Hasse Walum

Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans

Pair-bonding has been suggested to be a critical factor in the evolutionary development of the social brain. The brain neuropeptide arginine vasopressin (AVP) exerts an important influence on pair-bonding behavior in voles. There is a strong association between a polymorphic repeat sequence in the 5′ flanking region of the gene (avpr1a) encoding one of the AVP receptor subtypes (V1aR), and proneness for monogamous behavior in males of this species. It is not yet known whether similar mechanisms are important also for human pair-bonding. Here, we report an association between one of the human AVPR1A repeat polymorphisms (RS3) and traits reflecting pair-bonding behavior in men, including partner bonding, perceived marital problems, and marital status, and show that the RS3 genotype of the males also affects marital quality as perceived by their spouses. These results suggest an association between a single gene and pair-bonding behavior in humans, and indicate that the well characterized influence of AVP on pair-bonding in voles may be of relevance also for humans.

The Swedish Twin Registry: Establishment of a Biobank and Other Recent Developments

The Swedish Twin Registry (STR) today contains more than 194,000 twins and more than 75,000 pairs have zygosity determined by an intra-pair similarity algorithm, DNA, or by being of opposite sex. Of these, approximately 20,000, 25,000, and 30,000 pairs are monozygotic, same-sex dizygotic, and opposite-sex dizygotic pairs, respectively. Since its establishment in the late 1950s, the STR has been an important epidemiological resource for the study of genetic and environmental influences on a multitude of traits, behaviors, and diseases. Following large investments in the collection of biological specimens in the past 10 years we have now established a Swedish twin biobank with DNA from 45,000 twins and blood serum from 15,000 twins, which effectively has also transformed the registry into a powerful resource for molecular studies. We here describe the main projects within which the new collections of both biological samples as well as phenotypic measures have been collected. Coverage by year of birth, zygosity determination, ethnic heterogeneity, and influences of in vitro fertilization are also described.

Variation in the Oxytocin Receptor Gene Is Associated with Pair-Bonding and Social Behavior

BACKGROUND In specific vole and primate species the neuropeptide oxytocin plays a central role in the regulation of pair-bonding behavior. Here we investigate the extent to which genetic variants in the oxytocin receptor gene (OXTR) are associated with pair-bonding and related social behaviors in humans. METHODS We first genotyped twelve single nucleotide polymorphisms (SNPs) in the TOSS (Twin and Offspring Study in Sweden) (n = 2309) and the TCHAD (Swedish Twin Study of Child and Adolescent Development) (n = 1240), comprising measures of self-reported pair-bonding behavior. In the TOSS sample we further investigated one of the SNPs for measures of marital status and quality. Moreover, in the TCHAD sample we explored the longitudinal relationship between precursors of pair-bonding during childhood and subsequent behavior in romantic relationships. Finally, in the TCHAD study and in the Child and Adolescent Twin Study of Sweden (CATSS) (n = 1771), the association between the same SNP and childhood behaviors was investigated. RESULTS One SNP (rs7632287) in OXTR was associated with traits reflecting pair-bonding in women in the TOSS and TCHAD samples. In girls the rs7632287 SNP was further associated with childhood social problems, which longitudinally predicted pair-bonding behavior in the TCHAD sample. This association was replicated in the CATSS sample in which an association between the same SNP and social interaction deficit symptoms from the autism spectrum was detected. CONCLUSION These results suggest an association between variation in OXTR and human pair-bonding and other social behaviors, possibly indicating that the well-described influence of oxytocin on affiliative behavior in voles could also be of importance for humans.

Statistical and Methodological Considerations for the Interpretation of Intranasal Oxytocin Studies

Over the last decade, oxytocin (OT) has received focus in numerous studies associating intranasal administration of this peptide with various aspects of human social behavior. These studies in humans are inspired by animal research, especially in rodents, showing that central manipulations of the OT system affect behavioral phenotypes related to social cognition, including parental behavior, social bonding, and individual recognition. Taken together, these studies in humans appear to provide compelling, but sometimes bewildering, evidence for the role of OT in influencing a vast array of complex social cognitive processes in humans. In this article, we investigate to what extent the human intranasal OT literature lends support to the hypothesis that intranasal OT consistently influences a wide spectrum of social behavior in humans. We do this by considering statistical features of studies within this field, including factors like statistical power, prestudy odds, and bias. Our conclusion is that intranasal OT studies are generally underpowered and that there is a high probability that most of the published intranasal OT findings do not represent true effects. Thus, the remarkable reports that intranasal OT influences a large number of human social behaviors should be viewed with healthy skepticism, and we make recommendations to improve the reliability of human OT studies in the future.

Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus)

The coppery titi monkey (Callicebus cupreus) is a socially monogamous New World primate that has been studied in the field and the laboratory to investigate the behavioral neuroendocrinology of primate pair bonding and parental care. Arginine vasopressin has been shown to influence male titi monkey pair-bonding behavior, and studies are currently underway to examine the effects of oxytocin on titi monkey behavior and physiology. Here, we use receptor autoradiography to identify the distribution of arginine vasopressin 1a receptor (AVPR1a) and oxytocin receptors (OXTR) in hemispheres of titi monkey brain (n=5). AVPR1a are diffuse and widespread throughout the brain, but the OXTR distribution is much more limited, with the densest binding being in the hippocampal formation (dentate gyrus, CA1 field) and the presubiculum (layers I and III). Moderate OXTR binding was detected in the nucleus basalis of Meynert, pulvinar, superior colliculus, layer 4C of primary visual cortex, periaqueductal gray (PAG), pontine gray, nucleus prepositus, and spinal trigeminal nucleus. OXTR mRNA overlapped with OXTR radioligand binding, confirming that the radioligand was detecting OXTR protein. AVPR1a binding is present throughout the cortex, especially in cingulate, insular, and occipital cortices, as well as in the caudate, putamen, nucleus accumbens, central amygdala, endopiriform nucleus, hippocampus (CA4 field), globus pallidus, lateral geniculate nucleus, infundibulum, habenula, PAG, substantia nigra, olivary nucleus, hypoglossal nucleus, and cerebellum. Furthermore, we show that, in the titi monkey brain, the OXTR antagonist ALS-II-69 is highly selective for OXTR and that the AVPR1a antagonist SR49059 is highly selective for AVPR1a. Based on these results and the fact that both ALS-II-69 and SR49059 are non-peptide, small-molecule antagonists that should be capable of crossing the blood-brain barrier, these two compounds emerge as excellent candidates for the pharmacological manipulation of OXTR and AVPR1a in future behavioral experiments in titi monkeys and other primate species.

Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment

BACKGROUND Oxytocin (OXT) modulates several aspects of social behavior. Intranasal OXT is a leading candidate for treating social deficits in patients with autism spectrum disorder, and common genetic variants in the human OXTR gene are associated with emotion recognition, relationship quality, and autism spectrum disorder. Animal models have revealed that individual differences in Oxtr expression in the brain drive social behavior variation. Our understanding of how genetic variation contributes to brain OXTR expression is very limited. METHODS We investigated Oxtr expression in monogamous prairie voles, which have a well-characterized OXT system. We quantified brain region-specific levels of Oxtr messenger RNA and oxytocin receptor protein with established neuroanatomic methods. We used pyrosequencing to investigate allelic imbalance of Oxtr mRNA, a molecular signature of polymorphic genetic regulatory elements. We performed next-generation sequencing to discover variants in and near the Oxtr gene. We investigated social attachment using the partner preference test. RESULTS Our allelic imbalance data demonstrate that genetic variants contribute to individual differences in Oxtr expression, but only in particular brain regions, including the nucleus accumbens, where oxytocin receptor signaling facilitates social attachment. Next-generation sequencing identified one polymorphism in the Oxtr intron, near a putative cis-regulatory element, explaining 74% of the variance in striatal Oxtr expression specifically. Males homozygous for the high expressing allele display enhanced social attachment. CONCLUSIONS Taken together, these findings provide convincing evidence for robust genetic influence on Oxtr expression and provide novel insights into how noncoding polymorphisms in OXTR might influence individual differences in human social cognition and 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.

The Dopamine Transporter Gene (DAT1) Polymorphism is Associated with Premature Ejaculation

INTRODUCTION Previous research has suggested brain dopamine (DA) neurotransmission to be involved in the control of ejaculation. Furthermore, previous studies indicate a partly hereditary background to premature ejaculation. AIM To investigate whether the dopamine transporter gene (DAT1) polymorphism is associated with premature ejaculation. METHODS Retrospective self-reports of four indicators reflecting ejaculatory function-anteportal ejaculation, number of penile thrusts, ejaculation latency time, and feeling of control over ejaculation-and saliva samples for DNA analysis were obtained from 1,290 men (M = 26.9, standard deviation = 4.7 years; range 18-45) with sexual experience. Main Outcome Measures. Calculations of allelic effects were computed using the Generalized Estimating Equations module of SPSS 17. RESULTS Carriers of the 10R10R genotype had scores indicating a lower threshold to ejaculate on each of the indicators compared to the combined 9R9R/9R10R carrier group. The differences were significant both for the composite score and for anteportal ejaculation, number of thrusts, and feeling of control over ejaculation, but not for ejaculation latency time. The effect of the polymorphism remained significant after controlling for age, homosexual experience, having a regular sexual partner, level of sexual desire, and frequency of sexual activity, hence suggesting that it is not secondary to an association between the studied polymorphism and some other aspect of sexual behavior, but due to a specific influence of DA on ejaculation. CONCLUSIONS The findings of the present study support results of previous studies indicating involvement of dopaminergic neurotransmission in ejaculation.

Perfect genetic correlation between number of offspring and grandoffspring in an industrialized human population

Significance Reproductive success (offspring quantity) is widely used as a measure of fitness (genetic contribution to future generations). Accurate predictions of the direction and magnitude of evolutionary change using this measure depend on the untested assumption that the genes influencing number of offspring are the same as those influencing number of grandoffspring. Using a population sample of identical and nonidentical Swedish twins and their descendants, we show that the genetic influences on number of offspring and grandoffspring are identical, supporting the use of reproductive success as a measure of fitness in comparable human populations. Reproductive success is widely used as a measure of fitness. However, offspring quantity may not reflect the genetic contribution to subsequent generations if there is nonrandom variation in offspring quality. Offspring quality is likely to be an important component of human fitness, and tradeoffs between offspring quantity and quality have been reported. As such, studies using offspring quantity as a proxy for fitness may yield erroneous projections of evolutionary change, for example if there is little or no genetic variance in number of grandoffspring or if its genetic variance is to some extent independent of the genetic variance in number of offspring. To address this, we performed a quantitative genetic analysis on the reproductive history of 16,268 Swedish twins born between 1915 and 1929 and their offspring. There was significant sex limitation in the sources of familial variation, but the magnitudes of the genetic and environmental effects were the same in males and females. We found significant genetic variation in number of offspring and grandoffspring (heritability = 24% and 16%, respectively), and genetic variation in the two variables completely overlapped—i.e., there was a perfect genetic correlation between number of offspring and grandoffspring. Shared environment played a smaller but significant role in number of offspring and grandoffspring; again, there was a perfect shared environmental correlation between the two variables. These findings support the use of lifetime reproductive success as a proxy for fitness in populations like the one used here, but we caution against generalizing this conclusion to other kinds of human societies.

Dynamic corticostriatal activity biases social bonding in monogamous female prairie voles

Adult pair bonding involves dramatic changes in the perception and valuation of another individual. One key change is that partners come to reliably activate the brain’s reward system, although the precise neural mechanisms by which partners become rewarding during sociosexual interactions leading to a bond remain unclear. Here we show, using a prairie vole (Microtus ochrogaster) model of social bonding, how a functional circuit from the medial prefrontal cortex to nucleus accumbens is dynamically modulated to enhance females’ affiliative behaviour towards a partner. Individual variation in the strength of this functional connectivity, particularly after the first mating encounter, predicts how quickly animals begin affiliative huddling with their partner. Rhythmically activating this circuit in a social context without mating biases later preference towards a partner, indicating that this circuit’s activity is not just correlated with how quickly animals become affiliative but causally accelerates it. These results provide the first dynamic view of corticostriatal activity during bond formation, revealing how social interactions can recruit brain reward systems to drive changes in affiliative behaviour.