Cellular mechanisms of social attachment

Pharmacological studies in prairie voles have suggested that the neuropeptides oxytocin and vasopressin play important roles in behaviors associated with monogamy, including affiliation, paternal care, and pair bonding. Our laboratory has investigated the cellular and neuroendocrine mechanisms by which these peptides influence affiliative behavior and social attachment in prairie voles. Monogamous prairie voles have a higher density of oxytocin receptors in the nucleus accumbens than do nonmonogamous vole species; blockade of these receptors by site-specific injection of antagonist in the female prairie vole prevents partner preference formation. Prairie voles also have a higher density of vasopressin receptors in the ventral pallidal area, which is the major output of the nucleus accumbens, than montane voles. Both the nucleus accumbens and ventral pallidum are key relay nuclei in the brain circuits implicated in reward, such as the mesolimbic dopamine and opioid systems. Therefore, we hypothesize that oxytocin and vasopressin may be facilitating affiliation and social attachment in monogamous species by modulating these reward pathways.     

以田鼠作为动物模型来研究社会行为的进化:基因、脑与行为

田鼠属的一些近缘种间具有独特的社会行为多态性。例如Microtusochrogaster和M .pinetorum为一夫一妻制 ,而M .montanus和M .pennsylvanicus则为独居和一夫多妻制。无论是在野外还是人工饲养的条件下 ,单配制的田鼠其雌、雄成年个体一经交配即在两者之间形成长期的配偶关系并且双亲共同哺育后代。已证明神经多肽加压素 (Vasopressin)参与了田鼠单配制行为的神经调控。本篇综述了过去以及近期关于加压素调控田鼠配偶关系形成的研究结果和进展。首先 ,阐述了加压素V1a受体 (V1aR)在脑分布的种间差异 ,并以此来鉴别特定脑区在配偶关系形成中的功能 ;其次 ,探讨了运用V1aR拮抗物的药理学方法来决定究竟哪些脑区参与配偶关系的形成 ,还描述了田鼠种间V1aR基因结构和功能的不同 ,以及这些不同对V1aR在大脑的分布和行为调控潜在的作用机制 ;最后 ,讨论了最新的研究结果 ,即对一夫多妻制田鼠进行脑V1aR基因的改造 ,从而使之表现出一夫一妻制田鼠的行为。总之 ,了解复杂的社会性行为的遗传和神经机制可以加深我们对种间和种内行为分歧进化的理解     

Trichostatin A (TSA) facilitates formation of partner preference in male prairie voles (Microtus ochrogaster)

In the socially monogamous prairie voles (Microtus ochrogaster), the development of a social bonding is indicated by the formation of partner preference, which involves a variety of environmental and neurochemical factors and brain structures. In a most recent study in female prairie voles, we found that treatment with the histone deacetylase inhibitor trichostatin A (TSA) facilitates the formation of partner preference through up-regulation of oxytocin receptor (OTR) and vasopressin V1a receptor (V1aR) genes expression in the nucleus accumbens (NAcc). In the present study, we tested the hypothesis that TSA treatment also facilitates partner preference formation and alters OTR and V1aR genes expression in the NAcc in male prairie voles. We thus observed that central injection of TSA dose-dependently promoted the formation of partner preference in the absence of mating in male prairie voles. Interestingly, TSA treatment up-regulated OTR, but not V1aR, gene expression in the NAcc similarly as they were affected by mating — an essential process for naturally occurring partner preference. These data, together with others, not only indicate the involvement of epigenetic events but also the potential role of NAcc oxytocin in the regulation of partner preference in both male and female prairie voles.     

Polymorphism at the avpr1a locus in male prairie voles correlated with genetic but not social monogamy in field populations

Integrative studies of genetics, neurobiology and behaviour indicate that polymorphism in specific genes contributes to variation observed in some complex social behaviours. The neuropeptide arginine vasopressin plays an important role in the regulation of a variety of social behaviours, including social attachment of males to females, through its action on the vasopressin 1a receptor (V1aR). In socially monogamous prairie voles ( Microtus ochrogaster ), polymorphism in the length of microsatellite DNA within the regulatory region of the gene ( avpr1a ) encoding the V1aR predicts differences among males in neural expression of V1aRs and partner preference under laboratory conditions. However, understanding the extent to which V1aR mediates variation in prairie vole social and reproductive behaviour observed in nature requires investigating the consequences of avpr1a polymorphism and environmental influences under ecologically relevant conditions. We examined the relationship between avpr1a length polymorphism and monogamy among male prairie voles living in 0.1 ha enclosures during a time similar to their natural lifespan. We found no evidence that avpr1a genotype of males predicts variation in social monogamy measured in the field but some indices of social monogamy were affected by population density. Parentage data indicated that a male's avpr1a genotype significantly influenced the number of females with which he sired offspring and the total number of offspring sired. Total brain concentrations of V1aR mRNA were not associated with either male behaviour or avpr1a genotype. These data show that melding ecological field studies with neurogenetics can substantially augment our understanding of the effects of genes and environment on social behaviours.     

avpr1a length polymorphism is not associated with either social or genetic monogamy in free-living prairie voles

Recent discoveries of single-gene influences on social behaviour have generated a great deal of interest in the proximate mechanisms underlying the expression of complex behaviours. Length polymorphism in a microsatellite in the regulatory region of the gene encoding the vasopressin 1a receptor (avpr1a) has been associated with both inter- and intra-specific variation in socially monogamous behaviour in voles (genus Microtus) under laboratory conditions. Here, we evaluate the relationship between avpr1a length polymorphism and social associations, genetic monogamy, and reproductive success in free-living prairie vole (M. ochrogaster) populations. We found no evidence of a relationship between avpr1a microsatellite length and any of our correlates of either social or genetic monogamy in the field. Our results, especially when taken in conjunction with those of recent experimental studies in semi-natural enclosures, suggest that avpr1a polymorphism is unlikely to have been a major influence in the evolution or maintenance of social monogamy in prairie voles under natural conditions.     

Association of vasopressin 1a receptor levels with a regulatory microsatellite and behavior

Vasopressin regulates complex behaviors such as anxiety, parenting, social engagement and attachment and aggression in a species-specific manner. The capacity of vasopressin to modulate these behaviors is thought to depend on the species-specific distribution patterns of vasopressin 1a receptors (V1aRs) in the brain. There is considerable individual variation in the pattern of V1aR binding in the brains of the prairie vole species, Microtus ochrogaster. We hypothesize that this individual variability in V1aR expression levels is associated with individual variation in a polymorphic microsatellite in the 5' regulatory region of the prairie vole v1ar gene. Additionally, we hypothesize that individual variation in V1aR expression contributes to individual variation in vasopressin-dependent behaviors. To test these hypotheses, we first screened 20 adult male prairie voles for behavioral variation using tests that measure anxiety-related and social behaviors. We then assessed the brains of those animals for V1aR variability with receptor autoradiography and used polymerase chain reaction to genotype the same animals for the length of their 5' microsatellite polymorphism in the v1ar gene. In this report, we describe the results of this discovery-based experimental approach to identify potential gene, brain and behavior interrelationships. The analysis reveals that V1aR levels, in some but not all brain regions, are associated with microsatellite length and that V1aR levels in those and other brain regions correlate with anxiety-related and social behaviors. These results generate novel hypotheses regarding neural control of anxiety-related and social behaviors and yield insight into potential mechanisms by which non-coding gene polymorphisms may influence behavioral traits.     

田鼠属动物婚配制度的研究范式

从社会组织的生态格局、熟悉性、社会等级和交配近况等择偶行为的影响因子,性二型和雄性射精能力等个体特征,配对关系的神经内分泌机制几方面综述了田鼠动物婚配制度的研究进展,同时从生态学、比较心理学、生理学、神经生物学等方面探讨择偶行类节式的特点。生态学方法,用鼠动物具有完整的婚配制度多样性格局,是婚配制度比较研究的哺乳动物类群。运用比较心理学方法,通过择偶行为实验可直接比较单配制与较研究的理想哺乳动物类     

Gene Targeting Approaches to Neuroendocrinology: Oxytocin, Maternal Behavior, and Affiliation

Transgenic technology affords exciting new opportunities in the field of behavioral neuroendocrinology. We have extended our research into the behavioral function of oxytocin in maternal and social behavior using two transgenic approaches: (i) targeted deletion of the oxytocin gene in mice and (ii) augmented oxytocin receptor expression in the brain. Mice genetically deficient in oxytocin can mate, give birth, and display normal maternal behavior; however, milk ejection and certain aspects of social behavior are affected. Comparative studies of oxytocin receptors have led to the observation that species differences in social organization are associated with differences in receptor distribution. Specifically, monogamous prairie voles and nonmonogamous, asocial montane voles exhibit different patterns of OT receptor expression in the brain. Transgenic mice have been created with a reporter gene driven by the prairie vole oxytocin receptor gene promoter. Analysis of the expression pattern suggests that it should be possible to manipulate receptor expression in the vole brain in order to examine the effects of receptor distribution on behavior.     

Perinatal and juvenile social environments interact to shape cognitive behaviour and neural phenotype in prairie voles

Social environments experienced at different developmental stages profoundly shape adult behavioural and neural phenotypes, and may have important interactive effects. We asked if social experience before and after weaning influenced adult social cognition in male prairie voles. Animals were raised either with or without fathers and then either housed singly or in sibling pairs. Males that were socially deprived before (fatherless) and after (singly housed) weaning did not demonstrate social recognition or dissociate spatial from social information. We also examined oxytocin and vasopressin receptors (OTR and V1aR) in areas of the forebrain associated with social behaviour and memory. Pre- and post-wean experience differentially altered receptor expression in several structures. Of note, OTR in the lateral septum—an area in which oxytocin inhibits social recognition—was greatest in animals that did not clearly demonstrate social recognition. The combination of absentee fathers on V1aR in the retrosplenial cortex and single housing on OTR in the septohippocampal nucleus produced a unique phenotype previously found to be associated with poor reproductive success in nature. We demonstrate that interactive effects of early life experiences throughout development have tremendous influence over brain–behaviour phenotype and can buffer potentially negative outcomes due to social deprivation.     

Field tests of cis-regulatory variation at the prairie vole avpr1a locus: association with V1aR abundance but not sexual or social fidelity

The neuropeptide vasopressin and its receptor V1aR are broadly implicated in social behavior and play a central role in several key aspects of male mating tactics in voles. In the prairie vole, a microsatellite in the cis-regulatory region of the gene encoding V1aR (avpr1a) provides a potential genetic basis for individual variation in neural phenotype and behavior; recent studies found that allele length predicts V1aR expression and male social attachment in the laboratory. Here, we explore the relationship between avpr1a microsatellite length, V1aR neural phenotype, and field measures of monogamy and fitness in male prairie voles. We found significant effects of allele length on V1aR expression in structures integral to pairbond formation. These effects did not, however, translate to differences in mating tactics or reproductive success. Together, these data suggest that, while length polymorphism in the avpr1a microsatellite influences neuronal phenotype, this variation does not contribute significantly to male reproductive success and field behavior. We propose that previously reported behavioral effects may be mediated primarily by sequence variation at this locus, for which allele length is an imperfect proxy. By combining genetic, neuronal and ecological approaches, these data provide novel insights into the contribution of genotype to natural diversity in brain and behavior.     

Field tests of cis-regulatory variation at the prairie vole avpr1a locus: Association with V1aR abundance but not sexual or social fidelity

The neuropeptide vasopressin and its receptor V1aR are broadly implicated in social behavior and play a central role in several key aspects of male mating tactics in voles. In the prairie vole, a microsatellite in the cis-regulatory region of the gene encoding V1aR (avpr1a) provides a potential genetic basis for individual variation in neural phenotype and behavior; recent studies found that allele length predicts V1aR expression and male social attachment in the laboratory. Here, we explore the relationship between avpr1a microsatellite length, V1aR neural phenotype, and field measures of monogamy and fitness in male prairie voles. We found significant effects of allele length on V1aR expression in structures integral to pairbond formation. These effects did not, however, translate to differences in mating tactics or reproductive success. Together, these data suggest that, while length polymorphism in the avpr1a microsatellite influences neuronal phenotype, this variation does not contribute significantly to male reproductive success and field behavior. We propose that previously reported behavioral effects may be mediated primarily by sequence variation at this locus, for which allele length is an imperfect proxy. By combining genetic, neuronal and ecological approaches, these data provide novel insights into the contribution of genotype to natural diversity in brain and behavior.     

Comparative distribution of central neuropeptide Y (NPY) in the prairie (Microtus ochrogaster) and meadow (M. pennsylvanicus) vole

Neuropeptide Y (NPY) has been implicated as a modulator of social behavior, often in a species-specific manner. Comparative studies of closely related vole species are particularly useful for identifying neural systems involved in social behaviors in both voles and humans. In the present study, immunohistochemistry was performed to compare NPY-like immunoreactivity (-ir) in brain tissue of the socially monogamous prairie vole and non-monogamous meadow vole. Species differences in NPY-ir were observed in a number of regions including the cortex, extended amygdala, septal area, suprachiasmatic nucleus, and intergeniculate leaf. Meadow voles had higher NPY-ir in all these regions as compared to prairie voles. No differences were observed in the striatum or hippocampus. The extended amygdala and lateral septum are regions that play a key role in regulation of monogamous behaviors such as pair bonding and paternal care. The present study suggests NPY in these regions may be an additional modulator of these species-specific social behaviors. Meadow voles had moderately higher NPY-ir in a number of hypothalamic regions, especially in the suprachiasmatic nucleus. Meadow voles also had much higher levels of NPY-ir in the intergeniculate leaflet, another key region in the regulation of circadian rhythms. Overall, species differences in NPY-ir were observed in a number of brain regions implicated in emotion, stress, circadian, and social behaviors. These findings provide additional support for a role for the NPY system in species-typical social behaviors.     

Oxytocin receptor density is associated with male mating tactics and social monogamy

Despite its well-described role in female affiliation, the influence of oxytocin on male pairbonding is largely unknown. However, recent human studies indicate that this nonapeptide has a potent influence on male behaviors commonly associated with monogamy. Here we investigated the distribution of oxytocin receptors (OTR) throughout the forebrain of the socially monogamous male prairie vole (Microtus ochrogaster). Because males vary in both sexual and spatial fidelity, we explored the extent to which OTR predicted monogamous or non-monogamous patterns of space use, mating success and sexual fidelity in free-living males. We found that monogamous males expressed higher OTR density in the nucleus accumbens than non-monogamous males, a result that mirrors species differences in voles with different mating systems. OTR density in the posterior portion of the insula predicted mating success. Finally, OTR in the hippocampus and septohippocampal nucleus, which are nuclei associated with spatial memory, predicted patterns of space use and reproductive success within mating tactics. Our data highlight the importance of oxytocin receptor in neural structures associated with pairbonding and socio-spatial memory in male mating tactics. The role of memory in mating systems is often neglected, despite the fact that mating tactics impose an inherently spatial challenge for animals. Identifying mechanisms responsible for relating information about the social world with mechanisms mediating pairbonding and mating tactics is crucial to fully appreciate the suite of factors driving mating systems. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.     

Central oxytocin receptors mediate mating-induced partner preferences and enhance correlated activation across forebrain nuclei in male prairie voles

Oxytocin (OT) is a deeply conserved nonapeptide that acts both peripherally and centrally to modulate reproductive physiology and sociosexual behavior across divergent taxa, including humans. In vertebrates, the distribution of the oxytocin receptor (OTR) in the brain is variable within and across species, and OTR signaling is critical for a variety of species-typical social and reproductive behaviors, including affiliative and pair bonding behaviors in multiple socially monogamous lineages of fishes, birds, and mammals. Early work in prairie voles suggested that the endogenous OT system modulates mating-induced partner preference formation in females but not males; however, there is significant evidence that central OTRs may modulate pair bonding behavior in both sexes. In addition, it remains unclear how transient windows of central OTR signaling during sociosexual interaction modulate neural activity to produce enduring shifts in sociobehavioral phenotypes, including the formation of selective social bonds. Here we re-examine the role of the central OT system in partner preference formation in male prairie voles using a selective OTR antagonist delivered intracranially. We then use the same antagonist to examine how central OTRs modulate behavior and immediate early gene (Fos) expression, a metric of neuronal activation, in males during brief sociosexual interaction with a female. Our results suggest that, as in females, OTR signaling is critical for partner preference formation in males and enhances correlated activation across sensory and reward processing brain areas during sociosexual interaction. These results are consistent with the hypothesis that central OTR signaling facilitates social bond formation by coordinating activity across a pair bonding neural network.     

单配制啮齿动物Pair Bond形成的神经调节机制

单配制啮齿动物社会结构的神经生物学原理可以通过实验室研究Social bonding而获得。在本文中,我们探讨了如何利用单配制的草原田鼠(Microtus ochrogaster)作为研究模型揭示pair bond形成的神经调控机制。我们进而探讨了单配制与多配制田鼠之间神经解剖学的差异以及神经化学物质的调节是怎样影响pair bond的。本篇综述还讨论了与pair bond形成有关的神经化学系统之间的相互影响以及pair bond形成过程中的两性差异。最后,我们预测了这一研究领域的未来研究方向以及研究social bonding的神经调控对人类健康的重要性。     

幼体生长发育特征可导致橙腹田鼠的单配体制吗?

橙腹田鼠(Microtus ochrogaster)和草原田鼠(M. pennsylvanicus)是两种亲缘关系很近,但有着完全不同交配体制的田鼠。本文试图通过他们头骨的形态学比较来验证幼体生长发育(paedomorphosis)可以印证单配制交配体制进化的假说。通过几种头骨的测量,我们发现草原田鼠头骨的长与宽比例大于橙腹田鼠,说明前者具有相对狭长的头骨。进一步的测量发现,这种不同是由于草原田鼠具有相对较长的鼻骨造成的。最后,我们对同种内成年和幼年的头骨进行了比较,发现单配制的橙腹田鼠相对于多配制的草原田鼠,其成年的头骨与幼年的头骨更相似。这些测量结果说明与多配制的田鼠相比,单配制的田鼠在形态及行为上保留更多的幼年状态,而这种行为很可能与其交配体制有关。     

Oxytocin-like receptors mediate pair bonding in a socially monogamous songbird

Although many species form socially monogamous pair bonds, relevant neural mechanisms have been described for only a single species, the prairie vole (Microtus ochrogaster). In this species, pair bonding is strongly dependent upon the nonapeptides oxytocin (OT) and vasopressin, in females and males, respectively. Because monogamy has evolved many times in multiple lineages, data from additional species are required to determine whether similar peptide mechanisms modulate bonding when monogamy evolves independently. Here we test the hypothesis that OT-like receptor activation is required for pair bond formation in the socially monogamous zebra finch (Taeniopygia guttata). Males and females were administered chronic intracerebroventricular infusions of saline or an OT receptor antagonist and were observed twice daily for 3 days in a colony environment. A variety of affiliative, aggressive and other behaviours were quantified. The antagonist produced significant and selective effects on pair bonding (latency to pair; number of sessions paired; stable pairing) and the associated behaviour of allopreening. Importantly, findings for males follow the trends of females; this yields main effects of treatment in two-way ANOVAs, although within-sex analyses are significant only for females. These data provide evidence for both convergent evolution and species diversity in the neuroendocrine mechanisms of pair bonding.     

A comparison of paternal behaviour in the meadow vole Microtus pennsylvanicus,the pine vole M. pinetorum and the prairie vole M. cchrogaster

Paternal care in microtines has been studied infrequently and few studies have compared patterns of direct and indirect paternal investment. The paternal behaviour of three vole species, the meadow vole (Microtus pennsylvanicus), the pine vole (M. pinetorum) and the prairie vole (M. ochrogaster) was examined in a semi-natural setting. Prairie and pine voles were found to exhibit high levels of paternal care. Prairie vole males contributed the most direct care by remaining in the natal nest for long periods of time in contact with the pups. Pine voles contributed less direct care than prairie voles as they spent less time in the natal nest with their offspring. In addition, both prairie and pine vole males were observed to groom their pups and retrieve them back to the nest area. Prairie vole males also engaged in such indirect forms of care as nest construction and maintenance, while pine voles provided indirect care in the form of tunnel construction and food caching. Meadow vole males were the least paternal of the three species and rarely engaged in either direct or indirect care. These findings support predictions that M. pennsylvanicus is promiscuous and that male and female meadow voles occupy separate territories. They are also consistent with studies which indicate that prairie and pine voles are monogamous and have a structured social organization with members interacting closely with one another.