Nature Neuroscience
7, 1048 - 1054 (2004)
Published online: 26 September 2004; | doi:10.1038/nn1327
The neurobiology of pair bondingLarry J Young1
& Zuoxin Wang21
Center for Behavioral Neuroscience, Department of Psychiatry and Behavioral Sciences, and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia
30322, USA. 2
Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida
32306, USA.
Correspondence should be addressed to Larry J Young lyoun03@emory.eduA neurobiological model for pair-bond formation has emerged from studies in monogamous rodents. The neuropeptides oxytocin and vasopressin contribute to the processing of social cues necessary for individual recognition. Mesolimbic dopamine is involved in reinforcement and reward learning. Concurrent activation of neuropeptide and dopamine receptors in the reward centers of the brain during mating results in a conditioned partner preference, observed as a pair bond. Differential regulation of neuropeptide receptor expression may explain species differences in the ability to form pair bonds. These and other studies discussed here have intriguing implications for the neurobiology of social attachment in our own species.Sexual attraction and the selective social attachments that often follow are two of the most powerful driving forces of human behavior, profoundly influencing art, music, literature and politics throughout history. The presence of strong, enduring relationships between sexual partners is widespread in nearly all societies, particularly in societies where monogamy is a predominant feature of the social organization. Whether humans have a biological propensity to practice monogamy (or perhaps more correctly, serial monogamy) is debatable; however, there is little doubt that the ability to form intense social attachments—or pair bonds—with a mate has a biological architecture with definable molecular and neural mechanisms. Studies using monogamous rodents as models for social attachment are providing insights into the biology of pair-bond formation.
The term 'monogamy' implies a social organization in which a male and female mate exclusively with each other, although extra-pair copulations are not unusual in monogamous species1. For this reason, the term 'monogamy' is used here to refer to a social organization in which each member of a mating pair displays selective (but not exclusive) affiliation and copulation, as well as nest sharing, with the partner; it also typically implies biparental care of offspring. Only 3−5% of mammals exhibit a monogamous social structure as defined by these criteria2. One group of species in particular, voles in the genus Microtus, has emerged as a valuable tool for investigating the neurobiological mechanisms of pair-bond formation3,
4. Here we review recent discoveries concerning the molecular, cellular and neurobiological pathways that result in the development of a pair bond in the monogamous prairie vole (Microtus ochrogaster). These studies provide a framework for understanding the regulation and evolution of complex social behavior and may provide insights into the human social brain.
Peptidergic regulation of the pair bond
Like humans, voles display a remarkable diversity in social organization. For example, prairie voles form enduring pair bonds and are biparental, but montane (Microtus montanus) and meadow (Microtus pennsylvanicus) voles are nonmonogamous and typically do not display biparental care5,
6,
7. In nature, the majority of prairie voles that lose a mate never take on another partner8.
In the laboratory, researchers study pair-bond formation using a partner-preference test. The testing apparatus consists of three chambers connected by tubes. The 'partner' and a novel 'stranger' are tethered in their own chambers, whereas the subject is free to move throughout the apparatus during a 3-h test. Pair bonding is inferred when subjects spend significantly more time in close proximity to the partner compared to the stranger (partner preference). In prairie voles, mating facilitates formation of partner preference, although cohabitation without mating may also result in partner-preference formation under some circumstances9.
Two neuropeptides emerged initially as critical mediators of partner-preference formation in prairie voles: oxytocin and arginine vasopressin (AVP). Oxytocin also regulates mother-infant bonding in sheep10, whereas AVP has been implicated in several male-typical social behaviors, including aggression, scent marking and courtship11,
12. Infusion of oxytocin into the cerebral ventricles of female prairie voles accelerates pair bonding, as these females require only a brief cohabitation with a male, without mating, to form a partner preference13. Likewise, central AVP infusion facilitates pair-bond formation in male prairie voles without mating14. Administration of selective oxytocin receptor (OTR) and AVP receptor 1a (V1aR) antagonists prevents pair-bond formation in female and male prairie voles, respectively13,
14,
15,
16. Although both peptides may facilitate pair-bond formation in either sex16, oxytocin seems to be more important in females, whereas AVP is more critical in males14,
15,
17. The mechanism underlying this sex difference in behavioral response to oxytocin and AVP is unclear, because receptor densities in the brain are similar in males and females. Early social experience may also influence adult social behavior, as developmental studies suggest that neonatal oxytocin exposure enhances the likelihood of partner preference formation in adult male prairie voles18. Although other factors, including stress and stress hormones, also modulate partner-preference formation19,
20,
21, for the sake of clarity we will restrict our focus to oxytocin and AVP, as well as their interactions with other neurotransmitter systems.
The first hypotheses about the neuroanatomical basis of pair-bond formation came from comparisons of OTR and V1aR distributions in the brains of monogamous and nonmonogamous vole species. Compared to nonmonogamous species, monogamous prairie voles have higher densities of OTR in the caudate putamen and nucleus accumbens (Fig. 1a,b)22 and higher densities of V1aR in the ventral pallidum, medial amygdala and mediodorsal thalamus (Fig. 1c,d)23. Some of these regions are involved in pair-bond formation. For example, infusion of an OTR antagonist into the prefrontal cortex and nucleus accumbens of females, but not the caudate putamen, blocks mating-induced partner-preference formation (Fig. 1e)24. In males before mating, blocking V1aR neurotransmission in the ventral pallidum, but not the medial amygdala or mediodorsal thalamus, also inhibits partner-preference formation (Fig. 1f)25. Infusion of V1aR antagonist into the lateral septum, which expresses some V1aR in both species, also prevents mating-induced pair-bond formation in males26.
 | | |
Sex, reward and pair bonding
Results from anatomical and pharmacological studies indicate that the prefrontal cortex, nucleus accumbens and ventral pallidum are all critical brain regions in pair-bond formation. These regions are also involved in the mesolimbic dopamine reward system, suggesting that pair-bond formation uses the same neural circuitry as reward. Reward processing depends on the mesocorticolimbic dopaminergic system consisting of dopamine neurons in the ventral tegmental area and their projections to the nucleus accumbens, prefrontal cortex and other brain areas27. The ventral pallidum is a major target of the nucleus accumbens28,
29, and it further processes and relays stimuli from the nucleus accumbens to mediate locomotor responses to rewarding stimuli30,
31. Dopamine release within this circuit is critically involved in natural reward (food intake and mating) as well as maladaptive (drug) reward27,
32,
33. Studies also implicate this circuit in conditioned reward learning, such as drug-induced place preferences34, in which neutral stimuli become associated with rewarding stimuli.
Given that mating is rewarding in rodents34,
35,
36 and facilitates pair-bond formation in voles, some researchers have hypothesized that pair bonding may be the result of conditioned reward learning, in which an association forms between the reinforcing properties of sex (unconditioned stimulus) and the specific olfactory signature of the partner (conditioned stimulus)3,
37. For example, both male and female rats prefer to spend time in the chamber in which they copulated (a conditioned place preference)38,
39, and this sexual conditioning depends on D1-type and D2-type dopamine receptor activation in the nucleus accumbens40.
Consistent with the hypothesis that pair bonding involves conditioned learning, dopamine within the nucleus accumbens is critical for partner preference formation in prairie voles (Fig. 2). The nucleus accumbens in voles contains dopamine terminals and receptors (Fig. 2b)41,
42 and mating results in an increase (51%) in extracellular dopamine in the nucleus accumbens of females (Fig. 2c)43. Mating also tends to increase dopamine turnover in the nucleus accumbens of males42. Systemic administration, or local injection into the nucleus accumbens, of haloperidol (a nonselective dopamine receptor antagonist) blocks mating-induced partner preferences, whereas apomorphine (a nonselective dopamine receptor agonist) facilitates partner preference without mating in both male and female prairie voles (Fig. 2a)42,
43.
| | |
The dopaminergic regulation of pair-bond formation in the nucleus accumbens is receptor subtype−specific: activation of D2, but not D1, receptors in the nucleus accumbens of female prairie voles accelerates partner preferences without mating, whereas blockade of D2 receptors antagonizes this behavior (Fig. 2d)43,
44. In males, D2 receptor activation also facilitates partner preference, but D1 receptor activation blocks partner preferences induced by mating or by D2 receptor activation41. Male prairie voles that have mated and pair bonded with a female for two weeks also show a significant increase in the density of D1, but not D2, receptors in the nucleus accumbens. No changes in dopamine receptor binding occur in other dopaminergic brain areas, including the caudate putamen41. As D1 activation in the nucleus accumbens prevents pair bonding in males41, this increase in D1 receptor density may serve to prevent the formation of new pair bonds, thereby maintaining the current pair bond and stabilizing the monogamous social organization.
Although mating-induced dopamine release in the nucleus accumbens is important for pair-bond formation in prairie voles, mating also induces dopamine release in the nucleus accumbens of other species of rodents, such as rats, which do not form pair bonds35,
36. Why then does dopamine induce pair bonding only in monogamous prairie voles? The answer may lie in the interaction of the oxytocin, AVP and dopamine systems within the reward circuitry.
In female prairie voles, administration of an OTR antagonist into the nucleus accumbens blocks partner preferences induced by D2 receptor activation, whereas blockade of D2 receptors in the nucleus accumbens prevents partner preference formation induced by oxytocin44 (Fig. 2e). These data indicate that dopamine and oxytocin are not acting sequentially, but rather that concurrent activation of both oxytocin and dopamine D2 receptors, and the interaction between these two systems in the nucleus accumbens, are necessary for pair-bond formation in females. Similar studies have not been done in males, but given that the D2 receptors in nucleus accumbens42 and V1aR in the ventral pallidum25,
45 are important for pair bonding in males, and that these two areas are interconnected28,
29, it is likely that the dopamine and AVP systems also interact in the nucleus accumbens−ventral pallidum circuitry to influence pair-bond formation in males. The nature of the interaction of these systems in voles is not clear. Studies on drug tolerance and addiction suggest that these neuropeptides may modulate the role of dopamine in the reward circuitry46. Furthermore, dopamine administration induces central oxytocin release, whereas oxytocin administration increases central dopamine levels in the rat47,
48. The interaction may also be indirect, with concurrent activation modulating downstream circuits involved in olfactory learning and conditioning, for example.
A neurobiological model for pair bonding
How might the oxytocin, AVP and dopamine systems interact to facilitate pair-bond formation? There are now several studies suggesting that both oxytocin and AVP are involved in the neural processing of sensory cues involved in social learning. In rodents, both neuropeptides are implicated in the processes required to identify the olfactory signatures of conspecifics (social recognition)49. Oxytocin knockout mice fail to recognize individuals to which they have been previously exposed50, and infusions of oxytocin in the medial amygdala completely restore social recognition in these mice51. Selective V1aR antagonist or antisense V1aR administered into the lateral septum of rats also inhibits social recognition52,
53, whereas infusion of AVP or overexpression of the V1aR in this region enhances social recognition abilities54. V1aR knockout mice also exhibit a complete loss of social recognition55. However, both oxytocin and V1aR knockout mice perform normally in other olfactory and cognitive tasks, suggesting that this deficit is specific for social discrimination50,
55. Given this role for oxytocin and AVP in social recognition and the interaction of these peptides with mesolimbic dopamine, a reasonable hypothesis is that pair bonding results from the convergence of social discrimination circuits and the reinforcing properties of the mesolimbic dopamine reward circuit (Fig. 3).
| | |
Mating in both males and females correlates with neural activity in several brain regions, including the ventral tegmental area (VTA), medial amygdala, preoptic area and hypothalamus25,
56. Dopaminergic projections from the VTA release dopamine in the nucleus accumbens and prefrontal cortex, which has strong glutamatergic projections back to the nucleus accumbens27. Concurrently, olfactory cues from the partner are processed by the main and accessory olfactory bulbs, and subsequently by the medial amygdala and lateral septum, which are critical for social recognition. The medial amygdala and bed nucleus of the stria terminalis are major sources of AVP fibers projecting to the ventral pallidum and lateral septum57, whereas oxytocin fibers in the nucleus accumbens most likely originate from neurons in the preoptic area or hypothalamus58. Activation of these areas during mating may result in local release of these peptides. Indeed, in vivo microdialysis shows that AVP is released in the male prairie vole ventral pallidum during mating (J.C. Morales and L.J.Y., unpublished data), and vaginocervical stimulation increases central oxytocin release in sheep59. Thus, mating ultimately results in the concurrent activation of D2 receptors in the nucleus accumbens of both sexes, OTR in the prefrontal cortex and nucleus accumbens of females and V1aR in the ventral pallidum of males. As a result, the reinforcing, hedonic properties of mating may become coupled with the olfactory signatures of the mate, resulting in a conditioned partner preference, much in the same way as drugs of abuse result in conditioned place preferences. In this model, the basic mechanism of bonding is similar in males and females; the neuropeptides are simply modulating two different nodes of the same circuits. In nonmonogamous species, sexual activity can also result in conditioned preferences for nonsocial stimuli, including neutral odors placed on the sexual partner60. However, in nonmonogamous species, the dopamine system and the oxytocin and AVP systems are uncoupled because of the low densities of OTR and V1aR in this pathway.
We must stress that the study of the neurobiology of social bonding in voles is in its infancy, and the model described here draws heavily on neuroanatomical, behavioral and pharmacological data obtained from rat studies, particularly those focusing on conditioned learning, reinforcement and addiction. Our model is clearly limited in scope, and raises many more questions than it answers. For example, what is the nature of the interactions between the peptide and dopamine systems? How are other neurotransmitters such as glutamate and GABA involved in pair bonding? How do the circuits involved in olfactory processing converge on the reward circuits, and how does this result in olfactory conditioning? Is there a role for other structures such as the hippocampus and cortex? And finally, what types of molecular and synaptic changes take place to lead to the development of a permanent pair bond. Thus, although this admittedly is an oversimplified model, it provides a neurobiological framework in which to generate and test hypotheses regarding pair bonding.
The molecular basis of the pair bond
If our current model is correct, one would predict that pair-bonding behavior could be potentially induced in a nonmonogamous species by expressing OTR or V1aR in the nucleus accumbens or ventral pallidum. We tested this prediction using viral vector−mediated gene transfer to overexpress Avpr1a, the gene encoding V1aR, in the ventral pallidum of the nonmonogamous male meadow vole6 (Fig. 4a,b). After cohabitation with a receptive female during which copulation occurred, these transgenic animals showed enhanced partner preference compared to controls. Pretreating virus-treated voles with a D2 receptor antagonist prevented partner preferences (Fig. 4a). This study has remarkable implications for the evolution of complex behavior, suggesting that mutations altering the expression pattern of a single gene can have a profound impact on complex social behaviors.
| | |
How did the differential patterns of V1aR and OTR expression emerge between monogamous and nonmonogamous species? Because researchers have studied this question most extensively with respect to Avpr1a, we will limit our discussion to this gene. The Avpr1a genes in the prairie vole and nonmonogamous montane vole are highly homologous61. However, approximately 660 base pairs upstream of the transcription start site, the prairie vole Avpr1a gene contains 500 base pairs of highly repetitive sequence, known as a microsatellite; in montane and meadow voles, this repetitive sequence is much shorter (Fig. 4c). Microsatellite sequences are highly unstable62, and there are several examples of genes for which polymorphic microsatellites in the regulatory region result in differential levels of expression63,
64. It is clear that the sequences proximal to the Avpr1a coding region determine the pattern of expression, as a transgenic mouse expressing a prairie vole Avpr1a gene that included 2.4 kb of upstream sequence expressed the Avpr1a gene in a pattern similar to that of the prairie vole61. The species-specific microsatellite also modulates gene expression in a cell type−specific manner. Replacing the prairie vole microsatellite with the shorter montane vole sequence increases reporter gene expression in a transcription reporter assay (Fig. 4d)65. Although the results, obtained in a cultured rat A7r5 cell line, are in the opposite direction from what one would predict from the species differences in ventral pallidal receptor binding, the effect is consistent with the higher level of V1aR expression in the septum of montane voles compared to prairie voles. As the effect of the microsatellite on expression is cell type−specific, it is likely that in other cell lines, and indeed in the brain itself, the prairie vole microsatellite might yield higher levels of transcription than the montane vole sequence. Together, these data suggest that expansion or contraction of this microsatellite in the 5' flanking regulatory region of this gene could have been the molecular event that resulted in the altered expression of the V1aR gene in the preexisting reward circuit, resulting in the biological potential to develop conditioned partner preferences. We do not know, however, which selective pressures influenced the frequency of the microsatellite alleles, and consequently the monogamous social structure, in voles. The human V1aR gene (AVPR1A) has three highly polymorphic microsatellite sequences in the 5' flanking region, and it has been suggested that variation in one of these sequences may be associated with autism66,
67.
Implications for human bonding
Undoubtedly there are numerous molecular and neurobiological pathways that could evolve to support pair-bond formation between mates, and different species may have achieved similar behaviors through a process of convergent evolution involving different circuits. We strongly emphasize that there are no hard data demonstrating common physiological mechanisms for pair-bond formation in voles and man. In addition, as with many human behaviors, the emergence of the neocortex and its ability to modify subcortical function cannot be ignored. Nevertheless, it is intriguing to consider the possibility that similar mechanisms may underlie the formation of pair bonds in both humans and rodents. Although it is not known whether human sexual intercourse results in central oxytocin or AVP release, plasma oxytocin levels are elevated at the time of orgasm in women, and similarly, plasma AVP concentrations increase during sexual arousal in men68,
69. These changes may or may not reflect central peptide release; it is intriguing, however, to consider how aspects of human sexuality may reflect the influence of intercourse on pair bonding. For example, human females are 'hidden ovulators' and engage in sexual activity throughout the ovarian cycle. This regular sexual activity may serve to activate the circuits underlying bonding, thus strengthening the pair bond. Furthermore, in contrast to other mammalian species, human females have enlarged mammary tissues independent of lactation, and breast and nipple stimulation are an integral part of human sexuality. Nipple stimulation during lactation is one of the most potent stimuli for oxytocin release70. If oxytocin is involved in human social attachment, this aspect of sexual activity may thus serve to reinforce sexual bonding.
Human imaging studies also provide evidence consistent with the hypothesis that reward and neuropeptide circuits are involved in pair bonding in humans. When human subjects viewed photographs of individuals with whom they claimed to be romantically in love, their brain activity patterns (as measured by functional magnetic resonance imaging, fMRI) looked remarkably similar to those observed after cocaine or  -opioid infusions, with heavy activation of the VTA and striatal dopamine regions71. Many of the regions activated are rich in oxytocin, AVP or their respective receptors72,
73. Similar patterns of activity occur when mothers view images of their own children, suggesting some overlap between the neural mechanisms of maternal attachment and those of romantic love74. In addition, the VTA and striatum show substantial activity (as measured by positron emission tomography, PET) during ejaculation in men, paralleling the activation pattern evoked by a heroin rush75.
The work reviewed here has focused primarily on the neurobiology of mating-induced, heterosexual pair bonds. It is also intriguing to consider whether other types of social bonds, including familial bonds, close friendships or homosexual relationships might use some of the same neurobiological mechanisms.
The pair bond is an integral aspect of human sexuality with important implications for both psychological and physical health. In the last few years, the neurobiological mechanisms underlying pair bonding in voles have provided valuable insights into the social brain. The convergence of mechanisms underlying reward, conditioning and the neural processing of social cues seems to result in the motivation to maintain selective contact with one's partner. It is unclear whether the same mechanisms are involved in rodent and human pair bonding, but it is likely that in both cases, the social brain and reward circuits are both involved, perhaps giving credence to the adage, "love is an addiction."
Received 23 June 2004; Accepted 10 August 2004; Published online: 26 September 2004.
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Acknowledgments
The authors acknowledge A.Z. Murphy, E.A.D. Hammock, M.M. Lim, B. Aragona and T. Curtis for discussion and comments during the writing of this manuscript. The authors especially thank C.S. Carter and T.R. Insel for their pioneering work, which laid the foundation for neurobiological studies of social bonding. Much of this work was supported by National Institute of Mental Health grants to L.J.Y. and Z.X.W.
Competing interests statement:
The authors declare that they have no competing financial interests. |
