There is an ongoing debate in psychology as to the relative roles of genes and environment on the development of human behavior. There is little doubt that genes play a significant role in shaping certain innate human behaviors, such as sexual and parental behavior, social bonding, fear, and aggression. As in all animals, genes determine the underlying neurochemistry and circuitry that drive human emotions and behavior, but the manifestation of each of these behaviors is also clearly influenced by culture. Furthermore, the frequencies of various alleles for these genes are subject to selection based on social and ecological factors, which in turn shape behavior. Thus, if we are to fully understand the nature, diversity, and evolution of human behavior, we must understand the socioecological factors that shape behavior and learn more about the ways that genes act in the brain to establish the biological mechanisms underlying behavior. Elsewhere in this volume, Kaplan and Lancaster (Chapter 7), and Gangestad (Chapter 8) provide a theoretical framework for understanding the evolution of mating patterns and parental investments. This chapter discusses in detail the biological mechanisms underlying pair bond formation in monogamous voles. It must be stated at the outset that there has not been enough research to provide evidence that these same mechanisms are involved in homologous human behaviors. Research results for monogamous voles are presented here as a model for understanding how genes can influence the expression of a social behavior critical for reproduction.
The human species is rather unusual among mammals in that we form long-lasting selective social bonds between mates in addition to the parent-child bond resulting in the nuclear family. The precise nature of the nuclear family varies from culture to culture, ranging from strict monogamy reinforced by society and religion to polygyny or polyandry. Whether or not one considers human beings to be truly monogamous, it is clear that the selective bond between mates, manifested in our species as an emotion we call love, is extremely powerful, and is undoubtedly rooted in our biology and genetic heritage.
Controlled experiments on the neurobiological basis of sociosexual behaviors in humans are not possible. Thus, we must rely on animal models to provide principles that might generalize to humans. How might we find a suitable animal model for human bonding? Approximately 90 percent of bird species are considered monogamous, at least over one breeding season. In contrast, only approximately 5 percent of mammals exhibit a monogamous social structure (Kleiman, 1977). The term “monogamy” does not imply lifelong exclusive mating with a single individual. In fact, many birds form pair bonds over a season, raise their offspring together, and then select another partner the following season. For biologists, monogamy implies selective (not exclusive) mating, a shared nesting area, and biparental care. In recent years, genetic analyses of offspring have provided evidence for extra-pair copulations even among species thought to mate exclusively monogamously.
Biomedical research relies heavily on rodent models because rodents are small, breed well in the laboratory, and are suitable for many types of experimental manipulations. The use of behaviorally monogamous rodent species is efficient for investigating the biology of monogamy and social attachment. Several species of voles, genus Microtus, fit these criteria and have become rodent models for research on the neurobiological basis of pair bonding (Insel and Young, 2001). This chapter reviews the progress in understanding the molecular, cellular and neurobiological nature of pair bonding emerging from intensive studies of monogamous prairie voles, and discusses the implications of this research for human behavior.
Prairie voles (Microtus ochrogaster) are field mice found in the Midwestern prairie of the United States. Studies in the field indicate that prairie voles form long-term social bonds with their mates and produce multiple litters together (reviewed in Carter et al., 1995). In fact, one study reported that in pairs in which one individual disappears, fewer than 20 percent of the survivors took on a new mate. However, despite their social monogamy, not all prairie voles display exclusive mating, since females have been reported to carry mixed-paternity litters. The selective pressures leading to the evolution of monogamy in prairie voles are unclear. In theory, monogamous social structures are thought to be favored under conditions of low food availability, high nest predation, and low population density. Males in monogamous species typically display paternal care of their offspring by contributing food resources and by defending the nest from predators while the mother forages.
Prairie voles are believed to have evolved in the tall-grass prairies, which are very low in food resources and where population densities are likely to be very low. Under these conditions, males may enhance their reproductive success by nesting with a single female and producing multiple litters, rather than risk not finding a fertile mate. An alternative explanation proposes that, since prairie voles utilize a saturated habitat, dispersal opportunities are low. Thus, natural selection favors the production of high-quality, low-quantity offspring reared by two parents. In contrast, polygamous species, such as meadow voles, occupy patchy habitats, where dispersal success is more dependent on high-number, low-quality offspring. Data to support these potential explanations for the evolution of monogamy in prairie voles have been inconclusive. Interestingly, some populations of prairie voles are not monogamous, illustrating that even within a species there is a fair degree of plasticity in the neural circuits underlying pair bonding (Cushing et al., 2001). Thus, prairie voles, along with several other species of voles with various mating patterns, provide an opportunity to test hypotheses regarding mating patterns.
The pair bonding process in voles can be observed in the laboratory using a partner preference paradigm. In this procedure an adult male prairie vole and a female prairie vole are paired under differing experimental manipulations (i.e., duration of cohabitation, presence or absence of mating, antagonist infusions). After the designated time of cohabitation, the pair is separated and then placed in a partner preference testing arena. The arena is constructed of three chambers—the “partner” chamber in which the partner is tethered to restrict its movement to that chamber; the “stranger” chamber in which an unfamiliar animal of equal stimulus value as the partner is tethered; and the neutral chamber, which is connected to the other two chambers via tubing. The experimental subject is placed in the neutral chamber and is observed as it roams freely between the chambers. An animal is said to have developed a partner preference, the laboratory measure of a pair bond, if it spends more than twice as much time in contact with its partner than with the novel stimulus animal.
Data collected during tests of partner preference formation in prairie voles suggest that mating facilitates partner preference formation in both male and female prairie voles. For example, 6 hours of cohabitation without mating was not sufficient for the female to develop a partner preference, while the same duration of cohabitation with mating was sufficient (Williams et al., 1992). Similar results were obtained with males (Insel et al., 1995). However, in some cases, longer periods of cohabitation without mating are sufficient to result in the formation of a pair bond. Thus, it appears that both the quality and the quantity of social interactions between a pair of prairie voles contribute to the likelihood of partner preference formation and that mating acts to strengthen the pair bond. Using the partner preference paradigm in conjunction with pharmacological manipulations, we have begun to understand the chemical triggers and neural circuits underlying this pair-bonding process.
THE NEUROCHEMISTRY OF THE PAIR BOND
What neurotransmitter or hormone systems might be involved in the pair bond process? As mentioned above, social attachment is fairly rare between adult mammals; however, strong attachments between mothers and their offspring are widespread. It is conceivable that similar neural and molecular mechanisms that have evolved for regulating the mother-infant bond have been co-opted to produce the pair bond. This in fact appears to be the case. First, what hormones are involved in mother-infant bonding?
Not surprisingly, maternal nurturing behavior is facilitated by hormones released during pregnancy and parturition (Young and Insel, 2002). For example, in rats the levels of estrogens and progestins rise during pregnancy and then progestins decline at parturition. Maternal behavior is facilitated in virgin rats when estrogen and progestin treatment is followed by progestin withdrawal. Parental behavior in primates appears to be less dependent on hormonal stimulation; however, estrogen treatment in ovariectomized rhesus macaques does increase interaction with infants. In addition to these steroid hormones, oxytocin (OT) is a hormone that has multiple functions in the parturient mother, including the regulation of maternal behavior. OT is a nine amino acid cyclical neuropeptide hormone produced in the hypothalamus, which sends projections to the posterior pituitary as well as the brain (Gainer and Wray, 1994). OT is released into the plasma from the posterior pituitary gland during labor and is thought to play a role in facilitating parturition through its actions on uterine OT receptors. OT is also released into the plasma in a pulsatile manner during nursing, where it stimulates the milk ejection reflex, making breast-feeding possible. Studies in rodents and sheep have suggested that OT released in the brain also plays an important role in initiating maternal behavior as well as facilitating the selective bond between the mother and her offspring (Pedersen et al., 1994; Kendrick et al., 1997).
Several studies have now demonstrated that oxytocin plays a role in the development of the pair bond in the female prairie vole. Injections of an OT antagonist, a drug that blocks activation of the OT receptor, directly into the female prairie vole brain prior to cohabitation and mating inhibits the subsequent development of a partner preference (Insel and Hulihan, 1995). Furthermore, infusion of OT directly into the brain facilitates formation of a partner preference despite the absence of mating (Williams et al., 1994). Some studies have suggested that OT's role in partner preference formation is specific only for females, while other studies have found similar effects in both sexes (Cho et al., 1999). However, in males there is clear evidence that the peptide arginine vasopressin (AVP) plays a significant role in the formation of the pair bond of the male for its mate. AVP is structurally related to OT, differing from OT in only two amino acids. Like OT, AVP is synthesized in the hypothalamus and transported to the posterior pituitary gland (Gainer and Wray, 1994). However, extrahypothalamic AVP neurons from the amygdala and bed nucleus of the stria terminalis project into the forebrain where they are thought to influence behavior through interactions with the V1a subtype of the AVP receptor (V1aR). These extrahypothalamic AVP projections are sexually dimorphic, with males producing far more AVP than females (DeVries, 1990). Infusion of a compound that blocks V1aR activation prior to cohabitation and mating prevents male prairie voles from displaying a partner preference (Winslow et al., 1993). Conversely, infusion of AVP during an abbreviated cohabitation without mating facilitates formation of a partner preference.
The fact that OT and AVP are involved in the formation of the pair bond does not imply that these factors act alone in this process. Pair bond formation is surely a highly complex process involving multiple brain structures, neurochemicals, and sensory modalities in rodents. However, the knowledge that OT and AVP appear to play a critical role in this process provides investigators with a useful starting point for understanding the molecular basis of the pair bond. This research is further facilitated by the existence of vole species that are genetically very similar to prairie voles yet differ dramatically in their social structure. For example, montane voles, from the Rocky Mountains region of the United States, look very similar to prairie voles but are rather asocial and do not form pair bonds between mates. In fact, males of this species are polygynous. Therefore, the prairie and montane voles provide a comparative approach for understanding the biology of the pair bond.
Since OT and AVP are involved in pair bond formation in the prairie vole and montane voles fail to produce a pair bond, one might hypothesize that montane voles show lower levels of these peptides in the brain. This appears not to be the case, as peptide distribution in the brain appears to be similar between the monogamous and polygamous species (Wang et al., 1996). It is possible that the nonmonogamous species simply do not release these peptides in response to social stimulation and mating, explaining the lack of pair bond formation, and there is some evidence to support this hypothesis (Bamshad et al., 1993; Wang et al., 1994). However, there is another intriguing possibility. Using a technique called receptor autoradiography, it is possible to determine the distribution and density of the receptors for OT and AVP in the brain. Receptors are the molecules on the target cells that transduce the signal of the peptide. Insel found that there are striking species differences in the distribution of OT and V1aR in the brains of the monogamous versus nonmonogamous vole species (Insel and Shapiro, 1992; Insel et al., 1994). Thus, a release of OT or AVP in the brain, which presumably occurs during mating, would activate different neural circuits in a monogamous species compared to a nonmonogamous species.
NEURAL CIRCUITS OF PAIR BOND FORMATION
What are the relevant neural circuits involved in pair bond formation? Comparison of the locations of high-receptor densities in the monogamous prairie and the montane vole provides interesting clues. For example, Insel found that the nucleus accumbens and the prelimbic cortex of the prairie vole are rich in oxytocin receptors, whereas these regions have few receptors in the montane vole. Likewise, the prairie vole ventral striato-pallidal region is rich in vasopressin receptors, while the montane vole ventral striato-pallidal region is not (Young et al., 2001). These regions are excellent candidates for facilitating pair bond formation because they are rich in dopamine, a neurotransmitter associated with reward and addiction. Amphetamines and cocaine are thought to produce their euphoric effects by modulating the dopamine system in these regions (McBride et al., 1999). In fact, injection of cocaine into these regions of the rat brain results in the development of a conditioned place preference (Gong et al., 1996). That is, the rat prefers to be in the environment where it received an injection of the drug.
Thus one could hypothesize that activation of the oxytocin and vasopressin receptors in these reward centers might result in the development of a conditioned partner preference in prairie voles. Since montane voles have few receptors in these regions, mating and/or the release of peptides in the brain would not result in the formation of a partner preference but may instead elicit other types of behaviors.
Interestingly, comparisons of vasopressin receptors in other species of mammals reveal that monogamous behavior is associated with elevated vasopressin receptors in the ventral striato-pallidum. For example, the monogamous California mouse (Peromyscous californicus) has a high density of vasopressin receptors in this region, whereas the closely related but nonmonogamous white-footed mouse (P. leucopus) does not (Bester-Meredith et al., 1999). Likewise, this region of the monogamous marmoset, a primate, has a high density of vasopressin receptors, whereas the nonmonogamous rhesus monkey does not (Young, 1999).
There is direct experimental evidence in voles that these reward circuits are involved in pair bonding. First, infusion of an oxytocin receptor blocker into the nucleus accumbens and prelimbic cortex prevents formation of pair bonds in females who have mated (Young et al., 2001). This same drug had no effect when injected into an adjacent area. In another study, Pitkow used a gene therapy approach to increase vasopressin receptors in the ventral striato-pallidum of male prairie voles. In this study a viral vector was used to deliver the prairie vole vasopressin receptor gene into the ventral striato-pallidum of male prairie voles. This modified virus infected the cells around the injection site and inserted the receptor gene into the neurons in the region. This gene was then expressed, leading to a significant increase in vasopressin receptor in the ventral striato-pallidum. Control animals were injected in the same region with a different virus carrying a control gene or with the same virus but in an adjacent brain area. Those animals with artificially elevated vasopressin receptors in the ventral pallidum displayed increased levels of affiliative behavior toward a novel juvenile (i.e., increased investigation and huddling) and readily formed strong pair bonds even in the absence of mating (Pitkow et al., 2001). Both studies examining the OT and AVP receptors strongly suggested that the activation of these receptors in the reward circuitry is important for development of the pair bond.
THE GENETICS OF PAIR BONDING
From the outside, prairie (monogamous) and montane (polygamous) voles look quite similar, and are, in fact, indistinguishable to the untrained eye. Their shared physical characteristics attest to their close genetic relationship, yet their brain neurochemistry and social structure differ dramatically. How can this be explained genetically? The distribution of oxytocin and vasopressin receptors in the brain, not the binding characteristics of the receptors, is different between these species. This suggests that something must be different in the part of the receptor genes that determines in which brain region the genes are expressed. Genes are composed of a coding sequence, which defines the structure of the final protein, and a regulatory sequence, which determines when and in what cells the gene is going to be expressed. Therefore, we hypothesized that there must be species differences in the regulatory regions of these genes that result in the species-specific pattern of receptor.
The vasopressin receptor gene has been characterized in both montane and prairie voles (Young et al., 1999). Not surprisingly, the coding sequences of the vasopressin receptor are virtually identical between these species. However there is a 420-bp stretch of sequence in the 5 prime regulatory region of the prairie vole gene that is absent in the montane vole gene. This sequence is also found in another monogamous vole species, the pine vole, but not in the nonmonogamous meadow vole. This prairie vole sequence is rich in highly repetitive sequences, or microsatellite DNA, which are known to be genetically unstable. Perhaps this instability in the regulatory region of the vasopressin receptor gene, as a result of the microsatellite DNA, results in the rapid evolution of receptor expression patterns, which in turn results in the evolution of social behaviors.
For example, there is an extraordinary amount of individual variation in both microsatellite length and brain vasopressin receptor binding patterns in a single population of prairie voles (Hammock and Young, 2002). Furthermore, there is a significant correlation between microsatellite length and receptor densities in specific brain regions. Thus, within the population there is variation in gene sequence that corresponds with variation in receptor binding. If these individual differences in receptor densities in the brain translate into variations in behavior, natural selection could quickly change social behavior in the population through changes in the frequency of vasopressin receptor alleles.
IS THE VASOPRESSIN RECEPTOR THE “MONOGAMY” GENE?
The data presented above suggest that a single gene can have a profound influence on the expression of complex behaviors defining reproductive strategies. In fact, the data suggest that simple changes in the locations in the brain that express the receptor for vasopressin can have a major impact on behavior. This was demonstrated conclusively by inserting the prairie vole vasopressin receptor gene along with regulatory elements into the mouse genome. Mice transgenic for the prairie vole vasopressin receptor gene displayed a pattern of V1aR binding that was remarkably similar to that of prairie voles but very different from nontransgenic mice (Young et al., 1999). When injected with vasopressin, the mice with a prairie vole pattern of vasopressin receptor expression in the brain responded similarly to prairie voles by exhibiting increased levels of affiliative behavior. Vasopressin injections did not alter social behavior in the nontransgenic mouse. This proves that simple changes in vasopressin receptor expression patterns can alter social behavior. This is certainly not the first study to demonstrate that mutations in a single gene can alter behavior. For example, one study in the nematode C. elegans identified a single gene that was responsible for strain differences in social interaction during feeding. When the gene, a homologue of the mammalian neuropeptide Y receptor gene, was transferred from one strain to the other, the recipient strain exhibited the behavior of the donor (de Bono and Bargmann, 1998). In addition, a large number of single-gene mutant mice have been created that have unusual behaviors, ranging from lack of parental care, increased or absent aggression, lack of social recognition, and deficits in mating behavior (Pfaff, 2001).
How can a single gene have such a large impact on a single behavior? In reality there are a multitude of genes involved in pair bonding in monogamous species. For example, pheromones must be detected, social stimuli processed, and a social memory formed. Many genes are involved in the development of the brain circuitry for the senses, cognition, learning, and memory. The V1aR itself cannot function in a vacuum but is coupled to a G-protein that activates the intracellular signaling pathway. Activation of the intracellular signaling pathways then likely modulates the expression of a number of other genes. So the V1aR is simply one protein in a complex of genes and gene products that produce the biochemical and neural circuit underlying social attachment. Every species has a reward circuitry, which evolved to promote certain behaviors beneficial for the reproductive success of the species. Perhaps by placing the V1aR in that pathway, social cues are processed by the addiction circuitry to yield an enduring social attachment. Thus, there is no single monogamy gene, but the V1aR gene, acting in concert with many other factors, profoundly influences social behavior.
In addition to pair bonding, the V1aR appears to alter other aspects of social behavior. For example, infusion of AVP into the prairie vole brain increases general social interaction. It is conceivable that AVP and OT may modulate many types of social bonds, not just parent-infant or pair bonds. Perhaps these neuropeptides play some role in the establishment or maintenance of social bonds or even social hierarchies in nonmonogamous primate species. To date, there is no experimental evidence to support this, but it is an area for future exploration.
IMPLICATIONS FOR HUMANS
Voles have provided a wealth of knowledge on the molecular, cellular, and systems neurobiology underlying pair bond formation. Undoubtedly, these rodents will continue to provide a detailed understanding of how social attachments can form and lead to a better understanding of the formation of social relationships in our own species. However, to the disappointment of many, it is unlikely that this research will result in drugs or gene therapies that ensure fidelity in relationships. That of course, is not the goal of this research. However, it may help us understand the neurobiological underpinnings of love and pair bonding in humans and enhance our understanding of human behavior and the factors associated with intimate human relationships. It may also provide hypotheses regarding the evolution and diversity in social relationships in our species. It must be noted that there is no direct evidence that the hormones oxytocin or vasopressin are actually involved in bonding in humans. Such data would be extremely difficult to obtain. These neuropeptides do not efficiently cross the blood-brain barrier, making pharmacological experiments in people difficult. However, there is evidence that oxytocin and vasopressin are released during sexual intercourse. One study demonstrated that plasma oxytocin levels increased at the time of orgasm in males (Carmichael et al., 1987), and another study reported that plasma vasopressin levels were elevated during sexual arousal prior to orgasm (Murphy et al., 1987). However, the relationship between plasma hormone levels and brain levels is unclear, so care must be taken in interpreting these results.
Molecular studies in voles suggest that mutations in the 5 prime regulatory region of the vasopressin receptor could be responsible for the species differences in receptor expression patterns in the brain. Interestingly, the human vasopressin receptor gene also has highly repetitive sequences in the same region of the gene (Thibonnier et al., 2000). As mentioned above, these sequences tend to be highly unstable due to their repetitive nature. The repetitive sequences in the human vasopressin receptor are highly variable among individuals, although not to the degree found between prairie and montane voles. Thus, if vasopressin receptors are important in social relationships in humans and these variations in sequence are associated with variations in expression in the brain, one would predict that some aspects of social attachment may, in fact, be affected by these genetic elements. A recent study found a nominally significant transmission disequilibrium between one allele of the human V1aR gene and autism (Kim et al., 2002). It would be interesting to perform genetic analyses to determine whether social-behavioral traits in the normal range correlate with these variable alleles of the vasopressin receptor. Certainly, if the individual variability in human V1aR sequence translates into individual variability in the distribution of receptor expression as it does in voles, this single gene could be responsible for individual differences in social behavior, which could be subject to natural selection in different ecological and cultural conditions.
Studies in voles suggest that, while sex may not be essential to formation of the pair bond, it does facilitate it. This observation likely has implications for human relationships. Our species is unusual in the animal kingdom in that sexual activity is not always associated with reproduction. In most mammals, a female become sexually receptive only during the period of the ovarian cycle when she can become pregnant, usually just before or after ovulation. In these species, sex has a single purpose—procreation. In human beings, sexual activity does not vary drastically with the ovarian cycle. It is possible that this has important social implications unrelated to fertility, namely strengthening the bond between mates. Perhaps frequent sexual activity stimulates the neural circuits responsible for maintaining the pair bond, preserving the strength of the bond over time.
Studies of voles have produced an exciting hypothesis that suggests pair bond formation is regulated by the same brain regions involved in the actions of drugs of abuse. These so-called reward circuits are regions of the brain that regulate feelings of pleasure and reward. These regions are activated by a neurotransmitter called dopamine, which is increased in the brain after taking cocaine and amphetamines. Those experiencing love often report feelings of euphoria when intimate with their partners, and these feelings are often reported as being similar to being “high.” There is some scientific evidence that these reward circuits may in fact be involved in the psychobiology of love. One study examined brain activation in people while viewing photographs of someone to whom the subject reported being deeply in love. Brain activity was also determined while these same subjects viewed photographs of other familiar individuals. The authors reported that viewing photographs of their lovers elicited brain activation that was remarkably similar to that seen in other studies after drug consumption (Bartels and Zeki, 2000). This suggests that perhaps similar neural circuits are used to facilitate pair bonding in voles and humans. Perhaps the saying “love is an addiction” has biological support.
The biological basis of the pair bond in humans may change with time. In the early years of a relationship, love is experienced as an incredibly intense sensation that often drives the behavior of the individual. People experience a euphoria that may be similar to that experienced by drugs of addiction, and this experience undoubtedly has a specific neurochemistry underlying it. The individuals in these relationships are consumed by thoughts of being with their partner, often at the expense of other relationships. However, often in later years of a marriage, the nature of this bond changes and becomes less visceral and more a relationship of codependence. Perhaps for our primitive ancestors, the transition between these two types of love, which would occur after the offspring of the relationship are less dependent on the mother, would mark the dissolution of the relationship. However, for modern humans it is desirable to remain together in marriage as long as possible. Perhaps through understanding the neurobiology of the pair bond and how it is regulated, we may be able to discover strategies to maintain and reinvigorate the pair bond in couples, ultimately leading to strengthening of the nuclear family.
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Larry J. Young.
National Academies Press (US), Washington (DC)
Young LJ. The Neural Basis of Pair Bonding in a Monogamous Species: A Model for Understanding the Biological Basis of Human Behavior. In: National Research Council (US) Panel for the Workshop on the Biodemography of Fertility and Family Behavior; Wachter KW, Bulatao RA, editors. Offspring: Human Fertility Behavior in Biodemographic Perspective. Washington (DC): National Academies Press (US); 2003. 4.