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Neurobiology

Why voles stick together

The tendency for animals to form social bonds after sexual activity varies greatly from species to species. Work with voles illuminates a molecular pathway in the brain that influences such differences.

A report on page 754 of this issue continues a fascinating line of inquiry into the basic brain mechanisms that contribute to social behaviour. There, Lim and colleagues1 show that increasing the expression of a single protein in a particular brain region of male meadow voles makes them more socially cohesive — rather like their close relation the prairie vole.

There is much that researchers would like to know about the social behaviour of animals (including ourselves, as discussed on page 705 of this issue2). What, for instance, are the brain mechanisms that mediate the formation of bonds between individuals? How do these mechanisms change within and between populations and species over evolutionary time? The humble vole has provided a wonderful opportunity to pursue these issues.

There are many species of vole, and they exhibit markedly different patterns of social attachment. For instance, male prairie voles in captivity are likely to form preferential associations with one female, defined by close physical contact, choosing to spend more time with her when given equal access to several females, and keeping other males away from her3. These preferential associations form most readily after sexual activity. Captive male prairie voles also tend to interact with and care for their young. (Both traits vary in degree among wild populations4.) Captive males of the closely related meadow vole, by contrast, exhibit weaker ‘pair-bonding’ with females (again, this is variable in the wild5), and give little attention to young.

Studies of the social organization, behavioural ecology and hormones of voles6,7 have linked such differences in ‘affiliative behaviour’ to variation in the expression patterns of the receptors for two related signalling molecules, oxytocin and arginine vasopressin (vasopressin for short)3. These molecules are released in the brain after sex, and are also involved in other reproduction-related behaviours and in unrelated functions such as water retention and stress.

Notably, the vasopressin 1a receptor (V1aR) is expressed in greater numbers in the ventral pallidum region of the forebrain in male prairie voles than in male meadow voles8. Although the exact relationships of the ventral pallidum to other brain regions and to behaviour are still unclear, the neighbouring nucleus accumbens is part of the brain's ‘reward system’, which signals that a particular behaviour is worth doing again. In prairie voles, manipulation either of signals mediated by the neurotransmitter dopamine in the nucleus accumbens9, or of vasopressin signalling within (at least in part) the ventral pallidum10,11, can substitute for or block the effects of sexual activity on preferential association — showing the importance of both regions in forming attachments. The expression of dopamine receptors shows little natural variation between species, however, hinting that the key to the differing behaviour of prairie and meadow voles might lie in the variation in vasopressin receptors.

Lim et al.1 now take us beyond correlations in the study of these receptors, by experimentally manipulating the expression of V1aR. The authors wanted to find out whether adult male meadow voles that have prairie-vole-like expression of vasopressin receptors also show prairie-vole-like social behaviour. They discovered that, as a group, male meadow voles that have more V1aRs in the ventral pallidum spend more time both with their mates and near juveniles than do controls. They do not, however, engage in paternal care (consistent with previous suggestions that these traits can be dissociated in prairie voles3). Lim et al. also show that, as in prairie voles, preferential association in the experimentally manipulated meadow voles is prevented by prior blockage of dopamine receptors. A similar study of adult male prairie voles with above-average V1aR levels12 found a potentiation of preferential association with females, and increased time spent in proximity to unfamiliar juveniles.

So Lim et al. argue that, in male prairie voles, the sexually induced release of vasopressin triggers its receptors in the ventral pallidum, which somehow enable the intrinsically rewarding sensations experienced after copulation to become reliably associated with the individual features of a particular female, such as her odour. (It is unclear whether vasopressin signalling simply causes familiar animals to spend more time close to one another, allowing the association with the rewarding effects of sex to occur more reliably, or whether it directly causes changes in the inputs to, or function of, the brain reward systems.) Male meadow voles, by contrast, form weaker social bonds because of a lower level of signalling in the relevant brain region. But because the subsequent molecular and neuronal circuitry is highly similar in these species, changing the expression of this one receptor can profoundly alter the circuit's function — implying that evolutionary selection can act on this single molecule to produce major changes in social behaviour.

If the V1aRs are indeed the adjustable nozzle atop a social-glue dispenser in the mammalian brain, these results could have wider significance for understanding social behaviour — and some of its dysfunctions, as seen, for instance, in autism — in humans and animals. Caution is warranted on three fronts, however. First, several studies4,13,14 indicate that changes in V1aR expression alone might not fully account for naturally observed differences in pair-bond formation in voles. Individuals from populations and species with similar V1aR levels but different behaviour will be valuable in the search for other molecular and cellular components of the social glue.

Second, vasopressin signalling mediates many other reproductively related and unrelated functions. So the experimental change in the meadow-vole ventral pallidum might detrimentally affect other brain functions in manipulated individuals — unless they have additional, compensatory genetic modifications, as prairie voles evidently do. An understanding of the wider evolutionary significance of this manipulation must await a fuller documentation of its physiological consequences.

Finally, it has been suggested1,3,15 that variation in the expression of the V1aR gene, and hence evolutionary changes in vole social behaviour, can be attributed solely to variation in the gene's regulatory DNA sequences. But perhaps we should not be so quick to leap to this conclusion. For instance, mice engineered to include a prairie-vole V1aR gene (plus control sequences) fail to display prairie-vole-like levels of V1aR expression in the ventral pallidum16. Similarly, control sequences from the prairie-vole V1aR gene do not yield higher expression levels in rat brain cell lines than do such sequences from montane voles (which are similar to meadow voles)15. Gene variation in signalling or regulatory molecules that interact with the V1aR control region are also likely to be important.

Understanding the role of genetic variation in the evolution of any trait requires knowledge of the major genes involved, their distribution among individuals, the distribution of genetically defined individuals in different environments, and the dependence of the trait on the environment for each individual and at each stage of development. This is a tall order, especially for behavioural characteristics. But the research on voles gives us hope that classical comparative studies of natural populations, judiciously coupled with modern molecular and cellular neurobiology, will continue to provide insights into the relationships between genes, brain-cell collectives, ecology and chance in social behaviour.

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Balaban, E. Why voles stick together. Nature 429, 711–712 (2004). https://doi.org/10.1038/429711a

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