Female squirrel monkeys' (Saimiri boliviensis) responses to inequity in a group context; testing a link between cooperation and inequity responses.

Primates of several species respond negatively to receiving less preferred rewards than a partner for completing the same task (inequity responses), either rejecting rewards or refusing to participate in the task when disadvantaged. This has been linked to cooperation, with species that cooperate frequently refusing to participate in inequity tasks (the 'cooperation hypothesis'). However, inequity is a social response, and previous research has involved dyads, precluding studying the effects of additional social partners. While dyads allow for tighter control in experimental settings, dyadic interactions in nature do not take place in a social vacuum, so understanding the role of the social context is needed to verify that the pattern of results supports the cooperation hypothesis. Here we focus on Bolivian squirrel monkeys, Saimiri boliviensis, a highly social species that does not generally cooperate and has not responded to inequity in previous dyadic research, although they do respond to receiving a lower reward than they expected. In the current study, we provide a more nuanced test by studying female Bolivian squirrel monkeys, the demographic most likely to cooperate in both field and laboratory contexts, in a more socially relevant group setting. For some reward values, females responded in both the inequity condition, rejecting less preferred rewards when they were disadvantaged relative to their social group, and a contrast condition, wherein all animals received a lower reward than they expected, making it difficult to disentangle contrast from inequity. As in capuchin monkeys, refusals increased when monkeys were to receive low-value rewards compared to medium-value rewards. These results suggest that the relationship between cooperation and inequity responses may be more nuanced than previously suggested, with demographic, social context and reward value potentially influencing outcomes even within species.

Phenotypic and genetic associations between gray matter covariation and tool use skill in chimpanzees (Pan troglodytes): Repeatability in two genetically isolated populations.

Humans and chimpanzees both exhibit a diverse set of tool use skills which suggests selection for tool manufacture and use occurred in the common ancestors of the two species. Our group has previously reported phenotypic and genetic associations between tool use skill and gray matter covariation, as quantified by source-based morphometry (SBM), in chimpanzees. As a follow up study, here we evaluated repeatability in heritability in SBM components and their phenotypic association with tool use skill in two genetically independent chimpanzee cohorts. Within the two independent cohorts of chimpanzees, we identified 8 and 16 SBM components, respectively. Significant heritability was evident for multiple SBM components within both cohorts. Further, phenotypic associations between tool use performance and the SBM components were largely consistent between the two cohorts; the most consistent finding being an association between tool use performance and an SBM component including the posterior superior temporal sulcus (STS) and superior temporal gyrus (STG), and the interior and superior parietal regions (p < 0.05). These findings indicate that the STS, STG, and parietal cortices are phenotypically and genetically implicated in chimpanzee tool use abilities.

Refinements to captive chimpanzee (Pan troglodytes) care: a self-medication Paradigm.

In an effort to enhance welfare, behavioural management continually refines methods of non-human primate (NHP) care. Chimpanzees (Pan troglodytes) are one of the most cognitively complex captive NHPs and they have been observed to self-medicate in the wild. The population of captive chimpanzees in the US is aged (due to a breeding moratorium instituted in 1998) and will progressively require more medical care as they get older. To functionally simulate natural self-medication behaviour, provide chimpanzees with the opportunity to voluntarily participate in their own healthcare, and open new avenues of communication between caregivers and chimpanzees, we used a medication choice paradigm that allowed chimpanzees to choose their daily arthritis medication. We provided four arthritic, mobility-impaired chimpanzees with meloxicam or ibuprofen in blue or green Gatorade® to establish associations between the coloured drinks and the effects of the medications. We subsequently gave each chimpanzee a choice between the two medications. Behaviour was recorded using 15-min focal animal observations. Mobility was assessed using interactive mobility tests and a caregiver-rating system. One chimpanzee showed a medication preference (ibuprofen over meloxicam). The chimpanzees exhibited no significant behavioural or mobility differences over time, suggesting that ibuprofen and meloxicam may not differ significantly in their ability to alleviate arthritic symptoms. Whether or not the chimpanzees show a medication preference, the opportunity to make meaningful choices and the functional simulation of a complex behaviour, self-medication, is present when using this medication choice technique. Furthermore, the paradigm itself could have potential applications for additional medication options and treatment regimens.

Delayed response task performance as a function of age in cynomolgus monkeys (Macaca fascicularis).

We compared delayed response task performance in young, middle-aged, and old cynomolgus monkeys using three memory tests that have been used with non-human primates. Eighteen cynomolgus monkeys--6 young (4-9 years), 6 middle-aged (10-19 years), and 6 old (above 20 years)--were tested. In general, the old monkeys scored significantly worse than did the animals in the two other age groups. Longer delays between stimulus presentation and response increased the performance differences between the old and younger monkeys. The old monkeys in particular showed signs of impaired visuo-spatial memory and deteriorated memory consolidation and executive functioning. These results add to the body of evidence supporting the utility of Macaca fascicularis in studies of cognition and as a potential translational model for age-associated memory impairment/dementia-related disorders.

Correlations between serum levels of beta amyloid, cerebrospinal levels of tau and phospho tau, and delayed response tasks in young and aged cynomolgus monkeys (Macaca fascicularis).

BACKGROUND: In an attempt to explore cynomolgus monkeys as an animal model for Alzheimer's disease, the present study focused on the Alzheimer's biomarkers beta amyloid 1-42 (Aß42 ) in serum, and total tau (t-tau) and phosphorylated tau (p-tau) levels in cerebrospinal fluid. METHODS: We measured biomarker levels in Young and Aged cynomolgus monkeys and correlated these with performance on three delayed response tasks. RESULTS: The Aß42 concentration of the Aged monkeys was significantly lower than in the Young subjects, while the t-tau and p-tau did not significantly differ between the groups. The Young subjects performed significantly better than the Aged individuals on the memory tests. Only Aß42 levels were significantly correlated with performance in the three delayed response tasks. CONCLUSIONS: Circulating Aß42 levels were lower in Aged monkeys and were correlated with inferior performance on delayed response tasks in Aged animals; therefore, both measures may be useful in establishing cynomolgus monkeys as models for studies of AD.

Identification of the social and cognitive processes underlying human cumulative culture.

The remarkable ecological and demographic success of humanity is largely attributed to our capacity for cumulative culture, with knowledge and technology accumulating over time, yet the social and cognitive capabilities that have enabled cumulative culture remain unclear. In a comparative study of sequential problem solving, we provided groups of capuchin monkeys, chimpanzees, and children with an experimental puzzlebox that could be solved in three stages to retrieve rewards of increasing desirability. The success of the children, but not of the chimpanzees or capuchins, in reaching higher-level solutions was strongly associated with a package of sociocognitive processes-including teaching through verbal instruction, imitation, and prosociality-that were observed only in the children and covaried with performance.

Space use selectivity by chimpanzees and gorillas in an indoor-outdoor enclosure.

Understanding the relationship between physical environments and nonhuman primate behavior is a key element for effective care and management in a range of settings. The physical features of the captive environment, including not only gross useable space but also environmental complexity, can have a significant influence on primate behavior and ultimately, animal welfare. But despite this connection, there remains relatively little conclusive data on how captive primates, especially great apes, use the spaces provided to them, especially in modern, indoor-outdoor enclosures that have become more prevalent in recent years. In this study, we used four years of detailed data on where 23 great apes (chimpanzees and gorillas) positioned themselves within a modern, indoor-outdoor zoo enclosure to determine not only how the apes utilized their space but also how access to outdoor areas affected their spatial selectivity. We found that both species used relatively little of their available space: chimpanzees and gorillas spent half their time in only 3.2 and 1.5% of their useable three-dimensional space, respectively. Chimpanzees utilized the outdoor space more than gorillas, but access to the outdoors did not affect space selectivity in the indoor area for either species. Although both species of ape were highly selective in their space use, consideration should be given to the importance of providing the choice to locate in a variety of spaces, including outdoor areas. These data represent an extremely detailed account of space selectivity by great apes in an indoor-outdoor environment and have substantial implications for future facility design and captive primate management.

Ape behavior in two alternating environments: comparing exhibit and short-term holding areas.

In many facilities, primates are voluntarily transferred between different enclosures on a daily basis to facilitate animal husbandry and exhibit maintenance. This procedure is particularly relevant in the management of great apes living in zoos, where the requirements of functional management must be balanced with the desire to maintain enriching and naturalistic exhibit enclosures that benefit ape residents and attract the visiting public. In these settings, examinations of ape behavior and welfare typically focus exclusively on activity in the primary exhibit area. However, physical, social and sensory experiences unique to each area may shape different patterns of behavior. In the current study, zoo-living chimpanzees and gorillas were moved each day from exhibit areas to off-exhibit holding areas for a short duration as a part of regular management procedures. Behavioral data indicated species-specific reactions to the holding area, including increased aggression and self-directed behavior by chimpanzees and increased activity and prosocial behavior among gorilla subjects. Both species showed more feeding-foraging behavior while in the exhibit enclosure. Results suggest that holding areas may not meet all behavior needs of captive great apes and demonstrate the importance of including all components of the captive enclosure in comprehensive analyses of great ape behavior and welfare.

Handedness for tool use in captive chimpanzees (Pan troglodytes): Sex differences, performance, heritability and comparison to the wild.

There is continued debate over the factors influencing handedness in captive and wild primates, notably chimpanzees. Previous studies in wild chimpanzees have revealed population-level left handedness for termite fishing. Here we examined hand preferences and performance on a tool use task designed to simulate termite fishing in a sample of 190 captive chimpanzees to evaluate whether patterns of hand use in captive chimpanzees differed from those observed for wild apes. No population-level handedness was found for this task; however, significant sex differences in preference and performance were found, with males showing greater left handedness and poorer performance compared to females. We also found that the hand preferences of offspring were significantly positively correlated with the hand preferences of their mothers. Lastly, older females performed more slowly on the task compared to younger individuals. The overall results neither confirm nor reject previous hypotheses claiming that raising chimpanzees in captivity induces right-handedness, but rather suggest that other factors may account for differences in hand preferences for tool use seen in wild and captive chimpanzees.

Stress in cynomolgus monkeys (Macaca fascicularis) subjected to long-distance transport and simulated transport housing conditions.

The stress associated with transportation of non-human primates used in scientific research is an important but almost unexplored part of laboratory animal husbandry. The procedures and routines concerning transport are not only important for the animals' physical health but also for their mental health as well. The transport stress in cynomolgus monkeys (Macaca fascicularis) was studied in two experiments. In Experiment 1, 25 adult female cynomolgus monkeys were divided into five groups of five animals each that received different diets during the transport phase of the experiment. All animals were transported in conventional single animal transport cages with no visual or tactile contact with conspecifics. The animals were transported by lorry for 24 h at ambient temperatures ranging between 20 degrees C and 35 degrees C. Urine produced before, during and after transport was collected and analysed for cortisol by enzyme-linked immunosorbent assay (ELISA). All monkeys exhibited a significant increase in cortisol excretion per time unit during the transport and on the first day following transport.Although anecdotal reports concerning diet during transport, including the provision of fruits and/or a tranquiliser, was thought likely to influence stress responses, these were not corrobated by the present study. In Experiment 2, behavioural data were collected from 18 cynomolgus macaques before and after transfer from group cages to either single or pair housing, and also before and after a simulated transport, in which the animals were housed in transport cages. The single housed monkeys were confined to single transport cages and the pair housed monkeys were kept in their pairs in double size cages. Both pair housed and singly housed monkeys showed clear behavioural signs of stress soon after their transfer out of their group cages.However, stress-associated behaviours were more prevalent in singly housed animals than in pair housed animals, and these behaviours persisted for a longer time after the simulated transport housing event than in the pair housed monkeys. Our data confirm that the transport of cynomolgus monkeys is stressful and suggest that it would be beneficial for the cynomolgus monkeys to be housed and transported in compatible pairs from the time they leave their group cages at the source country breeding facility until they arrive at their final laboratory destination in the country of use.

Manipulating the affiliative interactions of group-housed rhesus macaques using positive reinforcement training techniques.

Social housing, whether continuous, intermittent, or partial contact, typically provides many captive primates with opportunities to express affiliative behaviors, important components of the species-typical behavioral repertoire. Positive reinforcement training techniques have been successfully employed to shape many behaviors important for achieving primate husbandry goals. The present study was conducted to determine whether positive reinforcement training techniques could also be employed to alter levels of affiliative interactions among group-housed rhesus macaques. Twenty-eight female rhesus were divided into high (n = 14) and low (n = 14) affiliators based on a median split of the amount of time they spent affiliating during the baseline phase of the study. During the subsequent training phase, half of the low affiliators (n = 7) were trained to increase their time spent affiliating, and half of the high affiliators (n = 7) were trained to decrease their time spent affiliating. Trained subjects were observed both during and outside of training sessions. Low affiliators significantly increased the amount of time they spent affiliating, but only during nontraining sessions. High affiliators on the other hand, significantly decreased the amount of time they spent affiliating, but only during training sessions. These data suggest that positive reinforcement techniques can be used to alter the affiliative behavior patterns of group-housed, female rhesus monkeys, although the two subgroups of subjects responded differently to the training process. Low affiliators changed their overall behavioral repertoire, while high affiliators responded to the reinforcement contingencies of training, altering their proximity patterns but not their overall behavior patterns. Thus, positive reinforcement training can be used not only as a means to promote species-typical or beneficial behavior patterns, but also as an important experimental manipulation to facilitate systematic analyses of the effects of psychosocial factors on behavior and potentially even immunology.

Religious beliefs and opinions on clinical xenotransplantation--a survey of university students from Kenya, Sweden and Texas.

This study investigated the association between religious beliefs and opinions on xenotransplantation among students from three different countries. A lower proportion of religious students accepted xenotransplantation than did non-religious students. A higher proportion of Protestant students seemed to accept xenotransplantation than did Muslim and Roman Catholic students. A higher proportion of the religious respondents had not formed an opinion on xenotransplantation compared to non-religious students. There was no difference according to gender on views on xenotransplantation, but a higher proportion of older students seemed to accept xenotransplantation than did younger students. A higher proportion of non-vegetarians reported acceptance of xenotransplantation than did vegetarians. Acceptance of xenotransplantation was higher in Sweden compared to the two other regions, and the proportion of students who had formed an opinion was higher as well.

Differences in functional immune responses of high vs. low hardy healthy individuals.

An association between the personality trait of hardiness and immune responses was explored. Blood samples were collected from 21 healthy individuals under nonstressful conditions, who had either high or low levels of hardiness. Functional immune assays tested for natural killer (NK) cell activity and proliferation responses to Candida albicans (Candida), purified protein derivative from Mycobacterium tuberculosis (PPD), lipopolysaccharide (LPS), concanavalin A (Con A), and Staphylococcus enterotoxin A (Staph A). Differences between high and low hardy groups on these immune responses were examined using Bonferroni adjusted independent t-tests. Results revealed significant differences between the groups for Candida, PPD, Con A, and Staph A. In all instances, the high hardy group had larger mean proliferative responses than the low hardy group. Implications of the study as well as avenues for future research are discussed.

Accumulated means analysis: a novel method to determine reliability of behavioral studies using continuous focal sampling.

During the past decade, the behavioral needs, and especially the social needs, of laboratory animals have received increasing attention. New captive care guidelines have been developed, and these advocate group housing of laboratory animals whenever possible and appropriate. Analyses of behavioral observations are commonly used to assess the effects of experimental manipulations on behavioral responses. In studies of animal welfare, stress levels and effects on well being can be measured in this manner. Collecting the proper amount of data both to allow statistical analyses and to optimize time investment in data collection is a practical concern in behavioral research. The aim of the present study was to develop a simple method to estimate how much behavioral data should be collected in order to achieve a preset level of reliability across observations. This paper examines the behavior of 12 rhesus monkeys (Macaca mulatta) housed in two small social groups. Each monkey was observed for a total of two hours in 10 minute observation periods spread over 12 days. Accumulated Means Analysis, in which the accumulated mean for a behavior across successive observation sessions must meet several criteria, is proposed as a method to assess reliability across observations, thereby providing information concerning the optimum number of observational data sessions that need to be collected. The data in this study indicate that this optimum number of observations varies with the behavior being measured and with the group observed, as does the value of the Accumulated Means Analysis technique. Six hours of observation of rhesus macaques may be sufficient to provide the type of simple, yet reliable time budget (for a specific window of time) needed by those managing groups of primates. Accumulated Means Analysis should be applicable to behavioral data collected during multiple time periods on other non-human primate species, both in captivity and in the field.

Evaluation of cellular immune responses in rhesus monkeys subjected to adenovirus-mediated gene transfer into the cervix.

We reported previously that direct injection of a recombinant adenovirus (rAd), Ad5CMV-beta-gal, into the cervix of the rhesus monkey resulted in efficient beta-galactosidase expression in the cervix within 3 days. In these studies, we also observed the induction of anti-adenovirus (Ad)-specific immunoglobulin G responses after 22 days. In the continuation of evaluating the anti-Ad-specific immune responses resulting from this approach of gene targeting to the cervix, we measured the cellular immune responses. The introduction of Ad5CMV-beta-gal into the cervix by direct injection, but not by the abrasion technique, resulted in the induction of strong proliferative responses against extracts of cells infected with Ad5CMV-beta-gal but not against control uninfected cells. These responses were initially detected at 22 days postinjection and coincided with the abrogation of transgene expression. Significant levels of proliferative responses were maintained for < or =83 days. Multiple injections of rAds had no significant enhancing effect on either the level or longevity of the proliferative responses. At 3 days after the injection of Ad5CMV-beta-gal, when the transgene expression in the cervix was clearly evident, proliferative responses against the rAd were not detectable. However, the production of low but significant amounts of interleukin-10, a cytokine characteristic of T helper type 2 responses that promote humoral immune responses, was observed at the 3-day point in these animals. These results suggest that significant differences exist between the kinetics of transgene expression and the priming of specific host immune responses, and that these differences may be important for devising alternate strategies to improve techniques for Ad-mediated gene therapy of cervical cancer.

Preclinical toxicity study of intrathecal administration of the pain relievers dextrorphan, dextromethorphan, and memantine in the sheep model.

Objectives To determine the toxicity window for the continuous intrathecal administration of dextrorphan, dextromethorphan, and memantine via an implanted delivery pump. Materials and Methods Using 48 sheep with programmable continuous intrathecal infusion systems we determined the behavioral, motor, neurological, and histopathological changes produced by a 43-day continuous infusion study of dextrorphan, dextromethorphan, and memantine dissolved in 0.9% NaCl. Daily doses of each N-methyl-D-aspartate (NMDA) antagonist were 0.013, 0.051, 0.203, 0.510, 0.811, and 2.533 mg/kg/day, flow rates ranged from 13.25 ml/day to 0.051 ml/day at a concentration of 10 mg/ml. Control animals received saline in the range of 7.9985 ml/day to 1 ml/day. Conclusions Infusion of saline in the control animals produced no behavioral or motor changes. However, infusion of dextrorphan, dextromethorphan, and memantine at the higher doses (> 0.051 mg/kg/day) produced dose-dependent negative behavioral, motor, and histopathologic changes as indicated by a series of nonparametric statistical analyses. The minimal toxic doses were dextrorphan dose 3, dextromethorphan dose 1 and memantine dose 1. This study suggests that continuous intrathecal infusion of dextrorphan, dextromethorphan, and memantine via an implantable pump system can cause significant toxicities at the higher doses studied.

Evidence for specific immune response against P210 BCR-ABL in long-term remission CML patients treated with interferon.

Interferon-alpha treatment induces complete cytogenetic remission in 25% of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) patients. These remissions are durable unlike remissions induced with other therapies and yet residual leukemia is detectable in most of these patients. Total peripheral blood mononuclear cells (PBMCs) from CML patients in long-term remission following interferon treatment exhibited significantly higher proliferative responses (four- to 15-fold over background) than normals directed against P210 BCR-ABL in extracts of transfected monkey fibroblast cells. Surprisingly, similar enhanced levels of specific proliferative responses were observed with extracts from cells expressing Bcr and/or Abl proteins. In contrast, extracts from vector only or v-Mos-expressing cells had background level responses. Control monkey fibroblast cells lacking BCR-ABL expression failed to induce proliferation over background levels. Normal individuals had no significant responses to Bcr/Abl extracts. On the other hand, peripheral blood mononuclear cells from allogeneic bone marrow transplant CML patients had proliferative responses to cell extracts independent of Bcr-Abl. These data indicate that patients in remission due to alpha-interferon treatment have significantly higher levels of specific cellular immunoreactivity against Bcr/Abl sequences than normal controls, which could play a role in maintaining cytogenetic remission in Ph-positive CML patients.

A synthetic peptide from the first conserved region in the envelope protein gp160 is a strong T-cell epitope in HIV-infected chimpanzees and humans.

We reported earlier that synthetic peptides corresponding to highly conserved regions in the envelope protein gp160 of the human immunodeficiency virus type 1 (HIV-1), in particular an 11-amino acid sequence (peptide 104) from the first conserved region at the amino-terminus, were capable of inducing strong HIV-specific T-cell proliferative responses in several inbred mouse strains as well as in outbred Rhesus monkeys. We have now obtained evidence of the presence of significant levels of proliferative response to peptide 104 in 7 of 9 chimpanzees chronically infected with HIV-1 (p < or = 0.05) and 8 of 17 HIV+ individuals (p < or = 0.001). Further, four other conserved HIV envelope-derived peptides, identified previously in our murine and Rhesus monkey model systems, were widely recognized as T-cell epitopes in both chimpanzees and humans infected with HIV-1. In none of the infected subjects did peripheral blood mononuclear cells show proliferative responses to unrelated control peptides. Also, neither the control normal chimpanzees nor HIV-seronegative individuals showed proliferative responses to the conserved peptides. With respect to the humoral responses, serum samples from none of the chimpanzees showed reactivity with any of the conserved peptides, and only low levels of antibody responses against peptide 104 were observed in 3 of the 17 patients (p > 0.05). Importantly, three of the conserved envelope-derived peptides, including peptide 104, overlap with sequences that were reported in the literature to be epitopes for virus-induced cytotoxic T lymphocytes in asymptomatic HIV+ individuals. These observations, together with our results in multiple animal models and humans, establish that these conserved HIV envelope-derived peptides, particularly peptide 104, are significant T-cell epitopes with potential usefulness for induction of HIV-specific cell-mediated immune responses in humans.

Cross-reactive T-cell proliferative responses to V3 peptides corresponding to different geographical HIV-1 isolates in HIV-seropositive individuals.

We have investigated the proliferative response of peripheral blood mononuclear cells from individuals infected with human immunodeficiency virus type 1 (HIV-1) to synthetic peptides from the third variable loop region (V3) in the envelope protein gp120. We tested a total of 14 peptides, corresponding to 14 HIV-1 isolates belonging to four geographical locations (clades U, A, B, and D). Although differences in relative level of responses exist between individual peptides and patients, the proliferation in response to all 14 V3 peptides was significantly greater than that to unrelated control peptides. Additionally, we observed that proliferative responses of blood cells from the 10 HIV-seropositive individuals studied from the clade B region to peptides from within clades U, A, B, and D were not significantly different, indicating the cross-reactive nature of the V3-specific cell-mediated immune responses. Even though the majority of patients also exhibited antibody responses against several V3 peptides, serum samples from 50% of clade B patients exhibited antibody cross-reactivity, while proliferative responses to V3 peptides from more than one clade were observed in 80% of patients. Importantly, in two patients, decreased CD4+ cell numbers, an important surrogate marker of disease progression, significantly correlated with loss of V3 peptide-specific proliferative responses but not antibody responses. These results have important implications toward evaluating the utility of V3 peptides for designing therapeutic and/or vaccine reagents against HIV-1.