Review published: 11 October 2017 doi: 10.3389/fendo.2017.00265
Vasopressinergic Neurocircuitry Regulating Social Attachment in a Monogamous Species Maria C. Tickerhoof and Adam S. Smith* Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, United States
Edited by: Aras Petrulis, Georgia State University, United States Reviewed by: Steven Phelps, University of Texas at Austin, United States Elizabeth Hammock, Florida State University, United States *Correspondence: Adam S. Smith
[email protected] Specialty section: This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Endocrinology Received: 31 May 2017 Accepted: 21 September 2017 Published: 11 October 2017 Citation: Tickerhoof MC and Smith AS (2017) Vasopressinergic Neurocircuitry Regulating Social Attachment in a Monogamous Species. Front. Endocrinol. 8:265. doi: 10.3389/fendo.2017.00265
The prairie vole (Microtus ochrogaster) is a socially monogamous rodent species that forms a lasting connection between mates, known as a pair bond. The pair bond is primarily characterized by three distinct behaviors: partner preference, selective aggression, and biparental care of the young. The presence of these behaviors in the prairie vole and their absence in closely related non-monogamous species makes the prairie vole an important model of social relationships and facilitates the study of the neurobiological mechanisms of social affiliation and attachment. The nona-peptide arginine-vasopressin (AVP) is an important neuromodulator of social behavior and has been implicated in the regulation of the pair bond-related behaviors of the prairie vole, through activation of the AVP receptor subtype 1a (AVPR1a). Modulation of AVPR1a activity in different regions of the prairie vole brain impacts pair bond behavior, suggesting a role of AVP in neurocircuitry responsible for the regulation of social attachment. This review will discuss findings that have suggested the role of AVP in regulation of the pair bond-related behaviors of the prairie vole and the specific brain regions through which AVP acts to impact these unique behaviors. Keywords: vasopressin, prairie vole, pair bond, partner preference, aggression, parental care
INTRODUCTION The prairie vole (Microtus ochrogaster) is a small, mouse-sized rodent native to the Midwest region of the United States. This species performs behaviors related to social monogamy, a trait seen in fewer than 5% of mammalian species (1). This social exclusivity is beneficial in areas where populations of animals are spread out such as in the vast Midwest grasslands, as it may be difficult to encounter potential new mates. In fact, opposite-sex pairs of prairie voles are caught together more frequently in areas where the population is less dense (2). The pair bond is a unique, strong affiliative connection between mates of a socially monogamous species. This bond is characterized primarily by behavioral and physiological hallmarks, including preference for a social partner over unfamiliar conspecifics, selective aggression toward intruding conspecifics, nesting together during gestation, and displaying biparental care of offspring, distress, and social-seeking behavior during periods of separation or social loss, and stress alleviation among reunion and consoling behaviors (1, 3). The prairie vole exhibits these distinctive characteristics (2), but closely related non-monogamous species such as the meadow vole (Microtus pennsylvanicus) and the montane vole (M. montanus) do not (4, 5). Thus, manipulation and description of these behaviors in the prairie vole, as well as cross-species comparison with the meadow vole or montane vole, allows for the study and understanding of the neural mechanisms behind pair bond-related behaviors. For these reasons, the prairie vole has
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become an attractive model for studying the neurobiological basis of behaviors related to social affiliation and attachment that are not easily modeled in other laboratory species. Social behavior is regulated by a number of neuromodulators, such as the neuropeptide arginine-vasopressin (AVP). AVP is a key regulator of a number of social behaviors, including social recognition (6, 7), aggression (8, 9), and maternal care (10). Furthermore, it has been determined that the AVP system in the vole brain functions as a neuromodulator of a number of social behaviors critical for the establishment and maintenance of the pair bond between breeding pairs, including partner preference, selective aggression, and paternal care.1 AVP primarily acts through three G protein-coupled receptors: the AVP receptor subtype 1a (AVPR1a), subtype 1b (AVPR1b), and AVP receptor type 2 (AVPR2). The distribution of AVPR1a in the prairie vole brain has been well established (11–17). However, the distribution of AVPR1b and AVPR2 in the prairie vole brain has not been characterized, and thus the regulation of social behavior by AVP is primarily attributed to AVPR1a action. Comparative studies of AVPR1a distribution in closely related Microtus species have revealed an expression pattern in prairie voles that is similar to the monogamous pine vole (M. pinetorum) (11) and distinct from non-monogamous species such as the montane vole and the meadow vole (12–14). As these distribution patterns correlate with unique patterns of social organization and behavior, it has been theorized that expression of AVPR1a has some role in the neurobiological basis of social affiliation and attachment. The first study to investigate the role of central AVP administration in both prairie voles and montane voles found that AVP promoted pair bond-related behavior, namely selective aggression, in the prairie vole, but not in the montane vole (12). In addition, this study found that AVPR1a binding distribution correlated with avpr1a mRNA expression levels. Transgenic mice expressing the prairie vole avpr1a gene not only display more affiliative behaviors but also have a “prairie vole-like” distribution pattern of AVPR1a that is distinct from that of wildtype mice (18). These findings suggest a relationship between the avpr1a gene and AVPR1a protein distribution patterns, thus prompting investigation into the genetic basis of the role of AVPR1a in social behavior. While both monogamous and non-monogamous vole species share 99% sequence homology of the avpr1a gene, prairie vole avpr1a is preceded by an extended 5′ flanking microsatellite region that is not present in non-monogamous species (18). It was originally suggested that this microsatellite region contains cis-regulatory elements, controlling avpr1a gene expression through binding of transcription factors or secondary DNA structure formation, and promotes species differences in AVPR1a expression and social behavior. However, there are incongruences in the reported relationship between microsatellite length and neuronal and behavioral phenotypes (19). For example, variation in microsatellite length has contrasting correlates with variation of AVPR1a binding in several brain regions and bond-related
behaviors of the prairie vole (19–25). Furthermore, insertion of either prairie or meadow vole microsatellite structure ahead of the mouse avpr1a coding region leads to measurable differences in AVPR1a density in mice brains, though these results do not fully explain the distribution variability observed among vole species (26). Recent work has expanded beyond microsatellite length into other sources of genetic variation. Single-nucleotide polymorphisms within regulatory sequences have been demonstrated to be good predictors of individual differences in cortical AVPR1a expression, sexual fidelity, and spatial use (23, 27, 28), though this is a weaker relationship in wild-caught voles compared with laboratory-reared animals potentially due to increased variation in the developmental environment in wild populations. Further research is needed to explain how cis-regulatory variants and other regulatory elements affect individual and species level AVPR1a distribution patterns and social behavior. Nevertheless, the relationship between AVPR1a distribution patterns and pair bond-related behaviors remains, and thus, it is appropriate to investigate the role of AVPR1a in the modulation of such behaviors unique to monogamous species such as the prairie vole. This review will discuss the role of general and site-specific AVPR1a activity in regulation of three key pair bond-related behaviors of the prairie vole: partner preference, selective aggression, and paternal care of the young.
PARTNER PREFERENCE One of the defining characteristics of pair bond behavior in prairie voles is a preference for contact with the mate over an opposite-sex stranger, also known as partner preference (2, 29). In the lab, partner preference is measured using a three-chamber social interaction test in which the subject may choose to spend time by itself in a neutral chamber or interact with either the partner or a novel opposite-sex conspecific. If the subject shows a selective preference for contact with the partner rather than with the stranger during a 3-h assessment period, it is determined that a partner preference has been established (30). Male prairie voles will establish a partner preference after 24 h of cohabitation with a new mate (29, 31), and females exhibit this behavior as well (30, 32). This partner preference is enduring and lasts for at least 2 weeks of separation from the mate (33, 34). This preference is not infallible, however, and is diminished after 4 weeks of separation from the mate (33) and may be interrupted if the breeding pair is reproductively unsuccessful (35). Recognition and affiliation are vital components of partner preference formation, and AVP has been implicated as necessary for these behaviors in mice (6, 7). Winslow and colleagues first demonstrated that male prairie voles will form a partner preference when receiving a central infusion of AVP during a short, non-mated cohabitation but not if receiving a central administration of a selective AVPR1a antagonist (AVPA) immediately prior to a long, mated cohabitation with a female (29). Another study later corroborated these results and revealed that AVP is involved in partner preference formation in female prairie voles as well (32). It has also been suggested that AVP is not only important in the formation of partner preference but also its expression (36). The display of a partner preference is inhibited in male prairie
1 While AVP is an important neuromodulator of stress physiology [e.g., functioning as a secondary hypothalamic-pituitary-adrenal (HPA) axis secretagogue], it has yield to be determined the role that AVP serves in separation distress, consoling behavior, or social buffering.
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voles that received centrally administered AVPA at the start of a 24-h mated cohabitation or immediately prior to behavioral testing. However, this was not the case for control subjects or those that received AVPA following the 24-h mated cohabitation period in which partner preference was assessed 3 d later, indicating that each administration of AVPA prior to cohabitation and the partner preference test was uniquely responsible for suppression of partner preference behavior. While these studies have suggested both the necessity and sufficiency of AVP in modulating partner preference, they do not suggest which regions of the brain may be involved in AVP-mediated partner preference neurocircuitry. There are a number of regions within the prairie vole brain with high levels of expression of AVPR1a that have been quantified (11–16). Of these regions, AVP signaling in the lateral septum (LS) has been thought to modulate social behavior and organization, and shows different AVPR1a binding levels between monogamous and non-monogamous vole species (11). In addition, the ventral pallidum (VP) shows differential AVPR1a binding between monogamous and non-monogamous vole species, and AVPR1a in this region promotes partner preference (37, 38). Thus, the LS and VP have become regions of interest in
the study of the role of AVP in the modulation of partner preference behavior (Figure 1).
Lateral Septum
Activity of AVP in the LS is known to be vital for social recognition in rats and mice (43–46). Gene transfer of prairie vole AVPR1a in the septum of the rat brain improves recognition of familiar juveniles and promotes more active social interaction behavior (47). Similarly, higher expression of AVPR1a in the LS of male prairie voles is correlated with higher levels of investigatory behavior in response to a novel female (48). In addition, while AVPR1a expression is lower in the LS of male prairie voles compared with male meadow voles, vasopressinergic fiber density in the LS of male prairie voles is significantly higher than that of male meadow voles (39). This suggests that distinct and, potentially, more robust AVP signaling from presynaptic neurons into the LS, and despite lower postsynaptic receptor expression may serve as a mechanism of partner preference behavior. The LS receives vasopressinergic signaling from the bed nucleus of the stria terminalis (BNST) (39, 49), and AVP mRNA expression in the BNST is increased in male prairie voles
FIGURE 1 | Role of AVP in modulation of prairie vole partner preference. (A) A prairie vole breeding pair in direct side-by-side contact. Duration of this kind of contact is a typical marker for affiliation in a partner preference test. Photo credit: Charles Badland. (B) Male prairie voles have significantly greater AVP-ir fiber density in the LS compared with male meadow voles. *p
