Female Rhesus Macaques Research Articles

Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques.

As in women with polycystic ovary syndrome (PCOS), hyperinsulinemia is associated with anovulation in PCOS-like female rhesus monkeys. Insulin sensitizers ameliorate hyperinsulinemia and stimulate ovulatory menstrual cycles in PCOS-like monkeys. To determine whether hyperinsulinemia (>694 pmol/L), alone, induces PCOS-like traits, five PCOS-like female rhesus monkeys with minimal PCOS-like traits, and four control females of similar mid-to-late reproductive years and body mass index, received daily subcutaneous injections of recombinant human insulin or diluent for 6–7 months. A cross-over experimental design enabled use of the same monkeys in each treatment phase. Insulin treatment unexpectedly normalized follicular phase duration in PCOS-like, but not control, females. In response to an intramuscular injection of 200 IU hCG, neither prenatally androgenized nor control females demonstrated ovarian hyperandrogenic responses while receiving insulin. An intravenous GnRH (100 ng/kg) injection also did not reveal evidence of hypergonadotropism. Taken together, these results suggest that experimentally induced adult hyperinsulinemia, alone, is insufficient to induce PCOS-like traits in female rhesus monkeys and to amplify intrinsic PCOS-like pathophysiology.

Sex and social status modify the effects of fluoxetine on socioemotional behaviors in Syrian hamsters and rhesus macaques

Social subordination increases risk for psychiatric disorders, while dominance increases resilience to these disorders. Fluoxetine, a selective serotonin (5HT) reuptake inhibitor whose actions are mediated in part by the 5HT1A receptor (5HT1AR), has sex- and social status-specific effects on socioemotional behavior and aggressive behavior. However, the impact of social status on these sex-specific effects remains unclear. The current study evaluated the impact of acute fluoxetine treatment and social status on dominance-related behaviors in female and male hamsters, and the impact of chronic fluoxetine treatment on socioemotional behavior and 5HT1AR binding potential (5HT1ARBP) in female rhesus macaques. We hypothesized that sex differences in the effects of fluoxetine on aggression in hamsters would be diminished in dominant and enhanced in subordinate males and that aggression in female hamsters would be enhanced in dominants and diminished in subordinates. In female rhesus macaques, we hypothesized that chronic fluoxetine would alter socioemotional behaviors and site-specific 5HT1ARBP in a status-dependent manner. Male (n = 46) and female (n = 56) hamsters were paired with conspecifics for three days to establish social rank. Hamsters received a single dose of 20 mg/kg fluoxetine or vehicle two-hours prior to a test with a non-aggressive intruder. Female rhesus monkeys (n = 14) housed were administered fluoxetine (2.8 mg/kg/day) or vehicle injections chronically for 14-days, separated by a three-week washout period. On Day 15, positron emission tomography neuroimaging for 5HT1ARBP was conducted. Fluoxetine treatment decreased aggression in subordinate female monkeys and subordinate female hamsters but not in dominant females of either species. Fluoxetine decreased aggression in dominant but not in subordinate male hamsters. Fluoxetine also reduced and increased prefrontal 5HT1ARBP in dominant and subordinate females, respectively. Taken together, these results provide cross-species evidence that social status and sex impact how increased 5HT modulates agonistic behavior.

Long-term Hyperandrogenemia and/or Western-style Diet in Rhesus Macaque Females Impairs Preimplantation Embryogenesis.

Hyperandrogenemia and obesity are common in women with polycystic ovary syndrome, but it is currently unclear how each alone or in combination contribute to reproductive dysfunction and female infertility. To distinguish the individual and combined effects of hyperandrogenemia and an obesogenic diet on ovarian function, prepubertal female rhesus macaques received a standard control (C) diet, testosterone (T) implants, an obesogenic Western-style diet (WSD), or both (T + WSD). After 5 to 6 years of treatment, the females underwent metabolic assessments and controlled ovarian stimulations. Follicular fluid (FF) was collected for steroid and cytokine analysis and the oocytes fertilized in vitro. Although the T + WSD females exhibited higher insulin resistance compared to the controls, there were no significant differences in metabolic parameters between treatments. Significantly higher concentrations of CXCL-10 were detected in the FF from the T group, but no significant differences in intrafollicular steroid levels were observed. Immunostaining of cleavage-stage embryos revealed multiple nuclear abnormalities in the T, WSD, and T + WSD groups. Single-cell DNA sequencing showed that while C embryos contained primarily euploid blastomeres, most cells in the other treatment groups were aneuploid. Despite yielding a higher number of mature oocytes, T + WSD treatment resulted in significantly reduced blastocyst formation rates compared to the T group. RNA sequencing analysis of individual blastocysts showed differential expression of genes involved in critical implantation processes between the C group and other treatments. Collectively, we show that long-term WSD consumption reduces the capacity of fertilized oocytes to develop into blastocysts and that the addition of T further impacts gene expression and embryogenesis.

Testing the role of testosterone versus estrogens in mediating reproductive transitions in female rhesus macaques

In male vertebrates, testosterone is generally known to coordinate reproductive trade-offs, in part by promoting the transition to the next reproduction at the expense of current parental care. The role of testosterone in reproductive transitions has been little tested in female vertebrates, especially in mammals. The present study sought to fill this gap, by first undertaking an experimental study, in which we identified DHT, androstenediol, and in particular etiocholanolone, as fecal androgen metabolites which reflect serum testosterone concentration in female rhesus macaques (Macaca mulatta). Using concentrations of fecal etiocholanolone as proxy for circulating testosterone, we then conducted a field study on 46 free-ranging rhesus macaques of Cayo Santiago, Puerto Rico, to test if testosterone mediates the trade-off between reproductive transition (a higher chance of reproducing in the next year) and current reproduction (providing more care to current offspring). While the evidence for testosterone was weak, the testing of fecal immunoreactive estrogen metabolites suggested a potential role of estrogen in reproductive trade-offs. We found large individual differences in fecal etiocholanolone concentrations during the early postpartum period that were unexplained even after accounting for sociodemographic factors such as age and dominance rank. Further investigation is needed to understand this variation. Our study suggests that the actions of testosterone in females may not have evolved to fulfil the same role in primate reproductive transitions as it does in males, and we encourage more studies to consider the function of testosterone in reproductive behaviors and life history transitions in females of mammalian taxa.

The ontogeny of sexual dimorphism in free-ranging rhesus macaques.

Reconstructing the social lives of extinct primates is possible only through an understanding of the interplay between morphology, sexual selection pressures, and social behavior in extant species. Somatic sexual dimorphism is an important variable in primate evolution, in part because of the clear relationship between the strength and mechanisms of sexual selection and the degree of dimorphism. Here, we examine body size dimorphism across ontogeny in male and female rhesus macaques to assess whether it is primarily achieved via bimaturism as predicted by a polygynandrous mating system, faster male growth indicating polygyny, or both. We measured body mass in a cross-sectional sample of 364 free-ranging rhesus macaques from Cayo Santiago, Puerto Rico to investigate size dimorphism: 1) across the lifespan; and 2) as an outcome of sex-specific growth strategies, including: a) age of maturation; b) growth rate; and c) total growth duration, using regression models fit to sex-specific developmental curves. Significant body size dimorphism was observed by prime reproductive age with males 1.51 times the size of females. Larger male size resulted from a later age of maturation (males: 6.8-7.8 years versus females: 5.5-6.5 years; logistic model) and elevated growth velocity through the pre-prime period (LOESS model). Though males grew to larger sizes overall, females maintained adult size for longer before senescence (quadratic model). The ontogeny of size dimorphism in rhesus macaques is achieved by bimaturism and a faster male growth rate. Our results provide new data for understanding the development and complexities of primate dimorphism.

Agonism and grooming behaviour explain social status effects on physiology and gene regulation in rhesus macaques.

Variation in social status predicts molecular, physiological and life-history outcomes across a broad range of species, including our own. Experimental studies indicate that some of these relationships persist even when the physical environment is held constant. Here, we draw on datasets from one such study-experimental manipulation of dominance rank in captive female rhesus macaques-to investigate how social status shapes the lived experience of these animals to alter gene regulation, glucocorticoid physiology and mitochondrial DNA phenotypes. We focus specifically on dominance rank-associated dimensions of the social environment, including both competitive and affiliative interactions. Our results show that simple summaries of rank-associated behavioural interactions are often better predictors of molecular and physiological outcomes than dominance rank itself. However, while measures of immune function are best explained by agonism rates, glucocorticoid-related phenotypes tend to be more closely linked to affiliative behaviour. We conclude that dominance rank serves as a useful summary for investigating social environmental effects on downstream outcomes. Nevertheless, the behavioural interactions that define an individual's daily experiences reveal the proximate drivers of social status-related differences and are especially relevant for understanding why individuals who share the same social status sometimes appear physiologically distinct. This article is part of the theme issue 'The centennial of the pecking order: current state and future prospects for the study of dominance hierarchies'.

Characterization of cerebrospinal fluid biomarkers associated with neurodegenerative diseases in healthy cynomolgus and rhesus macaque monkeys.

Monkeys are becoming important translational models of neurodegenerative disease. To facilitate model development, we measured cerebrospinal fluid (CSF) concentrations of key biomarkers in healthy male and female cynomolgus and rhesus macaques. Amyloid beta (Aβ40, Aβ42), tau (total tau [t‐tau], phosphorylated tau [pThr181]), and neurofilament light (NfL) concentrations were measured in CSF of 82 laboratory‐housed, experimentally naïve cynomolgus (n = 33) and rhesus (n = 49) macaques. Aβ40 and Aβ42 were significantly higher in rhesus, and female rhesus were higher than males. NfL and t‐tau were higher in males, and NfL was higher in rhesus macaques. p‐tau was not affected by species or sex. We also examined whether sample location (lumbar or cisterna puncture) affected concentrations. Sample acquisition site only affected NfL, which was higher in CSF from lumbar puncture compared to cisterna magna puncture. Establishing normative biomarker values for laboratory‐housed macaque monkeys provides an important resource by which to compare to monkey models of neurodegenerative diseases.

Issue Information

Ecology and EvolutionVolume 12, Issue 1 e07687 ISSUE INFORMATIONOpen Access Issue Information First published: 10 January 2022 https://doi.org/10.1002/ece3.7687AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Front Cover: An infant and three female adult rhesus macaques (Macaca mulatta) resting in Cayo Santiago, Puerto Rico. Photo by Raisa Hernández-Pacheco. Volume12, Issue1January 2022e07687 RelatedInformation

Normalization by valence and motivational intensity in the sensorimotor cortices (PMd, M1, and S1)

Our brain’s ability to represent vast amounts of information, such as continuous ranges of reward spanning orders of magnitude, with limited dynamic range neurons, may be possible due to normalization. Recently our group and others have shown that the sensorimotor cortices are sensitive to reward value. Here we ask if psychological affect causes normalization of the sensorimotor cortices by modulating valence and motivational intensity. We had two non-human primates (NHP) subjects (one male bonnet macaque and one female rhesus macaque) make visually cued grip-force movements while simultaneously cueing the level of possible reward if successful, or timeout punishment, if unsuccessful. We recorded simultaneously from 96 electrodes in each the following: caudal somatosensory, rostral motor, and dorsal premotor cortices (cS1, rM1, PMd). We utilized several normalization models for valence and motivational intensity in all three regions. We found three types of divisive normalized relationships between neural activity and the representation of valence and motivation, linear, sigmodal, and hyperbolic. The hyperbolic relationships resemble receptive fields in psychological affect space, where a unit is susceptible to a small range of the valence/motivational space. We found that these cortical regions have both strong valence and motivational intensity representations.

Long-term effects of wildfire smoke exposure during early life on the nasal epigenome in rhesus macaques

BackgroundWildfire smoke is responsible for around 20% of all particulate emissions in the U.S. and affects millions of people worldwide. Children are especially vulnerable, as ambient air pollution exposure during early childhood is associated with reduced lung function. Most studies, however, have focused on the short-term impacts of wildfire smoke exposures. We aimed to identify long-term baseline epigenetic changes associated with early-life exposure to wildfire smoke. We collected nasal epithelium samples for whole genome bisulfite sequencing (WGBS) from two groups of adult female rhesus macaques: one group born just before the 2008 California wildfire season and exposed to wildfire smoke during early-life (n = 8), and the other group born in 2009 with no wildfire smoke exposure during early-life (n = 14). RNA-sequencing was also performed on a subset of these samples. ResultsWe identified 3370 differentially methylated regions (DMRs) (difference in methylation ≥ 5%, empirical p < 0.05) and 1 differentially expressed gene (FLOT2) (FDR < 0.05, fold of change ≥ 1.2). The DMRs were annotated to genes significantly enriched for synaptogenesis signaling, protein kinase A signaling, and a variety of immune processes, and some DMRs significantly correlated with gene expression differences. DMRs were also significantly enriched within regions of bivalent chromatin (top odds ratio = 1.46, q-value < 3 × 10-6) that often silence key developmental genes while keeping them poised for activation in pluripotent cells. ConclusionsThese data suggest that early-life exposure to wildfire smoke leads to long-term changes in the methylome over genes impacting the nervous and immune systems. Follow-up studies will be required to test whether these changes influence transcription following an immune/respiratory challenge.

A New Method to Develop the Primate Model of Knee Osteoarthritis With Focal Cartilage Defect.

Objective: Osteoarthritis (OA) is a common degenerative joint disease, and animal models have proven pivotal in investigating this disease. This study aimed to develop a primate model of OA that may be more relevant to research studies on OA in humans. Method: Twelve female rhesus macaques were randomly divided into three groups. Four animals were untreated (Control group); four were subjected to the modified Hulth method, involving cutting of the anterior and posterior cruciate ligaments, and transecting the meniscus (Hulth group); and four were subjected to the modified Hulth method combined with cartilage defect (MHCD group). Each primate was subjected to motor ability tests, and underwent arthroscopic, radiographic, morphological, and pathological observation of the knee joints at various times for up to 180 days. Results: Motor ability on Day 180 was significantly lower in the MHCD group than in the Control (p＜0.01) and Hulth (p＜0.05) groups. Radiographic and morphological examination showed that the severity of knee joint deformity and articular cartilage injury were greater in the MHCD group than in the other groups. Pathological examination showed that cartilage thickness was significantly lower in the MHCD group than in the other groups at the same time points. The Mankin score on Day 180 was markedly higher in the MHCD group than in the Hulth (p＜0.05) and Control (p＜0.001) groups. Conclusion: The MHCD model of OA closely resembles the pathophysiological processes of spontaneous knee OA in humans. The time required to develop knee OA is shorter using the MHCD model than using the Hulth method.

Effects of estradiol supplementation on the brain transcriptome of old rhesus macaques maintained on an obesogenic diet.

Obesity, the cessation of ovarian steroids with menopause, and age are risk factors for mood disorders, dementia, and Alzheimer's disease (AD). However, immediate hormone therapy (HT) after menopause may have beneficial effects in different brain regions involved in memory and cognition. To more closely replicate the age, endocrine, and metabolic environment of obese postmenopausal women, either on or off HT, middle-aged female rhesus macaques were ovariectomized/hysterectomized (OvH) and maintained on a high-fat, high-sugar, obesogenic Western-style diet (WSD) for 30months; half of the animals received HT immediately after OvH and half served as placebo controls. RNAseq of the occipital (OC) and prefrontal cortex (PFC), hippocampus (HIP), and amygdala (AMG) identified 293, 379, 505, and 4993 differentially expressed genes (DEGs), respectively. Pathway enrichment analysis identified an activation of neuroinflammation in OC and HIP, but an inhibition in the AMG with HT. Synaptogenesis, circadian rhythm, mitochondrial dysfunction, mTOR, glutamate, serotonin, GABA, dopamine, epinephrine/norepinephrine, glucocorticoid receptor signaling, neuronal NOS, and amyloid processing were exclusively enriched in AMG. As compared to the placebo control group, most of these signaling pathways are downregulated after HT, suggesting a protective effect of HT in OvH females under a WSD. Overall, our results suggest that a chronic obesogenic diet may induce a wide range of alterations in multiple signaling pathways that are linked to age-associated brain pathology and dementia. In these individuals, HT seems to have a protective effect against neuroinflammation, amyloid beta depositions, and tau tangle formation.

The observed pattern and hidden process of female reproductive trajectories across the life span in a non-human primate.

Age-specific fertility trajectories are fundamental to understanding population structure and the evolutionary ecology of diverse life histories. However, characterizing reproductive ageing has been difficult with cross-sectional data, where senescence especially late in life can be confounded by selective disappearance. Addressing such challenge requires longitudinal data tracking the reproductive life span of known individuals, but such data are rare, especially for very long-lived species such as primates. We analyse the entire life span trajectory of annual fertility, from reproductive maturity to death, for 673 free-ranging female rhesus macaques, Macaca mulatta, on Cayo Santiago, Puerto Rico. Using generalized linear mixed-effects models (GLMMs), we first tested if time to death explains the ageing pattern independently of and additionally to chronological age, and if so, whether there is interaction between them. While GLMM captures the patterns in the data well, it is not a generative model. For example, given the GLMM and an individual's reproductive trajectory up to a given age, we cannot directly predict the probability of reproduction or death in the next year. For this reason, we further fitted a hidden Markov chain model (HMM) which allows just such a prediction, and additionally helps infer the process underlying the observed trajectory. We show that, after accounting for individual differences in fertility, reproductive ageing exhibits both age-dependent decline and also an abrupt terminal decline independently of age at death. We infer from the HMM that the underlying process of reproductive trajectory is where individuals cycle between reproductive bouts until they enter an irreversible frail condition that constrains fertility. The findings provide valuable insights into the longitudinal progression of reproductive trajectories in primates, by revealing both age-dependent and age-independent patterns and processes of ageing, and contribute to a growing body of literature on reproductive ageing and senescence across animal taxa.

Chronic binge alcohol and ovariectomy-mediated impaired insulin responsiveness in SIV-infected female rhesus macaques.

Aging people living with HIV (PLWH), especially postmenopausal women may be at higher risk of comorbidities associated with HIV, antiretroviral therapy (ART), hypogonadism, and at-risk alcohol use. Our studies in simian immunodeficiency virus (SIV)-infected male macaques demonstrated that chronic binge alcohol (CBA) reduced acute insulin response to glucose (AIRG), and at-risk alcohol use decreased HOMA-β in PLWH. The objective of this study was to examine the impact of ovariectomy (OVX) on glucose-insulin dynamics and integrity of pancreatic endocrine function in CBA/SIV-infected female macaques. Female macaques were administered CBA (12-15 g/kg/wk) or isovolumetric water (VEH) intragastrically. Three months after initiation of CBA/VEH administration, all macaques were infected with SIVmac251, and initiated on antiretroviral therapy (ART) 2.5 mo postinfection. After 1 mo of ART, macaques were randomized to OVX or sham surgeries (n = 7 or 8/group), and euthanized 8 mo post-OVX (study endpoint). Frequently sampled intravenous glucose tolerance tests (FSIVGTT) were performed at selected time points. Pancreatic gene expression and islet morphology were determined at study endpoint. There was a main effect of CBA to decrease AIRG at Pre-SIV and study endpoint. There were no statistically significant OVX effects on AIRG (P = 0.06). CBA and OVX decreased the expression of pancreatic markers of insulin docking and release. OVX increased endoplasmic stress markers. CBA but not OVX impaired glucose-insulin expression dynamics in SIV-infected female macaques. Both CBA and OVX altered integrity of pancreatic endocrine function. These findings suggest increased vulnerability of PLWH to overt metabolic dysfunction that may be exacerbated by alcohol use and ovarian hormone loss.

Between-subject and within-subject variability in measures of biochemical markers of bone turnover in cynomolgus and rhesus macaques

Development of optimal bone mass during early adulthood is determined by the balance between bone formation and resorption. The utility of minimally invasive biomarkers for monitoring bone turnover balance in maturing non-human primates has received limited attention. This study evaluated the biological variation of osteocalcin (a marker of bone formation), carboxyterminal cross-linking telopeptide of type 1 collagen (CTX, a marker of bone resorption), and the ratio of osteocalcin to CTX (reflecting bone turnover balance), in 136 rhesus and cynomolgus macaques aged 3.8–11.6 years. In a subsample of the animals (n = 28), blood samples were collected at monthly intervals over 4 months. Between-subject analysis revealed that there were no sex or species differences for CTX. Osteocalcin and the ratio of osteocalcin to CTX were higher in males than in females, and in rhesus macaques than in cynomolgus macaques. There were no changes in osteocalcin, CTX, or the ratio of osteocalcin to CTX across 4 months for any of the groups. In contrast, there was considerable within-subject variation in osteocalcin and CTX concentrations. However, differences in values exhibited no discernible pattern, suggesting that within-subject variation can be reduced by averaging repeat measurements. In summary, the data provide reference values for male and female rhesus and cynomolgus macaques and support the utility of osteocalcin and CTX as biomarkers to monitor bone turnover at the population level.

Temperament Predicts the Quality of Social Interactions in Captive Female Rhesus Macaques (Macaca mulatta).

Simple SummaryRhesus macaques are highly social animals that are used extensively in research. Providing them with a supportive social environment by pairing individuals with compatible partners improves their life quality and also their use as research animals. Therefore, identifying suitable social partners will benefit both the animals and the science. Previous work showed that female rhesus macaques were more likely to form successful pairs that exhibit little aggression if they showed similarities in certain personality traits measured in infancy. In the current study, we assessed the relationships between the same personality traits and the quality of social interactions between partners. This is important since by ensuring that animals benefit the most from being paired to a compatible partner, we are more likely to expose the animals to positive experiences instead of simply avoiding negative ones. We found that pairs with similar emotionality scores showed more positive social interactions, and pairs with similar nervous temperament used fewer behavioral signals to communicate their dominance relationship. Moreover, pairs that paid more attention to unfamiliar monkey faces were more anxious. These results highlight the importance of taking the animals’ personalities into consideration when attempting to match social partners and provide them with an environment that fits their needs.Previous reports suggest that female macaques with greater similarity in emotionality and nervous temperament, as evaluated in a well-established BioBehavioral Assessment (BBA) at the California National Primate Research Center, were more likely to form successful pairs. We tested whether the same measures can also predict the quality of social interactions among 20 female rhesus macaque pairs. We correlated the pairs’ emotionality and nervous temperament scores obtained in infancy and the levels of behaviors recorded systematically during the pairing process years later. Supporting previous findings, partners with similar emotionality scores were more affiliative, and pairs with similar nervous temperament expressed less dominance/submissive behavior. Exploratorily, we found that pairs that were better at processing social information (part of BBA) were also more anxious. Such animals should be prioritized to be introduced in rooms that house calmer, less aggressive animals and provide opportunities for hiding to alleviate their anxiety. Indeed, positive social experiences not only promote animal welfare, but also reduce stress related confounds and unexplained data variability. Therefore, by incorporating the animals’ temperament into the pair configuration process we increase the likelihood of forming high-quality pairs, both in terms of welfare and the research of which they are a part.

Preclinical evaluation of (S)-[18F]GE387, a novel 18-kDa translocator protein (TSPO) PET radioligand with low binding sensitivity to human polymorphism rs6971

PurposePositron emission tomography (PET) studies with radioligands for 18-kDa translocator protein (TSPO) have been instrumental in increasing our understanding of the complex role neuroinflammation plays in disorders affecting the brain. However, (R)-[11C]PK11195, the first and most widely used TSPO radioligand has limitations, while the next-generation TSPO radioligands have suffered from high interindividual variability in binding due to a genetic polymorphism in the TSPO gene (rs6971). Herein, we present the biological evaluation of the two enantiomers of [18F]GE387, which we have previously shown to have low sensitivity to this polymorphism.MethodsDynamic PET scans were conducted in male Wistar rats and female rhesus macaques to investigate the in vivo behaviour of (S)-[18F]GE387 and (R)-[18F]GE387. The specific binding of (S)-[18F]GE387 to TSPO was investigated by pre-treatment with (R)-PK11195. (S)-[18F]GE387 was further evaluated in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Sensitivity to polymorphism of (S)-GE387 was evaluated in genotyped human brain tissue.Results(S)-[18F]GE387 and (R)-[18F]GE387 entered the brain in both rats and rhesus macaques. (R)-PK11195 blocked the uptake of (S)-[18F]GE387 in healthy olfactory bulb and peripheral tissues constitutively expressing TSPO. A 2.7-fold higher uptake of (S)-[18F]GE387 was found in the inflamed striatum of LPS-treated rodents. In genotyped human brain tissue, (S)-GE387 was shown to bind similarly in low affinity binders (LABs) and high affinity binders (HABs) with a LAB to HAB ratio of 1.8.ConclusionWe established that (S)-[18F]GE387 has favourable kinetics in healthy rats and non-human primates and that it can distinguish inflamed from normal brain regions in the LPS model of neuroinflammation. Crucially, we have reconfirmed its low sensitivity to the TSPO polymorphism on genotyped human brain tissue. Based on these factors, we conclude that (S)-[18F]GE387 warrants further evaluation with studies on human subjects to assess its suitability as a TSPO PET radioligand for assessing neuroinflammation.

Effect of Housing Conditions on Cortisol and Body Fat Levels in Female Rhesus Macaques.

Simple SummaryMacaques are highly social animals and commonly used in biomedical research. These studies often require group-living animals to be pair-housed in a controlled environment. This controlled environment likely affects stress and body fat levels. This study investigates the effect of a change from group- to pair-housing on cortisol, as measure for stress, and body fat levels of 32 female rhesus macaques. Besides individual differences, cortisol levels were higher in pair-housing compared to group-housing. Body fat levels did not differ between housing conditions. Accordingly, there was no clear association between cortisol and body fat levels.Macaques are among the most commonly used non-human primates in biomedical research. They are highly social animals, yet biomedical studies often require group-living animals to be pair-housed in a controlled environment. A change in environment causes only short-term stress in adapting individuals, while non-adapting animals may experience long-term stress that can adversely affect study results. Individuals likely differ in their ability to adapt depending on individual characteristics. Changes in cortisol and body fat levels may reflect these different individual responses. Here, we investigate the long-term effect of a change from group- to pair-housing on cortisol and body fat levels in 32 female rhesus macaques, exploring whether age, dominance rank, original cortisol, and body fat levels are related to long-term stress in pair-housing. Hair samples were analyzed for cortisol levels, while anthropometric measurements and computed tomography were performed to quantify body fat. Monkeys served as their own control with a 7.5-month period between the measurements. Cortisol levels increased, while average body fat levels did not differ when individuals were moved from group- to pair-housing. Cortisol and body fat levels were not significantly correlated. Changes in cortisol were independent of age and dominance rank, whereas individual variation in body fat alterations was related to the group-housed body fat level and dominance rank. Although this study did not identify individual characteristics related to long-term stress in pair-housing, the individual variation confirms that some individuals are more resilient to change than others and provides possibilities for future refinement studies.

Factors influencing the success of male introductions into groups of female rhesus macaques: Introduction technique, male characteristics and female behavior.

In captive populations of rhesus macaques, novel adult males are commonly introduced to female groups every few years to prevent inbreeding, which mimics male dispersal in wild macaque populations. However, introducing adult males is challenging because macaques are aggressive to newcomers, which can result in serious injuries. Efforts to reduce trauma risk during the introduction process and increase the probability of success are needed. Here we investigate the impact of multiple factors, including male attributes (e.g., age, weight, rank, and experience), introduction method (punctuated vs. continual exposure to females), and female behavior, on males' trauma risk and integration success. We studied eight introductions of multimale cohorts (3-7 males each; N = 36 total) into existing female groups of rhesus macaques at the Yerkes National Primate Research Center. Four cohorts were introduced using the punctuated exposure method where adult males were moved each morning from run housing to the females' indoor enclosure and returned to run housing in the afternoon, and four cohorts were introduced using the continual exposure method where adult males were moved to an introduction enclosure attached to the females' outdoor compound, allowing males to live in protected contact next to the female group continuously. Generalized linear mixed models fitted to trauma risk (e.g., latency to first trauma; total trauma count) and success or failure to integrate (i.e., continual residence within the female group for greater than 53% of days within a 28-day window after first overnight stay) showed that continual exposure to females in the introduction enclosure reduced male trauma risk and increased the likelihood of successful integration compared to punctuated exposure. Males received less trauma when they received a higher rate of grooming from females. Male attributes had no effect. These findings highlight the importance of introduction technique and female behavior in the process of males' social integration into female groups.

Gene expression changes in male and female rhesus macaque 60 days after irradiation.

PurposeTranscriptome changes can be expected in survivors after lethal irradiation. We aimed to characterize these in males and females and after different cytokine treatments 60 days after irradiation.Material and methodsMale and female rhesus macaques (n = 142) received a whole-body exposure with 700 cGy, from which 60 animals survived. Peripheral whole blood was drawn pre-exposure and before sacrificing the surviving animals after 60 days.ResultsWe evaluated gene expression in a three-phase study design. Phase I was a whole-genome screening (NGS) for mRNAs using five pre- and post-exposure RNA samples from both sexes (n = 20). Differential gene expression (DGE) was calculated between samples of survivors and pre-exposure samples (reference), separately for males and females. 1,243 up- and down-regulated genes were identified with 30–50% more deregulated genes in females. 37 candidate mRNAs were chosen for qRT-PCR validation in phase II using the remaining samples (n = 117). Altogether 17 genes showed (borderline) significant (t-test) DGE in groups of untreated or treated animals. Nine genes (CD248, EDAR, FAM19A5, GAL3ST4, GCNT4, HBG2/1, LRRN1, NOG, SYT14) remained with significant changes and were detected in at least 50% of samples per group. Panther analysis revealed an overlap between both sexes, related to the WNT signaling pathway, cell adhesion and immunological functions. For phase III, we validated the nine genes with candidate genes (n = 32) from an earlier conducted study on male baboons. Altogether 14 out of 41 genes showed a concordantly DGE across both species in a bilateral comparison.ConclusionsSixty days after radiation exposure, we identified (1) sex and cytokine treatment independent transcriptional changes, (2) females with almost twice as much deregulated genes appeared more radio-responsive than males, (3) Panther analysis revealed an association with immunological processes and WNT pathway for both sexes.