Scientific Understanding of Consciousness
Nucleus Accumbens Social Reward, Oxytocin and Serotonin
Nature 501, 179–184 (12 September 2013)
Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin
Gül Dölen, et.al.
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA
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 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 serotonin (5-HT) in the nucleus accumbens, a mechanistic insight with implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism.
The mesocorticolimbic (MCL) circuit, implicated in encoding the rewarding properties of addictive drugs, is likely to have evolved to motivate behaviours that were important for survival and reproduction. Such incentive behaviours include eating, drinking and copulation, and are reinforced by so-called ‘natural rewards’ (for example, food, water, pheromones). Growing evidence suggests that social interaction itself can act as a natural reward. However, given the diversity of social behaviours (for example, parental investment, mating, cooperation) and the selection pressures that shaped their emergence (reproductive, predation, limited resources), it remains unclear whether evolutionarily conserved neural mechanisms exist to encode social reward.
An important clue comes from studies that have related pair-bonding behaviour in prairie voles (Microtus ochrogaster) to elevated expression of oxytocin receptors (OTRs) in the nucleus accumbens (NAc), a key component of the brain’s MCL reward circuit. However, the species-specific nature of this mating behaviour and the reported paucity of OTR expression in the NAc of mice questions the relevance of NAc OTRs to consociate social behaviours. This topic is of particular interest given that polymorphisms in the OTR gene have been associated with autism spectrum disorders, which are characterized by profound social deficits, and may be amenable to treatment with oxytocin (OT).
Mice are social animals: they live in consociate ‘demes’ consisting of five to ten adult members that share territorial defence and alloparental responsibilities, and exhibit several behaviours (for example, vocal communication, imitation, and empathy) that are the hallmarks of sociality. As in several other species including humans, OT has been linked to social behaviours in mice. However, OT and OTR knockout mice show a number of related behavioural deficits (such as memory impairment, anxiety, stress, aggressivity) that make it difficult to parse the function of OT as a social reward signal in the central nervous system. To examine the hypothesis that OT signalling in mice is required for the rewarding properties of social interactions, we used a conditioned place preference (CPP) assay that has traditionally been used to study the rewarding properties of drugs of abuse and recently has been expanded to include social reward.
We have demonstrated that the coordinated activity of OT and 5-HT is required for the reward associated with social interactions and modifies MCL circuit properties by generating LTD of excitatory synapses onto MSNs in the NAc. Moreover, our findings specifically implicate OT-mediated 5-HT release in the NAc in the regulation of social reward. Since OT-LTD occurs in both D1- and D2-receptor-expressing MSN subtypes, as does 5HT1B-LTD, these results suggest that social reward is not expressly governed by the dichotomies proposed by prevailing models of striatal function. Indeed, the two-pathway framework for striatal function is almost certainly oversimplified and computational modelling studies have proposed that reinforcement learning engages multiple neuromodulatory reward circuits in parallel. Furthermore, 5-HT and dopamine systems may represent reward in fundamentally different ways. Future studies examining the interplay between dopamine and 5-HT in the regulation of social reward will therefore be informative.
In light of estimates that the shift to social living preceded the emergence of pair-living by 35 million years, we suggest that the NAc-dependent social reward mechanisms described here are the predecessors of evolutionary specializations seen in prairie voles. These mechanisms utilize presynaptically localized OTRs, which couple to G-proteins, and thus may have been overlooked by previous studies that relied on receptor autoradiography and transcript tagging to conclude that OTRs do not exist in the NAc of consociate species like mice. Moreover, as it is these antecedent social behaviours that are disrupted in neuropsychiatric diseases such as autism, the elucidation of the neural mechanisms mediating social reward is a critical step towards the development of rational, mechanism-based treatments for brain disorders that involve dysfunction in social behaviours.
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