Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin

Abstract

Social behaviours in species as diverse as honey bees and humans promote group survival but often come at some cost to the individual. Although reinforcement of adaptive social interactions is ostensibly required for the evolutionary persistence of these behaviours, the neural mechanisms by which social reward is encoded by the brain are largely unknown. Here we demonstrate that in mice oxytocin acts as a social reinforcement signal within the nucleus accumbens core, where it elicits a presynaptically expressed long-term depression of excitatory synaptic transmission in medium spiny neurons. Although the nucleus accumbens receives oxytocin-receptor-containing inputs from several brain regions, genetic deletion of these receptors specifically from dorsal raphe nucleus, which provides serotonergic (5-hydroxytryptamine; 5-HT) innervation to the nucleus accumbens, abolishes the reinforcing properties of social interaction. Furthermore, oxytocin-induced synaptic plasticity requires activation of nucleus accumbens 5-HT1B receptors, the blockade of which prevents social reward. These results demonstrate that the rewarding properties of social interaction in mice require the coordinated activity of oxytocin and 5-HT in the nucleus accumbens, a mechanistic insight with implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism.

Figure 1. Oxytocin is required for sCPP

a, Protocol for sCPP. b,f, Experimental time course of i.p injections (b) and NAc reverse microdialysis (f) in sCPP. c,d,g,h Individual (top) and average (bottom) responses in animals receiving i.p. (c) or NAc (g) saline versus animals receiving i.p. (d) or NAc (h) OTR-A. For both i.p. and NAc delivery routes, saline, but not OTR-A treated, animals spend more time in social bedding cue following conditioning (n = 18 i.p. saline, n = 15 i.p. OTR-A; n = 9 NAc saline and n = 11 NAc OTR-A animals). e,i, Comparisons between treatment groups reveal significantly decreased normalized and subtracted social preference in both i.p. and NAc OTR-A treated animals. Summary data are presented as mean ± s.e.m (*p<0.05, Student’s t-test).

Figure 2. OT induces LTD in the NAc

a-h, Representative traces (a,d,g,j), summary time course (b,e,h,k), and average post-treatment magnitude comparisons (c,f.i,l) reveal significant EPSC response depression in OT treated but not OTR-A preincubated cells (a-c, n = 6 OT, n = 6 OT+ OTR-A preincubation cells); OT-response depression is not reversed by post-induction OTR-A chase (d-f, n = 7 cells); the magnitude of OT-LTD is significantly increased in cells from isolation versus socially reared animals (g-i, isolate, n = 14, social n = 27 cells); and the magnitude of EPSC OT-LTD is not different in D1 versus D2 MSNs (j-l, n = 9 D1, and n = 11 D2 cells). m-q Representative mEPSC traces (m), cumulative probability (n,o), and average (p,q) comparisons reveal mEPSC frequency (n,p), but not amplitude (o,q), is decreased in OT-treated versus control cells (control, n = 11, OT, n = 11 cells). r-t, Comparisons of representative traces (r) and average (s) paired pulse ratios PPR (n = 6 cells) as well as average (t) coefficient of variance, CV (n = 32 cells) reveal significant increases following induction of OT-LTD. Summary data are presented as mean ± s.e.m (*p<0.05, Student’s t-test).

Figure 3. Presynaptic OTRs are required for sCPP

a,e,i Experimental time course for (a) sham, (e) NAc-AAV-Cre-eGFP, and (i) NAc-RbV-Cre-eGFP injections. b,c,f,g,j,k, Individual (top) and average (bottom) responses in WT (b,f,j), versus cOTR (c,g,k) animals receiving sham (b,c), NAc-AAV-Cre-eGFP (f,g), or NAc-RbV-Cre-eGFP (j,k). WT animals, as well as sham and NAc-AAV-Cre-eGFP injected cOTR animals, but not cOTR animals injected with NAc-RbV-Cre-eGFP, spend more time in social bedding cue following conditioning (sham WT, n = 15, cOTR, n = 8; NAc-AAV-Cre-eGFP WT, n = 15, cOTR, n = 19; NAc-RbV-Cre-eGFP WT, n = 14, cOTR, n = 22). d,h,l, Comparisons between WT and cOTR animals reveal normal sCPP in sham and NAc-AAV-Cre-eGFP injected animals, while in NAc-RbV-Cre-eGFP injected animals sCPP is significantly decreased in cOTR versus WT controls. Summary data are presented as mean ± s.e.m (*p<0.05, Student’s t-test).

Figure 4. OTRs in dRph inputs to NAc are required for sCPP and OT-LTD

a, Experimental time course of dRph-AAV-Cre-eGFP injections in sCPP. b,c Individual (top) and average (bottom) comparisons reveal that dRph-AAV-Cre-eGFP injected WT (b), but not cOTR (c) animals spend significantly more time in the social bedding cue following conditioning (WT, n = 14, cOTR, n = 10). d, Comparisons between dRph-AAV-Cre-eGFP injected groups reveal significantly decreased sCPP in cOTR animals compared to WT controls. e-g, Representative traces (e), summary time course (f) and average post-treatment magnitude comparisons (g) reveal absence of OT-LTD in EPSCs recorded from AAV-Cre-eGFP dRph injected cOTR KO versus pooled WT control animals (dRph-AAV-Cre-eGFP injected cOTR, n = 6 cells; pooled WT control, n = 30 cells). Summary data are presented as mean ± s.e.m (*p<0.05, Student’s t-test).

Figure 5. OT-LTD in NAc requires 5HT1b receptors

a-i, Representative traces (a,d,g), summary time course (b,e,h), and average post-treatment magnitude comparisons (c,f,i) reveal EPSC depression in 5HTR1b agonist (CP-93129 dihydrochloride) treated cells is not augmented by subsequent application of OT (a-c, n = 5 cells); OT-LTD is significantly reduced in cells pre-treated with the 5HTR1b-antagonist (NAS-181) (d-f, control, n = 7, 5HTR1b antagonist, n = 7 cells); CP-LTD is induced in slices in which OTRs are pharmacologically blocked (g-i, n = 5 cells). j-n Representative mEPSC traces (j), cumulative probability (k,l), and average (m,n) comparisons reveal mEPSC frequency (k,m), but not amplitude (l,n), is decreased in OT-treated cells versus cells treated with OT in the presence of NAS-181 (OT, n = 17 cells, OT + 5HTR1b-A, n = 17 cells). Summary data are presented as mean ± s.e.m (*p<0.05, Student’s t-test).

Figure 6. sCPP requires NAc 5HT1b receptors

a, Experimental time course of NAc reverse microdialysis. b,c, Individual (top) and average (bottom) responses in animals receiving NAc saline (b) versus 5HTR1b-A (c). Saline, but not 5HTR1b-A treated, animals spend more time in social bedding cue following conditioning (NAc saline, n = 20, NAc 5HTR1b-A, n = 26 animals). d, Comparisons between treatment groups reveal significantly decreased normalized and subtracted social preference in NAc 5HTR1b-A treated animals compared to saline controls. Summary data are presented as mean ± s.e.m (*p<0.05, Student’s t-test).