the resident by an enclosure. (c) Retreats made by defeated (n=7) and control (n=7) mice in response to aggressors, females or a novel object (defeat: F[1,12] = 6.5, p = 0.026, stimulus: F[2,12]=3.48, p=0.047). (d) Time spent in the open arm (control, n=18; defeat, n=18), (e) number of unprotected and protected stretch attends (control, n=8; defeat, n=8), and (f) rearing in defeated and control mice in the elevated plus maze (control, n=8; defeat, n=8). (g) Immobility in defeated and control mice in the tail suspension test (control, n=9; defeat, n=9). a, b, red squares represent mean of defeated mice. c-g, grey circles represent individual control mice, light red squares represent individual defeated mice, horizontal bar denotes mean. All error bars represent standard error of the mean.

Supplementary Figure 2 Behavioral effects of ketamine on defeated and control mice.

(a) Timeline showing behavioral testing and ketamine/vehicle administration. (b) Time spent investigating (defeat: F[1, 57] = 65.8, p < 0.0001; defeat x ketamine: F[2,57] = 4.3, p = 0.018; control/vehicle, n=13; control/2.5, n=8; control/5, n=15; defeat/vehicle, n=8; defeat/2.5, n=8; defeat/5, n=11), (c) duration of investigation bout (control/vehicle, n=14; control/2.5, n=8; control/5, n=14; defeat/vehicle, n=9; defeat/2.5, n=8; defeat/5, n=10), (d) retreats (defeat: F[1,56] = 31.9, p < 0.0001; defeat x treatment: F[2, 56]= 5.9, P=0.0048; control/vehicle, n=14; control/2.5, n=7; control/5, n=14; defeat/vehicle, n=9; defeat/2.5, n=8; defeat/5, n=10) and (e) baseline locomotor behavior (control/vehicle, n=12; control/2.5, n=4; control/5, n=14; defeat/vehicle, n=8; defeat/2.5, n=4; defeat/5, n=9) in control and defeated mice given vehicle or ketamine. (f) Same arm returns (SARs) (control/vehicle, n=13; control/2.5, n=7; control/5, n=11; defeat/vehicle, n=8; defeat/2.5, n=7; defeat/5, n=9; defeat x drug: F[2, 49] = 5.56, P=0.0067), (g) spontaneous alternation (control/vehicle, n=14; control/2.5, n=8; control/5, n=12; defeat/vehicle, n=8; defeat/2.5, n=8; defeat/5, n=9), (h) latency to exit the start arm (control/vehicle, n=13; control/2.5, n=7; control/5, n=12; defeat/vehicle, n=8; defeat/2.5, n=8; defeat/5, n=8), and (i) overall distance (control/vehicle, n=14; control/2.5, n=8; control/5, n=12; defeat/vehicle, n=8; defeat/2.5, n=8; defeat/5, n=9) travelled in the Y-maze. 0.05<+p < 0.1, *p < 0.05; **p < 0.01; ***p < 0.001. b-i, grey circles represent individual control mice, light red squares represent individual defeated mice, horizontal bar denotes mean, error bars represent standard error of the mean. veh, vehicle.

Supplementary Figure 3 mPFC infection sites for mPFC–dPAG inhibition and behavioral effects of mPFC–SuColl inhibition in control mice.

Area of viral infection (AAV-Syn::Venus-2A-HAhM4D-WPRE) visualized by endogenous Venus in mPFC of (a) control and (b) defeated mice administered CNO. (c) Distance travelled in the home cage in (left) control and (right) defeated mice after intra-PAG administration of CNO or vehicle (control/vehicle, n=10; control/CNO, n=10; defeat/vehicle, n=10; defeat/CNO, n=12). (d-g) Schematic describing bilateral infection of the mPFC with AAV expressing Venus fluorescent protein and HA-tagged hM4D (AAV-Syn::Venus-2A-HA-hM4D), and implantation of a guide cannula over SuColl. (d) Time investigating the aggressor (vehicle, n=10; CNO, n=10), (e) investigation bouts (vehicle, n=10; CNO, n=10), (f) retreats (vehicle, n=10; CNO, n=10) and (g) overall activity (vehicle, n=8; CNO, n=6) in control mice administered CNO or vehicle prior to testing. (h) Quantification of c-Fos immunopositive cells in ventrolateral (vl) PAG (control/vehicle, n=10; control/CNO, n=10; defeat/vehicle, n=10; defeat/CNO, n=12). c-h, grey circles represent individual control mice, light red squares represent individual defeated mice, horizontal bar denotes mean. All error bars represent standard error of the mean. veh, vehicle.

Supplementary Figure 4 Effects of social defeat on mPFC–dPAG functional connectivity when distal to the aggressor.

(a) Electrode placements for LFPs recorded in mPFC and dPAG of control (grey) and defeated (red) mice. (b, c) Relative coherence (coherence differential) in defeated (n=8) and control (n=8) mice when distal to the aggressor. (d) Relative causality (causality differential) in the dPAG->mPFC and mPFC-> dPAG direction in defeated (n=8) and control (n=8) mice when distal to the aggressor (U=8, p=0.038). Power spectra differential (e, f) mPFC and (g, h) PAG of defeated (n=8) and control (n=8) mice when distal to the aggressor (beta, U=6, p=0.0047). Power spectra were averaged across mice. Power in each frequency band was calculated as the sum of the power values. *P<0.05; **P<0.01. c, d, f, h, grey circles represent individual control mice, light red squares represent individual defeated mice, horizontal bar denotes mean. All error bars represent standard error of the mean.

Supplementary Figure 5 Extracellular synaptic field potentials in dPAG and MDT of defeated and control mice.

Superimposed recordings illustrating extracellular synaptic field potentials recorded at (a) dPAG following electrical stimulation of mPFC and at (b) mPFC following electrical stimulation of MDT along the different sessions. (gray scale: control group; red scale: defeated group).

Supplementary Figure 6 Cell-specific retrograde labeling in GAD2::Cre mice and location of Vglut2+ neurons used for whole cell recordings.

(a) Summary of rabies-infected neurons (GFP+, mCherry-) in the forebrain of VGgat::Cre animals (percentage of the average number of retrograde neurons weighted to the number of starter cells present in each animal, n=7). No neurons were found in the olfactory bulb (grey), hippocampus (grey), or cortex. Areas not counted (midbrain and hindbrain) are indicated in white. Thal – thalamus; Hypothal – hypothalamus. (b) Schematic showing the location of all Vglut2+ neurons from which whole-cell recordings were made. Blue circles represent neurons with monosynaptic inputs from the PFC, and orange circles are neurons without PFC input. Aq – cerebral aqueduct; dmPAG – dorsomedial PAG; dlPAG – dorsolateral PAG; lPAG – lateral PAG; vlPAG – ventrolateral PAG; DR – dorsal raphe.

Supplementary Figure 7 Acquisition of social defeat in Vglut2::Cre mice and behavioral effects of inhibition of GAD2+ cells in the dPAG.

(a) Time spent investigating, (b) mean investigation bout, and (c) retreats in Cre+ and Cre- defeated and control mice during the three days of acquisition. (d) Time spent investigating (vehicle, n=6; CNO, n=7), (e) mean duration of investigation (vehicle, n=6; CNO=7) and (f) retreats (vehicle, n=6; CNO, n=7) after systemic administration of vehicle or CNO in GAD2::Cre mice infected with AAV-Syn::DIO-hM4D-mCherry in the dPAG (t(11)=2.2, p=0.016). a-c, black circles represent mean of control mice, red squares represent mean of defeated mice. d-f, grey circles represent individual control mice, light red squares represent individual defeated mice, horizontal bar denotes mean. All error bars represent standard error of the mean.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1–3 (PDF 1822 kb)

Supplementary Methods Checklist (PDF 469 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Franklin, T., Silva, B., Perova, Z. et al. Prefrontal cortical control of a brainstem social behavior circuit. Nat Neurosci 20, 260–270 (2017) doi:10.1038/nn.4470

Download citation

Further reading