Purpose The kappa opioid receptor (KOR) plays a pivotal role in stress- and anxiety-related behaviors, with growing evidence linking it to stress induced by social isolation and separation. Despite this, tools for studying KOR in clinically relevant social contexts remain limited. The socially monogamous coppery titi monkey offers a translational model for investigating pair bonding. This study evaluated the feasibility of [ 11 C]GR103545 PET imaging to characterize KOR activity in vivo , and its pharmacological blockade for the first time in titi monkeys. Methods Adult titi monkeys (N = 6) underwent [ 11 C]GR103545 PET brain scans at baseline and following administration of the KOR antagonist CERC-501. Non-displaceable binding potential (BP ND ) was calculated across 14 brain volumes of interest (VOIs) implicated in social bonding, using Simplified and Logan reference tissue models (SRTM and LRTM), with the cerebellum as the reference region. Results Baseline [ 11 C]GR103545 uptake patterns across VOIs were consistent with reports in humans, other primates and published autoradiography data. CERC-501 pretreatment significantly reduced BP ND (SRTM: 55.99%, LRTM: 59.68%) across several, but not all brain VOIs. Conclusions This study establishes [ 11 C]GR103545 PET as a viable tool for assessing KOR binding dynamics in titi monkeys, providing new opportunities to explore KOR modulation in social bonding and separation.

Social bonds influence physiology and behavior, which can shape how individuals respond to physical and affective challenges. Coppery titi monkey (Plecturocebus cupreus) offspring form selective bonds with their fathers, making them ideal for investigating how father-daughter bonds influence juveniles' responses to oxytocin (OT) and arginine-vasopressin (AVP) manipulations. We quantified the expression of father-daughter bond-related behaviors in females (n = 10) and gave acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or an OT receptor antagonist (OTA) to subjects prior to a parent preference test. While females spent more time in proximity to their parents than strangers, we found a large degree of individual variation. Females with greater expression of bonding behaviors responded to OT treatments in a dose-dependent manner. Subjects also spent less time in proximity to strangers when treated with High OT (p = 0.003) and Low OT (p = 0.007), but more time when treated with High AVP (p = 0.007), Low AVP (p = 0.009), and OTA (p = 0.001). Findings from the present study suggest that variation in the expression of bond-related behaviors may alter responsiveness to OT and AVP, increasing engagement with unfamiliar social others. This enhanced sociality with strangers may promote the formation of pair bonds with partners.

The coppery titi monkey (Plecturocebus cupreus) is an emerging nonhuman primate model system for behavioral and neurobiological research. At the same time, the almost entire absence of genomic resources for the species has hampered insights into the genetic underpinnings of the phenotypic traits of interest. To facilitate future genotype-to-phenotype studies, we here present a high-quality, fully annotated de novo genome assembly for the species with chromosome-length scaffolds spanning the autosomes and chromosome X (scaffold N50 = 130.8 Mb), constructed using data obtained from several orthologous short- and long-read sequencing and scaffolding techniques. With a base-level accuracy of ∼99.99% in chromosome-length scaffolds as well as benchmarking universal single-copy ortholog and k-mer completeness scores of >99.0% and 95.1% at the genome level, this assembly represents one of the most complete Pitheciidae genomes to date, making it an invaluable resource for comparative evolutionary genomics research to improve our understanding of lineage-specific changes underlying adaptive traits as well as deleterious mutations associated with disease.

Social bonds influence physiology and behavior, which can shape how individuals respond to physical and affective challenges. Coppery titi monkey ( Plecturocebus cupreus ) offspring form selective bonds with their fathers, making them ideal for investigating how father–daughter bonds influence juveniles’ responses to oxytocin (OT) and arginine-vasopressin (AVP) manipulations. We quantified the expression of father–daughter bond-related behaviors in females ( n = 10) and gave acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or an OT receptor antagonist (OTA) to subjects prior to a parent preference test. While females spent more time in proximity to their parents than strangers, we found a large degree of individual variation. Females with greater expression of bonding behaviors responded to OT treatments in a dose-dependent manner. Subjects also spent less time in proximity to strangers when treated with High OT ( p = 0.003) and Low OT ( p = 0.007), but more time when treated with High AVP ( p = 0.007), Low AVP ( p = 0.009), and OTA ( p = 0.001). Findings from the present study suggest that variation in the expression of bond-related behaviors may alter responsiveness to OT and AVP, increasing engagement with unfamiliar social others. This enhanced sociality with strangers may promote the formation of pair bonds with partners.

Strong social bonds are critical to human health; however, the mechanisms by which social bonds are formed and maintained are still being elucidated. The neurohormones oxytocin (OT) and vasopressin (AVP) are considered likely candidates. Primate females, both human and nonhuman, remain understudied populations. Here, we conducted a pharmacological study coupled with a behavioral partner preference test (PPT) to better understand the mechanistic basis of attachment in adult female titi monkeys (Plecturocebus cupreus). This pair-bonding species shares a conserved form of oxytocin with humans and is an excellent model organism to study the neural basis of social bonding. We performed intranasal administration of three doses of oxytocin (IN-OT), two doses of vasopressin (IN-AVP), one dose of an oxytocin antagonist (IN-OTA) and one dose of a saline treatment. We found that compared to the saline control, the IN-AVP treatment (lower dose, 40 IU/kg) decreased the time spent in proximity to the partner and increased lip-smacking toward the stranger. We found no effects of IN-OT or IN-OTA manipulation on partner preference. In contrast, low-dose IN-AVP weakened the partner preference in female titi monkeys.

Social interactions regulate our behavior and physiology, and strong social bonds can buffer us from stress. Coppery titi monkeys (Plecturocebus cupreus) are socially monogamous South American monkeys that display strong social bonds. Infants form selective bonds with their fathers, making them ideal for studying fatherdaughter bonds. We established a method for quantifying variability in expression of bond-related behaviors in females (n = 12), and the present study is the second to use this method for explaining titi monkey responses to behavioral tests. We also investigated how manipulations of oxytocin (OT) and vasopressin (AVP) influenced juvenile behavior and physiology. Subjects received acute intranasal treatments of saline, low/medium/high OT, low/high AVP, or OT receptor antagonist (OTA) prior to an acute social separation. General linear mixed-effects model results revealed fathers were significant behavioral and physiological stress buffers for their daughters, as evidenced by fewer distress vocalizations (p < 0.001), less locomotion (p < 0.001), and lower plasma cortisol (p < 0.001) in a social separation paradigm. Females vocalized less if they exhibited greater expression of bondrelated behaviors with their fathers as infants (p = 0.01), and this stress-buffering effect remained even when the daughter was separated from the father (p = 0.001). While treatments did not alter behaviors, OTA treatment caused the largest rise in plasma cortisol (p < 0.001), suggesting blockade of OT receptors can inhibit fathers' stress-buffering effects. Remarkably, females with greater expression of father-daughter bond-related behaviors exhibited an overall reduced physiological separation distress response (p = 0.04). Findings from the present study advance current knowledge of the neurobiological mechanisms foundational to female bonds and help inform how social disruptions may differently impact individuals based on expression of bond-related behaviors.

Pair bonding builds on preexisting dopamine connectivity to help form and maintain the bond. The involvement of dopaminergic pathways in pair bonding has stimulated research linking pair bonds to other dopamine -dependent processes, like addiction and social cognition (Burkett & Young, 2012; Yetnikoff, Lavezzi, Reich-ard, & Zahm, 2014). Less studied is the relationship of pair bonding to non-social cognitive processes. The first half of this review will provide an overview of pair bonding and the role of dopamine within social processes. With a thorough review of the literature, the current study will identify the ways the dopaminergic pathways critical for pair bonding also overlap with cognitive processes. Highlighting dopamine as a key player in pair bonds and non-social cognition will provide evidence that pair bonding can alter general cognitive processes like attention, working memory, cognitive flexibility, and impulse control.

Behavioral compatibility plays a critical role in shaping how potential mates interact with and evaluate each other and whether they choose to pursue a relationship. Compatibility is especially important for mate choice and relationship quality in pair-bonding species that form long-term attachments between mates. Although this process has been studied in humans and birds, relatively few studies have investigated it in non-human primates. In this study, we investigated whether pairing titi monkeys (Plecturocebus cupreus) based on initial compatibility increased postpairing affiliation between mates. Subjects were 12 unpaired adult titi monkeys (two cohorts of three males and three females). We determined each subject's initial interest in each opposite-sex potential mate in their cohort across a series of six 30-min interaction periods (i.e., "speed-dates"). To determine initial compatibility, we used the Social Relations Model to calculate relationship effects in initial interest (how much each subject uniquely preferred each potential mate beyond their own affiliative disposition and their partner's popularity). We then paired monkeys in a way that maximized net relationship effects between pairs, and measured longitudinal pair affiliation (Proximity, Contact, Tail Twining, and Combined Affiliation) for 6 months postpairing using daily scan-sample observations and monthly home-cage video recordings. Multilevel models showed that, on average, the six speed-dating pairs exhibited higher levels of Tail Twining (determined from scan-sample observations; β = 0.31) compared to a group of 13 age-matched colony pairs that were determined quasi-randomly without quantifying compatibility. The degree of initial compatibility within speed-dating pairs also predicted higher levels of Combined Affiliation (determined from video recordings) at earlier post-pairing time points, with the association peaking at 2 months postpairing (β = 0.57). These findings suggest that initial compatibility facilitates pair bonding in titi monkeys. We conclude by discussing how the speed-dating design can be used for colony management to inform pair-housing decisions.

Intranasal oxytocin (IN OXT) administration has been proposed as a pharmacological treatment for a range of biomedical conditions including neurodevelopmental disorders. However, studies evaluating the potential long-lasting effects of chronic IN OXT during development are still scarce. Here we conducted a follow-up study of a cohort of adult titi monkeys that received intranasal oxytocin 0.8 IU/kg (n = 15) or saline (n = 14) daily for six months during their juvenile period (12 to 18 months of age), with the goal of evaluating the potential long-lasting behavioral and neural effects one year post-treatment. Subjects were paired with an opposite-sex mate at 30 months of age (one year post-treatment). We examined pair affiliative behavior in the home cage during the first four months and tested for behavioral components of pair bonding at one week and four months post-pairing. We assessed long-term changes in brain glucose uptake using (18)FDG positron emission tomography (PET) scans. Our results showed that OXT-treated animals were more affiliative across a number of measures, including tail twining, compared to SAL treated subjects (tail twining is considered the "highest" type of affiliation in titi monkeys). Neuroimaging showed no treatment differences in glucose uptake between SAL and OXT-treated animals; however, females showed higher glucose uptake in whole brain at 23 months, and in both the whole brain and the social salience network at 33 months of age compared to males. Our results suggest that chronic IN OXT administration during development can have long-term effects on adult social behavior.

Steroid hormones are critical to the regulation of sociosexual behavior. Their role in the formation of pair bonds is complicated by the relative scarcity of this social system in mammals, as well as species and taxonomic differences in endocrine systems. In the present study, we experimentally manipulated the hypothalamic-pituitaryadrenal axis in female titi monkeys (Plecturocebus cupreus), a neotropical monkey studied for its strong, selective pair bonds. We validated an assay for plasma and urinary cortisol in this species, showing a strong suppression of cortisol following dexamethasone injection, and a significant but somewhat blunted response to adrenocorticotrophin hormone (ACTH) stimulation. Urinary androgens did not change in response to dexamethasone or ACTH. Plasma and urinary cortisol were moderately correlated, whereas urinary cortisol and androgens were only correlated when extreme cortisol values were included. In this study, we laid groundwork for studying the role of glucocorticoids and androgens (and eventually, their interactions with peptides) in the behavioral endocrinology of pair bonds in female titi monkeys.

Pair bonding is a psychological construct that we attempt to operationalize via behavioral and physiological measurements. Yet, pair bonding has been both defined differently in various taxonomic groups as well as used loosely to describe not just a psychological and affective phenomenon, but also a social structure or mating system (either social monogamy or just pair living). In this review, we ask the questions: What has been the historical definition of a pair bond? Has this definition differed across taxonomic groups? What behavioral evidence do we see of pair bonding in these groups? Does this observed evidence alter the definition of pair bonding? Does the observed neurobiology underlying these behaviors affect this definition as well? And finally, what are the upcoming directions in which the study of pair bonding needs to head?

Close social bonds are integral for good health and longevity in humans and non-human primates (NHPs), yet we have very little understanding of the neurobiological differences between healthy and unhealthy relationships. Our current understanding of social bonding is grounded in Bowlby's theory of attachment. Work done with human infants and adult couples has suggested that attachment behavior developed in infancy remains stable through development into adulthood. Unfortunately, knowledge of the neurobiological correlates of attachment behavior has been limited due to a lack of animal models with both infant and adult attachments similar to humans. To address this, we measured behavioral responses to separation from their primary attachment figure in infant and adult titi monkeys (Plecturocebus cupreus). In Experiment 1, we tested for a linear relationship between the subject's response to separation as an infant and their response to separation as an adult. We found greater decreases in infant locomotor behavior in the presence, as opposed to absence, of their primary attachment figure to be indicative of decreased anxiety-like behavior in the presence, as opposed to absence, of their adult pair mates during a novelty response task. In Experiment 2, we increased our sample size, accounted for adverse early experience, and tested a different outcome measure, adult affiliative behavior. We hypothesized that the level of intensity of an infant's response to separation would explain affiliative behavior with their mate as an adult, but adverse early experience could change this relationship. When we compared infant response to separation to adult affiliative behavior during the first 6 months of their first adult pair bond, we observed a linear relationship for infants with typical early experience, but not for infants with adverse early experience. Infants with a greater change in locomotive behavior between the father and alone conditions were more affiliative with their first adult pair mate. These data support the use of titi monkeys as an appropriate animal model for further investigation of the neurobiology underlying attachment behavior.

Pair-bonded primates have uniquely enduring relationships and partners engage in a suite of behaviors to maintain these close bonds. In titi monkeys, pair bond formation has been extensively studied, but changes across relationship tenure remain unstudied. We evaluated differences in behavioral indicators of pair bonding in newly formed (~6 months paired, n = 9) compared to well-established pairs (average 3 years paired, n = 8) of titi monkeys (Callicebus cupreus) as well as sex differences within the pairs. We hypothesized that overall males would contribute more to maintenance than females, but that the pattern of maintenance behaviors would differ between newly formed and well-established pairs. Each titi monkey (N = 34) participated in a partner preference test (PPT), where the subject was placed in a middle test cage with grated windows separating the subject from the partner on one side and an opposite-sex stranger on the other side. During this 150-min behavioral test, we quantified four key behaviors: time in proximity to the partner or stranger as well as aggressive displays toward the partner or stranger. Overall, we found different behavioral profiles representing newly formed and well-established pair-bond relationships in titi monkeys and male-biased relationship maintenance. Males spent ∼40% of their time in the PPT maintaining proximity to the female partner, regardless of relationship tenure. Males from well-established bonds spent less time (14%) near the female stranger compared to males from newly formed bonds (21%) at the trend level. In contrast, females from well-established bonds spent less (23%) time near the male partner in the PPT compared to females from newly formed bonds (47%). Aggressive displays were more frequent in newly formed bonds compared to well-established bonds, especially for females. Scan sampling for homecage affiliation showed that newly formed pairs were more likely to be found tail twining than well-established pairs.

[dataset for article in review] Steroid hormones are critical to the regulation of sociosexual behavior. Their role in the formation of pair bonds is complicated by the relative scarcity of this social system in mammals, as well as species and taxonomic differences in endocrine systems. In the present study, we experimentally manipulated the hypothalamic-pituitary-adrenal axis in female titi monkeys (Plecturocebus cupreus), a neotropical monkey studied for its strong, selective pair bonds. We validated a new assay for plasma and urinary cortisol in this species, showing a strong suppression of cortisol following dexamethasone injection, and a significant but somewhat blunted response to adrenocorticotrophin hormone (ACTH) stimulation. Urinary testosterone did not change in response to dexamethasone or ACTH. Plasma and urinary cortisol were highly correlated, whereas urinary cortisol and testosterone were only correlated when extreme cortisol values were included. In this study, we laid groundwork for studying the role of glucocorticoids and androgens (and eventually, their interactions with peptides) in the behavioral endocrinology of pair bonds in female titi monkeys.

Pair bonds are selective, enduring and often affiliative relationships that exist between two non-kin adults. We investigate pair bonding by detailing both ultimate and proximate mechanisms in its expression across taxa, including (1) evolutionary perspectives, (2) behavioral correlates, (3) and neurobiology. Our synthesis highlights comparisons between mammals and birds, demonstrating convergent behavioral and neurobiological mechanisms for pair bonding. We conclude with a novel model for the neurobiology of pair bonding in prairie voles and extrapolate its functionality to other pair-bonding species.

Conventional chemical synapses in the nervous system involve a presynaptic accumulation of neurotransmitter-containing vesicles, which fuse with the plasma membrane to release neurotransmitters that activate postsynaptic receptors. In taste buds, type II receptor cells do not have conventional synaptic features but nonetheless show regulated release of their afferent neurotransmitter, ATP, through a large-pore, voltage-gated channel, CALHM1. Immunohistochemistry revealed that CALHM1 was localized to points of contact between the receptor cells and sensory nerve fibers. Ultrastructural and super-resolution light microscopy showed that the CALHM1 channels were consistently associated with distinctive, large (1- to 2-μm) mitochondria spaced 20 to 40 nm from the presynaptic membrane. Pharmacological disruption of the mitochondrial respiratory chain limited the ability of taste cells to release ATP, suggesting that the immediate source of released ATP was the mitochondrion rather than a cytoplasmic pool of ATP. These large mitochondria may serve as both a reservoir of releasable ATP and the site of synthesis. The juxtaposition of the large mitochondria to areas of membrane displaying CALHM1 also defines a restricted compartment that limits the influx of Ca2+ upon opening of the nonselective CALHM1 channels. These findings reveal a distinctive organelle signature and functional organization for regulated, focal release of purinergic signals in the absence of synaptic vesicles.

In this paper, our goal is to explore what is known about the role of social touch during development. We first address the neural substrates of social touch and the role of tactile experience in neural development. We discuss natural variation in early exposure to social touch, followed by a discussion on experimental manipulations of social touch during development and “natural experiments”, such as early institutionalization. We then consider the role of other developmental and experiential variables that predict social touch in adults. Throughout, we propose and consider new theoretical models of the role of social touch during development on later behavior and neurobiology.