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.
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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.).
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.
(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.
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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
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