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Low cerebrospinal (CSF) arginine vasopressin (AVP) concentration is a biomarker of social impairment in low-social monkeys and children with autism, suggesting that AVP administration may improve primate social functioning. However, AVP administration also increases aggression, at least in "neurotypical" animals with intact AVP signaling. Here, we tested the effects of a voluntary drug administration method in low-social male rhesus monkeys with high autistic-like trait burden. Monkeys received nebulized AVP or placebo, using a within-subjects design. Study 1 (N = 8) investigated the effects of AVP administration on social cognition in two tests comparing responses to social versus nonsocial stimuli. Test 1: Placebo-administered monkeys lacked face recognition memory, whereas face recognition memory was "rescued" following AVP administration. In contrast, object recognition memory was intact and did not differ between administration conditions. Test 2: Placebo-administered monkeys did not respond to conspecific social communication cues, whereas following AVP administration, they reciprocated affiliative communication cues with species-typical affiliative responses. Importantly, AVP administration did not increase aggressive responses to conspecific aggressive or affiliative overtures. Study 2 (N = 4) evaluated the pharmacokinetics of this administration method. Following AVP nebulization, we observed a linear increase in cisternal CSF AVP levels, and a quadratic rise and fall in blood AVP levels. These findings indicate that nebulized AVP likely penetrates the central nervous system, selectively promotes species-typical responses to social information, and does not induce aggression in low-social individuals. Nebulized AVP therefore may hold promise for managing similar social symptoms in people with autism, particularly in very young or lower functioning individuals., Competing Interests: Competing interests statement:The Board of Trustees of the Leland Stanford Junior University filed a US patent application, 11,951,149 (“Intranasal Vasopressin Treatment for Social Deficits in Children with Autism”). This patent has not been licensed.

Background: Autism spectrum disorder (ASD) is characterized by persistent social interaction impairments and is male-biased in prevalence. We have established naturally occurring low sociality in male rhesus monkeys as a model for the social features of ASD. Low-social male monkeys exhibit reduced social interactions and increased autistic-like trait burden, with both measures highly correlated and strongly linked to low cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration. Little is known, however, about the behavioral and neurochemical profiles of female rhesus monkeys, and whether low sociality in females is a tractable model for ASD., Methods: Social behavior assessments (ethological observations; a reverse-translated autistic trait measurement scale, the macaque Social Responsiveness Scale-Revised [mSRS-R]) were completed on N = 88 outdoor-housed female rhesus monkeys during the non-breeding season. CSF and blood samples were collected from a subset of N = 16 monkeys across the frequency distribution of non-social behavior, and AVP and oxytocin (OXT) concentrations were quantified. Data were analyzed using general linear models., Results: Non-social behavior frequency and mSRS-R scores were continuously distributed across the general female monkey population, as previously found for male monkeys. However, dominance rank significantly predicted mSRS-R scores in females, with higher-ranking individuals showing fewer autistic-like traits, a relationship not previously observed in males from this colony. Females differed from males in several other respects: Social behavior frequencies were unrelated to mSRS-R scores, and AVP concentration was unrelated to any social behavior measure. Blood and CSF concentrations of AVP were positively correlated in females; no significant relationship involving any OXT measure was found., Limitations: This study sample was small, and did not consider genetic, environmental, or other neurochemical measures that may be related to female mSRS-R scores., Conclusions: Dominance rank is the most significant predictor of autistic-like traits in female rhesus monkeys, and CSF neuropeptide concentrations are unrelated to measures of female social functioning (in contrast to prior CSF AVP findings in male rhesus monkeys and male and female autistic children). Although preliminary, this evidence suggests that the strong matrilineal organization of this species may limit the usefulness of low sociality in female rhesus monkeys as a tractable model for ASD., (© 2024. The Author(s).)

Background: Quantitative autistic traits are common, heritable, and continuously distributed across the general human population. Patterns of autistic traits within families suggest that more complex mechanisms than simple Mendelian inheritance-in particular, parent of origin effects-may be involved. The ideal strategy for ascertaining parent of origin effects is by half-sibling analysis, where half-siblings share one, but not both, parents and each individual belongs to a unique combination of paternal and maternal half-siblings. While this family structure is rare in humans, many of our primate relatives, including rhesus macaques, have promiscuous breeding systems that consistently produce paternal and maternal half-siblings for a given index animal. Rhesus macaques, like humans, also exhibit pronounced variation in social functioning., Methods: Here we assessed differential paternal versus maternal inheritance of social functioning in male rhesus macaque offspring (N = 407) using ethological observations and ratings on a reverse-translated quantitative autistic trait measurement scale. Restricted Maximum Likelihood mixed models with unbounded variance estimates were used to estimate the variance components needed to calculate the genetic contribution of parents as the proportion of phenotypic variance (σ 2 P ) between sons that could uniquely be attributed to their shared genetics (σ 2 g ), expressed as σ 2 g /σ 2 P (or the proportion of phenotypic variance attributable to genetic variance), as well as narrow sense heritability (h 2 )., Results: Genetic contributions and heritability estimates were strong and highly significant for sons who shared a father but weak and non-significant for sons who shared a mother. Importantly, these findings were detected using the same scores from the same sons in the same analysis, confirmed when paternal and maternal half-siblings were analyzed separately, and observed with two methodologically distinct behavioral measures. Finally, genetic contributions were similar for full-siblings versus half-siblings that shared only a father, further supporting a selective paternal inheritance effect., Limitations: These data are correlational by nature. A larger sample that includes female subjects, enables deeper pedigree assessments, and supports molecular genetic analyses is warranted., Conclusions: Rhesus macaque social functioning may be paternally, but not maternally, inherited by sons. With continued investigation, this approach may yield important insights into sex differences in autism's genetic liability., (© 2023. The Author(s).)

Rhesus monkeys and humans are highly social primates, yet both species exhibit pronounced variation in social functioning, spanning a spectrum of sociality. Naturally occurring low sociality in rhesus monkeys may be a promising construct by which to model social impairments relevant to human autism spectrum disorder (ASD), particularly if low sociality is found to be stable across time and associated with diminished social motivation. Thus, to better characterize variation in sociality and social communication profiles, we performed quantitative social behavior assessments on N = 95 male rhesus macaques (Macaca mulatta) housed in large, outdoor groups. In Study 1, we determined the social classification of our subjects by rank-ordering their total frequency of nonsocial behavior. Monkeys with the greatest frequency of nonsocial behavior were classified as low-social (n = 20) and monkeys with the lowest frequency of nonsocial behavior were classified as high-social (n = 21). To assess group differences in social communication profiles, in Study 2, we quantified the rates of transient social communication signals, and whether these social signals were initiated by or directed towards the focal subject. Finally, in Study 3, we assessed the within-individual stability of sociality in a subset of monkeys (n = 11 low-social, n = 11 high-social) two years following our initial observations. Nonsocial behavior frequency significantly correlated across the two timepoints (Studies 1 and 3). Likewise, low-social versus high-social classification accurately predicted classification two years later. Low-social monkeys initiated less prosocial behavior than high-social monkeys, but groups did not differ in receipt of prosocial behavior, nor did they differ in threat behavior. These findings indicate that sociality is a stable, trait-like characteristic and that low sociality is linked to diminished initiation of prosocial behavior in rhesus macaques. This evidence also suggests that low sociality may be a useful construct for gaining mechanistic insight into the social motivational deficits often observed in people with ASD., (© 2022 Wiley Periodicals LLC.)

Background: Rhesus monkeys (Macaca mulatta) exhibit pronounced individual differences in social traits as measured by the macaque Social Responsiveness Scale-Revised. The macaque Social Responsiveness Scale was previously adapted from the Social Responsiveness Scale, an instrument designed to assess social and autistic trait variation in humans. To better understand potential biological underpinnings of this behavioral variation, we evaluated the trait-like consistency of several biological measures previously implicated in autism (e.g., arginine vasopressin, oxytocin, and their receptors, as well as ERK1/2, PTEN, and AKT(1-3) from the RAS-MAPK and PI3K-AKT pathways). We also tested which biological measures predicted macaque Social Responsiveness Scale-Revised scores., Methods: Cerebrospinal fluid and blood samples were collected from N = 76 male monkeys, which, as a sample, showed a continuous distribution on the macaque Social Responsiveness Scale-Revised. In a subset of these subjects (n = 43), samples were collected thrice over a 10-month period. The following statistical tests were used: "Case 2A" intra-class correlation coefficients of consistency, principal component analysis, and general linear modeling., Results: All biological measures (except AKT) showed significant test-retest reliability within individuals across time points. We next performed principal component analysis on data from monkeys with complete biological measurement sets at the first time point (n = 57), to explore potential correlations between the reliable biological measures and their relationship to macaque Social Responsiveness Scale-Revised score; a three-component solution was found. Follow-up analyses revealed that cerebrospinal fluid arginine vasopressin concentration, but no other biological measure, robustly predicted individual differences in macaque Social Responsiveness Scale-Revised scores, such that monkeys with the lowest cerebrospinal fluid arginine vasopressin concentration exhibited the greatest social impairment. Finally, we confirmed that this result held in the larger study sample (in which cerebrospinal fluid arginine vasopressin values were available from n = 75 of the subjects)., Conclusions: These findings indicate that cerebrospinal fluid arginine vasopressin concentration is a stable trait-like measure and that it is linked to quantitative social trait variation in male rhesus monkeys.

People with autism spectrum disorder (ASD) exhibit a variety of medical morbidities at significantly higher rates than the general population. Using an established monkey model of naturally occurring low sociality, we investigated whether low-social monkeys show an increased burden of medical morbidities compared to their high-social counterparts. We systematically reviewed the medical records of N = 152 (n = 73 low-social; n = 79 high-social) rhesus macaques (Macaca mulatta) to assess the number of traumatic injury, gastrointestinal, and inflammatory events, as well as the presence of rare medical conditions. Subjects' nonsocial scores, determined by the frequency they were observed in a nonsocial state (i.e., alone), and macaque Social Responsiveness Scale-Revised (mSRS-R) scores were also used to test whether individual differences in social functioning were related to medical morbidity burden. Medical morbidity type significantly differed by group, such that low-social monkeys incurred higher rates of traumatic injury compared to high-social monkeys. Nonsocial scores and mSRS-R scores also significantly and positively predicted traumatic injury rates, indicating that monkeys with the greatest social impairment were most impacted on this health measure. These findings from low-social monkeys are consistent with well-documented evidence that people with ASD incur a greater number of traumatic injuries and receive more peer bullying than their neurotypical peers, and add to growing evidence for the face validity of this primate model. LAY SUMMARY: People with autism exhibit multiple medical problems at higher rates than the general population. We conducted a comprehensive medical record review of monkeys that naturally exhibit differences in sociality and found that low-social monkeys are more susceptible to traumatic injuries than high-social monkeys. These results are consistent with reports that people with autism also incur greater traumatic injury and peer bullying and add to growing evidence for the validity of this monkey model., (© 2021 International Society for Autism Research, Wiley Periodicals LLC.)

Most primate species are highly social. Yet, within species, pronounced individual differences in social functioning are evident. In humans, the Social Responsiveness Scale (SRS) measures variation in social functioning. The SRS provides a quantitative measure of social functioning in natural social settings and can be used as a screening tool for autistic traits. The SRS was previously adapted for use in chimpanzees and recently refined for rhesus macaques, resulting in the macaque Social Responsiveness Scale-Revised (mSRS-R). Here, we performed an exploratory factor analysis on the mSRS-R in a large sample of male rhesus macaques (N = 233). We investigated the relationships of the resulting mSRS-R factors to quantitative social behavior (alone, proximity, contact, groom, and play) and to previously-established personality dimensions (Sociability, Confidence, Irritability, and Equability). Factor analysis yielded three mSRS-R factors: Poor Social Motivation, Poor Social Attractiveness, and Inappropriate Behavior. mSRS-R factors mapped closely to social behavior and personality dimensions in rhesus macaques, providing support for this instrument's convergent and discriminant validity. Animals with higher Poor Social Motivation were more likely to be observed alone and less likely to be observed in contact and grooming with conspecifics. Animals with higher Poor Social Attractiveness were less likely to be observed playing but more likely to be observed grooming with conspecifics. Inappropriate Behavior did not predict any behavioral measure. Finally, animals with higher Poor Social Motivation and higher Poor Social Attractiveness had less sociable personalities, whereas animals with more Inappropriate Behavior were more confident and more irritable. These findings suggest that the mSRS-R is a promising, psychometrically robust tool that can be deployed to better understand the psychological factors contributing to individual differences in macaque social functioning and, with relevant species-specific modification, the SRS may hold promise for investigating variation in social functioning across diverse primate taxa., (© 2021 Wiley Periodicals LLC.)

Naturally low-social rhesus macaques exhibit social impairments with direct relevance to autism spectrum disorder (ASD). To more efficiently identify low-social individuals in a large colony, we exploited, refined, and psychometrically assessed the macaque Social Responsiveness Scale (mSRS), an instrument previously derived from the human ASD screening tool. We performed quantitative social behavior assessments and mSRS ratings on a total of N = 349 rhesus macaques (Macaca mulatta) housed in large, outdoor corrals. In one cohort (N = 116), we conducted inter-rater and test-retest reliabilities, and in a second cohort (N = 233), we evaluated the convergent construct and predictive validity of the mSRS-Revised (mSRS-R). Only 17 of the original 36 items demonstrated inter-rater and test-retest reliability, resulting in the 17-item mSRS-R. The mSRS-R showed strong validity: mSRS-R scores robustly predicted monkeys' social behavior frequencies in home corrals. Monkeys that scored 1.5 standard deviations from the mean on nonsocial behavior likewise exhibited significantly more autistic-like traits, and mSRS-R scores predicted individuals' social classification (low-social vs. high-social) with 96% accuracy (likelihood ratio chi-square = 25.07; P < 0.0001). These findings indicate that the mSRS-R is a reliable, valid, and sensitive measure of social functioning, and like the human SRS, can be used as a high-throughput screening tool to identify socially impaired individuals in the general population. LAY SUMMARY: Variation in autistic traits can be measured in humans using the Social Responsiveness Scale (SRS). Here, we revised this scale for rhesus macaques (i.e., the mSRS-R), and showed that macaques exhibit individual differences in mSRS-R scores, and at the behavioral extremes, low-social vs. high-social monkeys exhibit more autistic-like traits. These results suggest that the mSRS-R can be used as a screening tool to rapidly and accurately identify low-social monkeys in the general population. Autism Res 2020, 13: 1465-1475. © 2020 International Society for Autism Research, Wiley Periodicals, Inc., (© 2020 International Society for Autism Research, Wiley Periodicals, Inc.)

Recent evidence within the field of comparative psychology has demonstrated that small differences in procedure may lead to significant differences in outcome. Therefore, failing to fully explore the impact of different contexts on a behavior limits our ability to fully understand that behavior. A behavior that has exhibited substantial variation, both within and across studies, is animals' responses to violations of their expectations, either when expectations were based on another's outcome (inequity) or one's previous outcome (contrast). We explored this further in capuchin monkeys, focusing on the following 2 factors that often vary in such tests but have not yet been rigorously explored: the relative values of the food rewards and the degree of separation of the subjects. Concerning the first, we examined responses to violation of expectations when the difference between what was expected (or what the partner got) and what was received differed in either quality or quantity. Concerning the second, we compared responses when the 2 individuals were separated by a clear partition (barrier condition) versus sharing the same enclosure without the partition (no-barrier condition). Our results suggest that responses to inequity are most likely to emerge when the food received is low-value food, regardless of the difference between the actual and the expected outcome. However, capuchins did not respond differently to different quantities of rewards, nor did the degree of separation between subjects significantly affect results. We consider the implications of this work for both studies of violation of expectation and other cognitive and behavioral tasks. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Several species besides humans respond negatively to inequity (i.e. receiving a less preferred outcome as compared to a social partner). Among primates, the taxon for which inequity responses have been most comprehensively studied, there are large individual differences in responses that have, thus far, not been well explained by demographic features such as sex, rank and age. Recent evidence shows that individuals' personalities are important in explaining differences in behavioural outcomes in other contexts. Thus, in the current study, we explored whether personality was associated with chimpanzees' responses to both inequity and contrast (i.e. receiving less than anticipated). Chimpanzees were paired with multiple members of their social groups. These pairs alternated trading a token to receive food rewards that either differed from what their partner received (inequity condition) or from what was initially offered (contrast condition) and we compared their responses to a control in which both subjects were offered and received the same reward for trading the token. We predicted that both personality and the quality and length of the pairs' relationship would influence subjects' reactions to unequal outcomes, as measured by their refusal to exchange tokens. The quality of subjects' relationships, based on a weighted average of grooming, contact and proximity, did not correlate with refusals to exchange, whereas pairs that had lived together longer were less likely to refuse in the contrast condition than were pairs that had lived together for less time. Considering personality, some of the dimensions influenced responses to both inequity and contrast similarly, but the more 'social' personality dimensions ('extraversion' and 'agreeableness') were more strongly correlated with sensitivity to inequity. These results highlight the importance of considering individual differences, including personality, when evaluating responses in cognitive and behavioural tests.

Background: Recently, much attention has been paid to the role of cooperative breeding in the evolution of behavior. In many measures, cooperative breeders are more prosocial than non-cooperatively breeding species, including being more likely to actively share food. This is hypothesized to be due to selective pressures specific to the interdependency characteristic of cooperatively breeding species. Given the high costs of finding a new mate, it has been proposed that cooperative breeders, unlike primates that cooperate in other contexts, should not respond negatively to unequal outcomes between themselves and their partner. However, in this context such pressures may extend beyond cooperative breeders to other species with pair-bonding and bi-parental care., Methods: Here we test the response of two New World primate species with different parental strategies to unequal outcomes in both individual and social contrast conditions. One species tested was a cooperative breeder (Callithrix spp.) and the second practiced bi-parental care (Aotus spp.). Additionally, to verify our procedure, we tested a third confamilial species that shows no such interdependence but does respond to individual (but not social) contrast (Saimiri spp.). We tested all three genera using an established inequity paradigm in which individuals in a pair took turns to gain rewards that sometimes differed from those of their partners., Conclusions: None of the three species tested responded negatively to inequitable outcomes in this experimental context. Importantly, the Saimiri spp responded to individual contrast, as in earlier studies, validating our procedure. When these data are considered in relation to previous studies investigating responses to inequity in primates, they indicate that one aspect of cooperative breeding, pair-bonding or bi-parental care, may influence the evolution of these behaviors. These results emphasize the need to study a variety of species to gain insight in to how decision-making may vary across social structures.

The ability to discriminate between quantities has been observed in many species. Typically, when an animal is given a choice between two sets of food, accurate performance (i.e., choosing the larger amount) decreases as the ratio between two quantities increases. A recent study reported that elephants did not exhibit ratio effects, suggesting that elephants may process quantitative information in a qualitatively different way from all other nonhuman species that have been tested (Irie-Sugimoto et al. in Anim Cogn 12:193-199, 2009). However, the results of this study were confounded by several methodological issues. We tested two African elephants (Loxodonta africana) to more thoroughly investigate relative quantity judgment in this species. In contrast to the previous study, we found evidence of ratio effects for visible and nonvisible sequentially presented sets of food. Thus, elephants appear to represent and compare quantities in much the same way as other species, including humans when they are prevented from counting. Performance supports an accumulator model in which quantities are represented as analog magnitudes. Furthermore, we found no effect of absolute magnitude on performance, providing support against an object-file model explanation of quantity judgment.

Although several primates respond negatively to inequity, it is unknown whether this results from homology or convergent processes. Behaviours shared within a taxonomic group are often assumed to be homologous, yet this distinction is important for a better understanding of the function of the behaviour. Previous hypotheses have linked cooperation and inequity responses. Supporting this, all species in which inequity responses have been documented are cooperative. In this study, we tested this hypothesis by investigating the response to inequity in squirrel monkeys, which share a phylogenetic family with capuchin monkeys, but do not cooperate extensively. Subjects exchanged tokens to receive food rewards in conditions in which the level of effort required and reward received varied. Squirrel monkeys did not respond negatively to inequity. However, the monkeys were sensitive to the variation present in the task; male subjects showed a contrast effect and, as in previous studies, subjects were more sensitive to differences in reward in the context of a task than when rewards were given for free. Taken with other results, these results support the hypothesis that a negative response to inequity evolved convergently in primates, probably as a mechanism for evaluating outcomes relative to one's partners in cooperative species.

There is great interest in the evolution of economic behavior. In typical studies, species are asked to play one of a series of economic games, derived from game theory, and their responses are compared. The advantage of this approach is the relative level of consistency and control that emerges from the games themselves; however, in the typical experiment, procedures and conditions differ widely, particularly between humans and other species. Thus, in the current study, we investigated how three primate species, capuchin monkeys, chimpanzees, and humans, played the Assurance (or Stag Hunt) game using procedures that were, to the best of our ability, the same across species, particularly with respect to training and pretesting. Our goal was to determine what, if any, differences existed in the ways in which these species made decisions in this game. We hypothesized differences along phylogenetic lines, which we found. However, the species were more similar than might be expected. In particular, humans who played using "nonhuman primate-friendly" rules did not behave as is typical. Thus, we find evidence for similarity in decision-making processes across the order Primates. These results indicate that such comparative studies are possible and, moreover, that in any comparison rating species' relative abilities, extreme care must be taken in ensuring that one species does not have an advantage over the others due to methodological procedures.

Several primate species form expectations based on others' outcomes, responding negatively when their outcomes differ from their partners'. The function and evolutionary pathway of this behavior are unknown, in part because all of the species which have been tested thus far share traits related to a gregarious lifestyle, intelligence, and cooperativeness. Our goal was to test whether inequity is a homology among primates or a convergence by comparing one species known to show social comparisons, the chimpanzee, to another great ape which differs on several of these life history characteristics. Using a protocol identical to one used previously with chimpanzees, we tested whether orangutans, an intelligent but predominantly solitary species with few opportunities to cooperate, responded similarly. To allow for a strong comparison with chimpanzees (and other species), we used socially housed adults of both sexes, tested with members of their social group. Orangutans did not respond negatively to inequity, supporting previous findings and indicating that inequity responses in apes are likely a convergence based on either sociality or cooperative tendency. These results in such closely related species highlight the need for additional comparative studies to understand better the function and evolution of social behaviors., (Copyright © 2011 S. Karger AG, Basel.)

An exo-beta (1 going to 3)-glucanohydrolase (EC 3.2.1.6) of sea urchin eggs (Strongylocentrotus purpuratus) was purified to homogeneity by DEAE-cellulose chromatography followed by affinity chromatography on gluconolactone-Sepharose. The increase in specific activity is 800- to 1500-fold. The native enzyme exists in aggregated forms on nondenaturiung gels, with a subunit molecular weight on sodium dodecyl sulfate gels of 68,000. The enzyme is stabilized by polyethylene glycol and retains activity in 0.2% sodium dodecyl sulfate. With soluble laminarin as substrate (0.67 mg/ml), the temperature optimum is 60 degrees C (pH 6.0) and the pH optimum is 5.4 (40 degrees C). The egg glucanase does not exhibit Michaelis-Menten kinetics, exhibiting instead sigmoidal kinetics with a Hill coefficient of 1.6. The maximum velocity is 80 mumol of glucose released from soluble laminarin min-1 mg-1 protein. The half-maximum velocity (at pH 6.0, 40 degrees C) occurs at about 58 micrograms of laminarin ml-1. The glucanase is inhibited by D-1,5-gluconolactone, D-erythritol, and DL-threitol. This affinity method of glucanase purification may be important in the study of glucanases from other sources.

A radioimmunoassay, capable of detecting the Dolichos biflorus lectin at concentrations as low as 400 ng/ml, was developed and used to follow the distribution of this lectin in the plant during its life cycle.The lectin was first detected in the seeds of the plant 27 days after flowering and rapidly attained the high level of lectin present in the mature seed. The lectin content of the plant is highest in the seeds and cotyledons and decreases as the storage materials of the cotyledons decrease.A low but measurable amount of material that reacts with antibodies to the seed lectin was detected in the leaves, stems, and pods of the plant. This material gives a precipitin band of only partial identity to the seed lectin when tested in immunodiffusion against antiserum to the seed lectin.No lectin was detected by the radioimmunoassay in the roots of the plant at any stage of development.