De Novo Genome Assembly for the Coppery Titi Monkey (Plecturocebus cupreus): An Emerging Nonhuman Primate Model for Behavioral Research.

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.

Expression of bond-related behaviors affects titi monkey responsiveness to oxytocin and vasopressin treatments.

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.

Intranasal oxytocin does not change partner preference in female titi monkeys (Plecturocebus cupreus), but intranasal vasopressin decreases it.

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.

Titi monkey father-daughter bond-related behaviors explain stress response variability.

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 father-daughter 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 bond-related 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.

Facial fractures: The "bottom-up" approach.

Given the demands of a busy high-volume trauma center, trauma radiologists are expected to evaluate an enormous number of images covering a multitude of facial bones in a short period of time in severely traumatized patients. Therefore, a comprehensive checklist, search pattern, and practical approach become indispensable for evaluation. Moreover, fracture complex classification conveys abundant information in a succinct shorthand fashion, which can be a large asset in a busy high-volume trauma center: reliably helping clinicians communicate urgent findings, make early treatment decisions, and effectively plan surgical approaches. Traditionally, radiologists' approach the CT axial dataset in top-down fashion: navigating their descent craniocaudal. However, a bottom-up approach may be advantageous, especially when it comes to facial fracture complex classification. Four key anatomic landmarks of the face, when evaluated sequentially in bottom-up fashion, are favorable to rapid single-sweep facial fracture characterization: the mandible, the pterygoid plates, the zygoma, and the bony orbits. That is, when done in succession: 1. Clearing the mandible rules out a panfacial smash fracture. 2. Clearing the pterygoid plates effectively rules out a Le Fort I, II, and III fracture. 3. Clearing the zygoma effectively rules out a zygomaticomaxillary complex (ZMC) type fracture. 4. Clearing the bony orbits effectively rules out a naso-orbital-ethmoid (NOE) fracture. Following this process of exclusion and elimination; as one ascends through the face, fracture characterization becomes more manageable and straightforward. Besides identifying all of the fractures and using the appropriate classification system, the radiologist also needs to recognize key clinically relevant soft tissue injuries that may be associated with facial fractures and thus should address these in the report.

Parental experience is linked with lower vasopressin receptor 1a binding and decreased postpartum androgens in titi monkeys.

Parenting induces many neurological and behavioral changes that enable parents to rear offspring. Vasopressin plays an important role in this process via its effects on cognition, affect, and neuroplasticity, and in some cases, via interactions with decreased parental androgens. Thus far, the role of these hormones has been primarily studied in rodents. To address this gap, we explored vasopressin receptors and androgens in titi monkeys, a pair-bonding and biparental primate species. In Studies 1 and 2, we used receptor autoradiography to correlate arginine vasopressin receptor 1a (AVPR1a) binding in the hippocampus (Study 1, n = 10) and the rest of the forebrain (Study 2, n = 23) with parental status, parental experience, parity, infant carrying, and pair affiliation. We found that parents exhibited lower AVPR1a binding than non-parents throughout most brain regions assessed, with especially strong effects in the hippocampus (ß = -.61), superior colliculus (ß = -.88), lateral septum (ß = -.35), and medial preoptic area (ß = -.29). The other measures of parental experience also tended to be negatively associated with AVPR1a binding across different brain regions. In Study 3 (n = 44), we compared pre- and postpartum urinary androgen levels in parents and non-parents and found that mothers exhibited a sustained androgen decrease across 3-4 months postpartum (relative to 3 months prepartum; ß ranged from -.72 to -.62 for different comparisons). For males, we found that multiparous fathers exhibited decreased androgen levels at 1-2 weeks postpartum (ß = -.25) and at 3-4 months postpartum (ß = -.40) compared to the prepartum, indicating both immediate and long-term reductions with subsequent paternal experience. Together, the results of this study suggest that decreases in AVPR1a binding and circulating androgens are associated with parental behavior and physiology in titi monkeys.

Initial compatibility during a "Speed-Dating" test predicts postpairing affiliation in titi monkeys (Plecturocebus cupreus).

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; ß = 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 (ß = 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.

Initial impressions of compatibility and mate value predict later dating and romantic interest.

Romantic first impressions seem to linger, but why? Few studies have investigated how romantic desire during initial interactions predicts later relational outcomes (e.g., later romantic interest, contact attempts) using a design that can tease apart different possible mechanisms (e.g., mate value, selectivity, compatibility). Across three speed-dating studies (n = 559) with longitudinal follow-ups (including college and community samples, and a sample of men who date men), we investigated whether different components of initial romantic impressions predicted later romantic outcomes and relationship initiation. Using the social relations model, we partitioned initial desire at speed dating (determined from 6,600+ total dates) into partner effects (a date's consensual desirability, e.g., mate value), actor effects (a participant's general desirousness, e.g., selectivity), and relationship effects (a participant's unique liking for a date over and beyond partner and actor effects, e.g., compatibility) to predict later evaluations (romantic interest, physical attraction, and desire to know better) and behaviors (direct messaging and going on dates). Meta-analyses across the three studies showed that, across 6,100+ follow-up reports, partner and relationship effects were especially strong predictors of relationship initiation variables. Consistent with evolutionary models of human pair bonding, these findings suggest that both consensually desirable traits and unique impressions of compatibility have lingering effects on relationship development, even from the moment that two potential partners meet.

Long term effects of chronic intranasal oxytocin on adult pair bonding behavior and brain glucose uptake in titi monkeys (Plecturocebus cupreus).

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 18FDG 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.

What is a pair bond?

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?

Relationships between cortisol and urinary androgens in female titi monkeys (Plecturocebus cupreus).

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 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.

Masculinized Second-to-Fourth Digit Ratio (2D:4D Ratio) Is Associated With Lower Cortisol Response in Infant Female Rhesus Monkeys (Macaca mulatta).

The second-to-fourth digit ratio (2D:4D ratio) is considered a postnatal proxy measure for the degree of prenatal androgen exposure (PAE), which is the primary factor responsible for masculinizing the brain of a developing fetus. Some studies suggest that the organizational effects of PAE may extend to the hypothalamic-pituitary-adrenal (HPA) axis response to stress. This study investigates the relationship between 2D:4D ratio and HPA axis functioning using a rhesus monkey (Macaca mulatta) model. Subjects were N = 268 (180 females, 88 males) rhesus monkey infants (3-4 months of age). Plasma cortisol concentrations were assayed from two blood samples obtained during a 25-h experimental social separation stressor at 2- and 7-h post-separation. Subjects' 2D:4D ratio was measured later in life (M age = 6.70 years). It was hypothesized that infant rhesus monkeys that exhibited a more masculine-like 2D:4D ratio would show lower levels of circulating cortisol after a social separation and relocation stressor. The results showed that there was a sex difference in the left-hand 2D:4D ratio. The results also showed that there was an overall sex difference in cortisol concentrations and that female, but not male, monkeys that exhibited a more masculine-like right- and left-hand 2D:4D ratio exhibited lower mean stress-induced cortisol concentrations early in life. These findings suggest that higher levels of prenatal androgens in females, as measured by 2D:4D ratio, may be related to an attenuated HPA axis stress-response, as measured by plasma cortisol levels. To the extent that these findings generalize to humans, they suggest that the organizational effects of PAE extend to the infant HPA axis, modulating the HPA axis response, particularly in females.

Oxytocin receptor binding in the titi monkey hippocampal formation is associated with parental status and partner affiliation.

Social cognition is facilitated by oxytocin receptors (OXTR) in the hippocampus, a brain region that changes dynamically with pregnancy, parturition, and parenting experience. We investigated the impact of parenthood on hippocampal OXTR in male and female titi monkeys, a pair-bonding primate species that exhibits biparental care of offspring. We hypothesized that in postmortem brain tissue, OXTR binding in the hippocampal formation would differ between parents and non-parents, and that OXTR density would correlate with frequencies of observed parenting and affiliative behaviors between partners. Subjects were 10 adult titi monkeys. OXTR binding in the hippocampus (CA1, CA2/3, CA4, dentate gyrus, subiculum) and presubiculum layers (PSB1, PSB3) was determined using receptor autoradiography. The average frequency of partner affiliation (Proximity, Contact, and Tail Twining) and infant carrying were determined from longitudinal observations (5-6 per day). Analyses showed that parents exhibited higher OXTR binding than non-parents in PSB1 (t(8) = - 2.33, p = 0.048), and that OXTR binding in the total presubiculm correlated negatively with Proximity (r = - 0.88) and Contact (r = - 0.91), but not Tail Twining or infant carrying. These results suggest that OXTR binding in the presubiculum supports pair bonding and parenting behavior, potentially by mediating changes in hippocampal plasticity.

Maternal neglect and the serotonin system are associated with daytime sleep in infant rhesus monkeys.

Environmental and biological factors contribute to sleep development during infancy. Parenting plays a particularly important role in modulating infant sleep, potentially via the serotonin system, which is itself involved in regulating infant sleep. We hypothesized that maternal neglect and serotonin system dysregulation would be associated with daytime sleep in infant rhesus monkeys. Subjects were nursery-reared infant rhesus macaques (n = 287). During the first month of life, daytime sleep-wake states were rated bihourly (0800-2100). Infants were considered neglected (n = 16) if before nursery-rearing, their mother repeatedly failed to retrieve them. Serotonin transporter genotype and concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) were used as markers of central serotonin system functioning. t tests showed that neglected infants were observed sleeping less frequently, weighed less, and had higher 5-HIAA than non-neglected nursery-reared infants. Regression revealed that serotonin transporter genotype moderated the relationship between 5-HIAA and daytime sleep: in subjects possessing the Ls genotype, there was a positive correlation between 5-HIAA and daytime sleep, whereas in subjects possessing the LL genotype there was no association. These results highlight the pivotal roles that parents and the serotonin system play in sleep development. Daytime sleep alterations observed in neglected infants may partially derive from serotonin system dysregulation.

Sexual Dimorphism in Titi Monkeys' Digit (2D:4D) Ratio is Associated with Maternal Urinary Sex Hormones During Pregnancy.

The second-to-fourth digit (2D:4D) ratio is a sexually-dimorphic biomarker for prenatal sex hormone exposure. We investigated whether titi monkeys (Plecturocebus cupreus) exhibit sexually-dimorphic 2D:4D ratio, and whether variation in 2D:4D ratio correlates with maternal testosterone and estrogen levels during early pregnancy. Subjects were 61 adult titi monkeys (32 males, 29 females). For 26 subjects, maternal urine samples were collected approximately 15-20 weeks before birth and assayed for testosterone and estrone conjugate (E1 C). Titi monkeys exhibited a human-like pattern of sexual dimorphism in right-hand 2D:4D ratio, with females exhibiting higher 2D:4D ratio than males (ß = -0.29, p = 0.023). For left-hand 2D:4D ratio, high levels of maternal E1 C predicted low offspring 2D:4D ratio (ß = -0.48, p = 0.009). For right-hand 2D:4D ratio, high levels of testosterone (ß = -0.53, p = 0.005) and testosterone-to-E1 C ratio (ß = -0.41, p = 0.028) predicted low offspring 2D:4D ratio. For 2D:4D ratio asymmetry (right-hand - left-hand), high levels of testosterone (ß = -0.43, p = 0.03) and testosterone-to-E1 C ratio (ß = -0.53, p = 0.003) predicted low (right-biased) asymmetry. This is the first report of sexually-dimorphic 2D:4D ratio in New World monkeys, and the results support a growing literature suggesting prenatal sex hormones may modulate offspring 2D:4D ratio.

Imaging of Spine Trauma.

Every year in North America, approximately 3 million patients are evaluated for spinal injury. Of blunt trauma patients presenting to the emergency department, 3% to 4% will have a cervical spine injury, and up to 18% will suffer a thoracolumbar spine injury. Failure to identify an unstable spine injury can lead to devastating outcomes.

Sex Differences in Rhesus Monkeys' Digit Ratio (2D:4D Ratio) and Its Association With Maternal Social Dominance Rank.

Prenatal androgen exposure (PAE) plays a pivotal role in masculinizing the developing body and brain, and extreme exposure may contribute to autism, anxiety disorder and schizophrenia. One commonly used biomarker for PAE is the pointer-to-ring-finger digit length (2D:4D) ratio. Although this biomarker is widely used in human studies, relatively few studies have investigated 2D:4D ratio in nonhuman primates, particularly rhesus macaques (Macaca mulatta), one of the most commonly used animals in biomedical research. Thus far, data suggest that sexual dimorphism in 2D:4D ratio may be in the opposite direction in some monkey species, when compared to the pattern exhibited by humans and great apes. Using a large sample size, we investigated whether rhesus monkeys' 2D:4D ratio shows the same sex-differentiated pattern present in other Old World monkey species. We also investigated whether individual differences in 2D:4D ratio are associated with the social dominance rank of subjects' mothers during pregnancy, and the social dominance rank the subjects attained as adults. Subjects were 335 rhesus monkeys between 3 years and 24 years of age (M = 6.6). Maternal dominance rank during pregnancy and subjects' adult dominance rank were categorized into tertiles (high, middle and low). Results showed that, across both hands, male rhesus monkeys exhibited higher 2D:4D ratio than females, a pattern consistent with other monkey species and a reversal from the pattern typically observed in humans and apes. This sex difference was modulated by maternal dominance rank, with female offspring of high-ranking and middle-ranking mothers exhibiting masculinized 2D:4D ratio, indicating that maternal dominance rank during pregnancy may influence levels of PAE. There was no association between subjects' 2D:4D ratio and the social dominance rank they attained as adults. These findings show a consistent sex difference in Old World monkeys' 2D:4D ratio that diverges from the pattern observed in apes and humans, and suggest maternal social dominance rank modulates PAE in rhesus monkeys.

Imaging Genitourinary Trauma.

Contrast-enhanced multidetector computed tomography (MDCT) has become a critical tool in the evaluation of the trauma patient. MDCT can quickly and accurately assess trauma patients for renal, ureteral, and bladder injuries. Moreover, CT guides clinical management triaging patients to those requiring discharge, observation, angioembolization, and surgery. Recognition of urinary tract trauma on initial scan acquisition should prompt delayed excretory phase imaging to identify urine leaks. Urethral and testicular trauma are imaged with retrograde urethrography and sonography, respectively.

Differentiating shunt-responsive normal pressure hydrocephalus from Alzheimer disease and normal aging: pilot study using automated MRI brain tissue segmentation.

Evidence suggests that normal pressure hydrocephalus (NPH) is underdiagnosed in day to day radiologic practice, and differentiating NPH from cerebral atrophy due to other neurodegenerative diseases and normal aging remains a challenge. To better characterize NPH, we test the hypothesis that a prediction model based on automated MRI brain tissue segmentation can help differentiate shunt-responsive NPH patients from cerebral atrophy due to Alzheimer disease (AD) and normal aging. Brain segmentation into gray and white matter (GM, WM), and intracranial cerebrospinal fluid was derived from pre-shunt T1-weighted MRI of 15 shunt-responsive NPH patients (9 men, 72.6 ± 8.0 years-old), 17 AD patients (10 men, 72.1 ± 11.0 years-old) chosen as a representative of cerebral atrophy in this age group; and 18 matched healthy elderly controls (HC, 7 men, 69.7 ± 7.0 years old). A multinomial prediction model was generated based on brain tissue volume distributions. GM decrease of 33% relative to HC characterized AD (P < 0.005). High preoperative ventricular and near normal GM volumes characterized NPH. A multinomial regression model based on gender, GM and ventricular volume had 96.3% accuracy differentiating NPH from AD and HC. In conclusion, automated MRI brain tissue segmentation differentiates shunt-responsive NPH with high accuracy from atrophy due to AD and normal aging. This method may improve diagnosis of NPH and improve our ability to distinguish normal from pathologic aging.