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Food supply is one of the major drivers of animal behavior, and the gut microbiome is an important mediator between food supply and its effects on physiology. However, predicting the outcome of diet change on microbiome and consequences for the animal has proven extremely challenging. We propose this reflects processes occurring at different scales. Inadequate accounting for the multi-level complexity of nutrition (nutrients, foods, diets) obscures the diet influence on microbiome and subsequently animal. Here, we present a detailed year-round, multi-level analysis of diet and microbiome changes in a wild population of a temperate primate, the rhesus macaque (Macaca mulatta). Total daily food and nutrient intake of 6 male and 6 female macaques was monitored in each of the 4 seasons (total 120 days observations). For each individual, we found significant variation in the microbiome between all 4 seasons. This response was more strongly correlated with changes in macronutrient intake than with food items and much of the response could be explained at the level of 6 ecological guilds-sets of taxa sharing similar responses to nutrient intake. We conclude that study of diet, microbiome, and animal performance in ecology will more effectively identify patterns if diet is recorded at the level of nutrient intake. Although microbiome response to diet does show variation in species-level taxa in response to food items, there is greater commonality in response at the level of guilds. A goal for microbiome researchers should be to identify genes encoding microbial attributes that can define such guilds.

Anthropogenic land-use changes increase the frequency of interactions and habitat overlap between humans and macaques which play an important role in zoonotic disease transmission. This exploratory qualitative study aimed to examine connections between land-use change and macaque-human interactions and assess the chance of zoonotic disease transmission. We conducted ethnographic interviews and focus group discussions in Old Dhaka, Madaripur, and Chandpur, Bangladesh. Participants reported significant anthropogenic landscape transformations leading to increased human-macaque contact in the study areas. Participants also reported that all three sites underwent substantial landscape alteration from natural or agricultural land to a human-altered environment with roads, commercial, and residential buildings. Participants noted that the disappearance of forestland appeared to increase the macaque dependence on backyard fruit trees. Where rivers and ponds were filled to support local construction, macaques were also observed as becoming more dependent upon human water sources. These changed may help expanding the macaques' foraging areas, and they appear to be invading new areas where people are not culturally habituated to living with them. In response, many residents reported reacting aggressively toward the macaques, which they believed led to more bites and scratches. However, other respondents accepted the presence of macaques around their homes. Few participants considered macaques to be a source of disease transmission. This study revealed that local environmental changes, deforestation, urban expansion, construction, and water bodies' disappearance are linked to increasing human-macaque interactions. Understanding these interactions is critical to develop successful mitigation interventions at interfaces with a high risk for viral disease spillover.

The technology, methodology and models used by visual neuroscientists have provided great insights into the structure and function of individual brain areas. However, complex cognitive functions arise in the brain due to networks comprising multiple interacting cortical areas that are wired together with precise anatomical connections. A prime example of this phenomenon is the frontal–parietal network and two key regions within it: the frontal eye fields (FEF) and lateral intraparietal area (area LIP). Activity in these cortical areas has independently been tied to oculomotor control, motor preparation, visual attention and decision-making. Strong, bidirectional anatomical connections have also been traced between FEF and area LIP, suggesting that the aforementioned visual functions depend on these inter-area interactions. However, advancements in our knowledge about the interactions between area LIP and FEF are limited with the main animal model, the rhesus macaque, because these key regions are buried in the sulci of the brain. In this review, we propose that the common marmoset is the ideal model for investigating how anatomical connections give rise to functionally-complex cognitive visual behaviours, such as those modulated by the frontal–parietal network, because of the homology of their cortical networks with humans and macaques, amenability to transgenic technology, and rich behavioural repertoire. Furthermore, the lissencephalic structure of the marmoset brain enables application of powerful techniques, such as array-based electrophysiology and optogenetics, which are critical to bridge the gaps in our knowledge about structure and function in the brain.

Human-modified landscapes play an important role in supporting the survival of primate populations, but they may also facilitate human–primate interactions, possibly leading to negative outcomes. We conducted a scalar investigation of the role of landscape structure in shaping the intensity of crop feeding by a generalist primate species, the rhesus macaque (Macaca mulatta) in northern India. At the species level, we used behavioral sampling techniques to assess habitat selection by two groups of rhesus macaques. At the landscape level, we used GIS-based analyses to quantify landscape structure in terms of class-level and patch-level metrics and correlated it with macaque crop feeding intensities. We found that, on average, both study groups spent only 15% of their total feeding time on cultivars. However, they spent a large proportion of their feeding (BH: 75% and CH: 36%) and ranging (BH: 72% and CH: 39%) time in agroecosystem habitats. Landscape level analysis showed that crop feeding intensity was not related to total area under cultivation. Instead, macaque crop feeding intensity was positively correlated to the arrangement of deciduous forest patches beside cultivated area patches. Our findings call for careful appraisal of landscape management practices as a potential mitigation strategy for primate crop-depredation in such human-modified landscapes.

[Aim] Understanding patterns and processes of geographic genetic variation within and among closely related species is the essence of phylogeography. Japanese macaques, also called snow monkeys, have been extensively studied, particularly in the fields of sociobiology, ecology and experimental biology; however, our knowledge of their evolutionary history is relatively limited. In this study we aimed to elucidate the geographic patterns of genetic variation in Japanese macaques and the processes that underlie them. [Location] Japan. [Taxa] Japanese macaque, Macaca fuscata; rhesus macaque, M. mulatta; Taiwanese macaque, M. cyclopis. [Methods] Double-digest restriction site-associated DNA (RAD) sequencing was used to identify genome-wide single nucleotide variants. We used fineRADstructure, ADMIXTURE and principal component analyses to estimate the genetic population structure. Phylogenetic relationships were then inferred based on neighbour-net, neighbour-joining, maximum likelihood and SVDquartets algorithms. We assessed gene flow using demographic inference and ABBA-BABA tests, and estimated past distributions during the Last Glacial Maximum (LGM) using ecological niche modelling. [Results] Japanese macaques show a sister group relationship with a clade comprising Chinese rhesus, Indian rhesus and Taiwanese macaques. Japanese macaques comprise major north-eastern and south-western clades, with a boundary located near central Japan, and gene flow between the north-eastern and south-western lineages was detected. Refugia during the LGM were estimated to be distributed in limited areas along the south coasts of the Japanese archipelago. [Main conclusions] Phylogeographic variation of Japanese macaques is likely due mainly to northeast–southwest divergence, which resulted from withdrawal into refugia during the glacial period, and subsequent gene flow.

Background The prevalent resurgence of pertussis has recently become a critical public health problem worldwide. To understand pertussis pathogenesis and the host response to both the pathogen and vaccines, a suitable pertussis animal model, particularly a non-human primate model, is necessary. Recently, a non-human primate pertussis model was successfully established with baboons. Rhesus macaques have been shown to be ideal animal models for several infectious diseases, but a model of infectious pertussis has not been established in these organisms. Studies on rhesus macaque models of pertussis were performed in the 1920s–1930s, but limited experimental details are available. Recent monkey pertussis models have not been successful because the typical clinical symptoms and transmission have not been achieved. Methods In the present study, infant rhesus macaques were challenged with Bordetella pertussis (B.p) using an aerosol method to evaluate the feasibility of this system as an animal model of pertussis. Results Upon aerosol infection, monkeys infected with the recently clinically isolated B.p strain 2016-CY-41 developed the typical whooping cough, leukocytosis, bacteria-positive nasopharyngeal wash (NPW), and interanimal transmission of pertussis. Both systemic and mucosal humoral responses were induced by B.p. Conclusion These results demonstrate that a model of pertussis was successfully established in infant rhesus macaques. This model provides a valuable platform for research on pertussis pathogenesis and evaluation of vaccine candidates.

Subcutaneous injection site reactions to sustained-release buprenorphine hydrochloride (Buprenorphine SR) in macaques have been reported in only a single case report. In the current study, we evaluated the incidence rate and predictors of buprenorphine SR reactions in the subcutaneous tissue of rhesus macaques (Macaca mulatta) based on retrospective review of macaque buprenorphine SR injection records. Potentially predictive variables were identified with logistic regression modeling and were evaluated using model selection based on Akaike information criterion. Record review revealed sub- cutaneous tissue reactions occurred in 52 (3%) of 1559 injections and were noted between 4 and 311 d after injection. Model selection showed that body weight and MHC allele Mamu-B*29 were the best predictors of subcutaneous reactions. Based on these results, we recommend consideration of potential risk factors prior to the administration of buprenorphine SR to a rhesus macaque. In addition, the authors advise that using the highest concentration of buprenorphine SR available may reduce injection site reaction rates due to the injection of less copolymer.

Ex vivo hematopoietic stem and progenitor cell (HSPC) expansion platforms are under active development, designed to increase HSPC numbers and thus engraftment ability of allogeneic cord blood grafts or autologous HSPCs for gene therapies. Murine and in vitro models have not correlated well with clinical outcomes of HSPC expansion, emphasizing the need for relevant pre-clinical models. Our rhesus macaque HSPC competitive autologous transplantation model utilizing genetically barcoded HSPC allows direct analysis of the relative short and long-term engraftment ability of lentivirally transduced HSPCs, along with additional critical characteristics such as HSPC clonal diversity and lineage bias. We investigated the impact of ex vivo expansion of macaque HSPCs on the engineered endothelial cell line (E-HUVECs) platform regarding safety, engraftment of transduced and E-HUVEC-expanded HSPC over time compared to non-expanded HSPC for up to 51 months post-transplantation, and both clonal diversity and lineage distribution of output from each engrafted cell source. Short and long-term engraftment were comparable for E-HUVEC expanded and the non-expanded HSPCs in both animals, despite extensive proliferation of CD34+ cells during 8 days of ex vivo culture for the E-HUVEC HSPCs, and optimization of harvesting and infusion of HSPCs co-cultured on E-HUVEC in the second animal. Long-term hematopoietic output from both E-HUVEC expanded and unexpanded HSPCs was highly polyclonal and multilineage. Overall, the comparable HSPC kinetics of macaques to humans, the ability to study post-transplant clonal patterns, and simultaneous multi-arm comparisons of grafts without the complication of interpreting allogeneic effects makes our model ideal to test ex vivo HSPC expansion platforms, particularly for gene therapy applications., Graphical Abstract, The rhesus macaque barcoded autologous competitive repopulation preclinical transplantation model was utilized to study the engraftment and safety of hematopoietic stem and progenitor cells expanded in co-culture with E4ORF-1 gene transduced human umbilical vein endothelial cell as compared to non-expanded cells, documenting polyclonal long-term multilineage hematopoiesis.

Retinitis pigmentosa (RP) is a form of inherited retinal degenerative diseases that ultimately involves the macula, which is present in primates but not in the rodents. Therefore, creating nonhuman primate (NHP) models of RP is of critical importance to study its mechanism of pathogenesis and to evaluate potential therapeutic options in the future. Here we applied adeno-associated virus (AAV)-delivered CRISPR/SaCas9 technology to knockout the RHO gene in the retinae of the adult rhesus macaque (Macaca mulatta) to investigate the hypothesis whether non-germline mutation of the RHO gene is sufficient to recapitulate RP. Through a series of studies, we were able to demonstrate successful somatic editing of the RHO gene and reduced RHO protein expression. More importantly, the mutant macaque retinae displayed clinical RP phenotypes, including photoreceptor degeneration, retinal thinning, abnormal rod subcellular structures, and reduced photoresponse. Therefore, we suggest somatic editing of the RHO gene is able to phenocopy RP, and the reduced time span in generating NHP mutant accelerates RP research and expands the utility of NHP model for human disease study.

The cynomolgus macaque is a non-human primate species widely used in drug metabolism studies. Despite the importance of genetic polymorphisms in cytosolic aldehyde oxidase (AOX) 1 in humans, genetic variants have not been investigated in cynomolgus or rhesus macaques.Genetic variants in AOX1 were identified and allele frequencies were assessed using the genomes of 24 cynomolgus and 8 rhesus macaques. The analysis identified 38 non-synonymous variants, some of which were unique to cynomolgus macaques (bred in Cambodia, Indochina, or Indonesia) or rhesus macaques, whereas many variants were shared by the two lineages.Among the variants observed at relatively high frequencies, eight were selected for functional analysis. Recombinant P605L and V1338I AOX1 variants showed substantially lower phthalazine and carbazeran oxidation activities than the wild-type AOX1 protein.In liver cytosolic fractions from cynomolgus and rhesus macaques genotyped for P605L and V1338I AOX1, groups of cytosolic fractions with P605L and/or V1338I AOX1 variants showed significantly lower phthalazine and carbazeran oxidation activities than the wild type.These results indicate that AOX1 is polymorphic in cynomolgus and rhesus macaques, just as it is in humans. Further investigation is needed to reveal the functional significance of these AOX1 variants in drug metabolism.

The rhesus macaque (Macaca mulatta) is the most widely distributed nonhuman primate species, and captive populations play an important role in biomedical research due to close phylogenetic and physiological similarity to human beings. However, to our best knowledge, the spondyloarthritis (SpA) in rhesus macaques has been exclusively reported in captive or semicaptive populations rather than wild counterparts. In the present study, we report 2 cases of SpA observed in Taihangshan macaques (Macaca mulatta tcheliensis) inhabiting the Taihangshan Macaque National Nature Reserve, Henan Province, China. Among these 2 cases, one can be diagnosed as ankylosing spondylitis (AS) following accepted medical criteria, and another case showed evident fusion at the pubic symphysis which could be specific to rhesus macaque AS. We discuss the potential causes leading directly or indirectly to the development of SpA.

Cryptococcus gattii was diagnosed in two female indoor-housed rhesus macaques. Gross and histopathologic findings included an isolated pulmonary cryptococcoma in a non-SIV-infected macaque and disseminated disease centered on the lungs of an SIV-infected macaque. Fungal yeast were positive with special stains, and the diagnoses were confirmed with a lateral flow assay and PCR.

A comparative study on grooming behavior was done on three species of macaques, namely, Assamese macaque (Macaca assamensis), rhesus macaque (Macaca mulatta) and northern pig-tailed macaque (Macaca leonina) under captivity in Aizawl Zoological Park, Aizawl, India. Observations were recorded by Focal Sampling Technique. Time spent on different acts of grooming, and grooming visible and non-visible sites was recorded. Generally 75% of the time was spent on removal of ectoparasite and skin flakes (hygiene related acts). The time spent on various grooming acts varied in different age and sex categories in all three species. Time spent on grooming visible and non-visible sites was more in the Assamese macaque. Time spent on visible and non-visible site by all age and sex categories in all three species was found to be significant (p

A 5 years-old Rhesus macaque was presented with abdominal enlargement. The clinical, radiographic and ultrasonographic findings suggested that a massive mass occupying the whole of the abdomen. The mass was surgically removed, and histopathology confirmed ovarian teratoma. The macaque recovered uneventfully; however, the management to avoid self-mutilation of skin sutures was challenging.

Given their genetic and anatomic similarities to humans, nonhuman primates (NHPs) may serve as animal models for urogenital diseases of humans. The purpose of this study was to examine the frequency of spontaneous urogenital lesions occurring over a 30-year period at the Yerkes and Southwest National Primate Research Centers and to compare and contrast lesions occurring in Old World versus New World primates. Lesions occurring in the chimpanzee ( Pan troglodytes), baboon ( Papio spp.), rhesus macaque ( Macaca mulatta), cynomolgus macaque ( Macaca fascicularis), pig-tailed macaque ( Macaca nemestrina), sooty mangabey ( Cercocebus atys), common marmoset ( Callithrix jacchus), cotton-top tamarin ( Sanguinus oedipus), and squirrel monkey ( Saimiri sciureus) are discussed. The most common lesions of the kidney were medullary amyloidosis, renal cysts, renal tubular degeneration, glomerulonephritis or glomerulopathy, nephritis, nephrocalcinosis, pyelonephritis, and hydronephrosis. Specific causes of renal tubular disease included pigmentary nephrosis and tubular lipidosis. Renal tumors, including renal adenoma and carcinoma, lymphoma, and nephroblastoma, were infrequent diagnoses in all species. Endometriosis was the most frequently diagnosed lesion of the female genital tract. Of the animals examined in this study, it was most frequent in Old World primates. Leiomyoma was the most common uterine tumor. Granulosa cell tumor was the most frequently observed neoplasm of the ovaries, followed by teratoma. Of animals included in the study, most ovarian tumors occurred in baboons. Neoplasms of the male reproductive tract included interstitial cell tumor, seminoma, penile squamous cell carcinoma, penile papilloma, and histiocytoma. In New World monkeys, renal lesions were reported more frequently than genital lesions.

Species in the genus Macaca typically live in multimale-multifemale social groups with male macaques exhibiting some of the largest testis: body weight ratios among primates. Males are believed to experience intense levels of sperm competition. Several spermatogenesis genes are located on the Y-chromosome and, interestingly, occasional hybridization between two species has led to the introgression of the rhesus macaque (Macaca mulatta) Y-chromosome deep into the range of the long-tailed macaque (M. fascicularis). These observations have led to the prediction that the successful introgression of the rhesus Y-haplotype is due to functional differences in spermatogenesis genes compared to those of the native long-tailed Y-haplotype. We examine here four Y-chromosomal loci-RBMY, XKRY, and two nearly identical copies of CDY-and their corresponding protein sequences. The genes were surveyed in representative animals from north of, south of, and within the rhesus x long-tailed introgression zone. Our results show a series of non-synonymous amino acid substitutions present between the two Y-haplotypes. Protein structure modeling via I-TASSER revealed different folding patterns between the two species' Y-proteins, and functional predictions via TreeSAAP further reveal physicochemical differences as a result of non-synonymous substitutions. These differences inform our understanding of the evolution of primate Y-proteins involved in spermatogenesis and, in turn, have biomedical implications for human male fertility.

Nonhuman primates are excellent models for studying human placentation as experimental manipulations in vitro can be translated to in vivo pregnancy. Our objective was to develop macaque trophoblast stem cells (TSCs) as an in vitro platform for future assessment of primate trophoblast development and function. Macaque TSC lines were generated by isolating first and second trimester placental villous cytotrophoblasts followed by culture in TSC medium to maintain cellular proliferation. TSCs grew as mononuclear colonies, whereas upon induction of syncytiotrophoblast (ST) differentiation multinuclear structures appeared, indicative of syncytium formation. Chorionic gonadotropin secretion was > 4000-fold higher in ST culture media compared to TSC media. The secretion of chorionic gonadotropin by TSC-derived ST reflects a reprogramming of macaque TSCs to an earlier pregnancy phenotype. Characteristic trophoblast hallmarks were defined in TSCs and ST including expression of C19MC miRNAs and the macaque placental nonclassical MHC class I molecule, Mamu-AG. Extravillous trophoblasts (EVTs) were derived that express macaque EVT markers Mamu-AG and CD56, and also secrete high levels of MMP2. Our analyses of macaque TSCs suggests that these cells represent a proliferative, self-renewing population capable of differentiating to STs and EVTs in vitro thereby establishing an experimental model of primate placentation.

Mutations play a key role in the development of disease in an individual and the evolution of traits within species. Recent work in humans and other primates has clarified the origins and patterns of single-nucleotide variants, showing that most arise in the father’s germline during spermatogenesis. It remains unknown whether larger mutations, such as deletions and duplications of hundreds or thousands of nucleotides, follow similar patterns. Such mutations lead to copy-number variation (CNV) within and between species, and can have profound effects by deleting or duplicating genes. Here, we analyze patterns of CNV mutations in 32 rhesus macaque individuals from 14 parent–offspring trios. We find the rate of CNV mutations per generation is low (less than one per genome) and we observe no correlation between parental age and the number of CNVs that are passed on to offspring. We also examine segregating CNVs within the rhesus macaque sample and compare them to a similar data set from humans, finding that both species have far more segregating deletions than duplications. We contrast this with long-term patterns of gene copy-number evolution between 17 mammals, where the proportion of deletions that become fixed along the macaque lineage is much smaller than the proportion of segregating deletions. These results suggest purifying selection acting on deletions, such that the majority of them are removed from the population over time. Rhesus macaques are an important biomedical model organism, so these results will aid in our understanding of this species and the disease models it supports.

Interlaminar astrocytes (ILAs) are a subset of cortical astrocytes that reside in layer I, express GFAP, have a soma contacting the pia, and contain long interlaminar processes that extend through several cortical layers. We studied the prenatal and postnatal development of ILAs in three species of primates (rhesus macaque, chimpanzee, and human). We found that ILAs are generated prenatally likely from radial glial (RG) cells, that ILAs proliferate locally during gestation, and that ILAs extend interlaminar processes during postnatal stages of development. We showed that the density and morphological complexity of ILAs increase with age, and that ILAs express multiple markers that are expressed by RG cells (Pax6, Sox2, and Nestin), specific to inner and outer RG cells (Cryab and Hopx), and astrocyte markers (S100β, Aqp4, and GLAST) in prenatal stages and in adult. Finally, we demonstrated that rudimentary ILAs in mouse also express the RG markers Pax6, Sox2, and Nestin, but do not express S100β, Cryab, or Hopx, and that the density and morphological complexity of ILAs differ between primate species and mouse. Together these findings contribute new information on astrogenesis of this unique class of cells and suggest a lineal relationship between RG cells and ILAs.

Increased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single-cell RNA sequencing (scRNAseq). From ∼24,000 single-cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque ( Macaca fascicularis ), rhesus macaque ( Macaca mulatta ), pig ( Sus scrofa ), and mouse ( Mus musculus ). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma and for using model systems to assess mechanisms and potential interventions.

Resource partitioning reduces the competition between different species within the same habitat, promoting their coexistence. To understand how such species co-adapt to reduce conflicts, we examined the behavior of two primates, Assamese macaque (Macaca assamensis) and rhesus macaque (Macaca mulatta), from April 2017 to March 2018 in Sivapuri Nagarjun National Park (SNNP), Kathmandu Valley, Nepal. We performed 1580 and 1261 scan sessions on wild multi-male/multi-female groups of Assamese and rhesus macaques, respectively, at 15-min sampling intervals. Assamese macaques consumed fewer plant species (38 species) than rhesus macaques (88 species). Overlapping food sources between the macaque species resulted in a Pianka index of 0.5. Assamese macaques consumed more items of tree, climber, and vine species, whereas rhesus macaques fed on more shrub, herb, and grass species. The proportions of plant parts consumed by the two species differed—more leaves, fruits and cones were used by Assamese macaques than rhesus macaques, whereas more flowers, seeds, and pods were consumed by rhesus macaques than Assamese macaques. Assamese macaques had a smaller home range (0.55 km2) than rhesus macaques (4.23 km2), and Assamese macaques had a shorter daily moving distance (1.6 km) than rhesus macaques (4.0 km). Although feeding time did not differ between the two macaque species, less time was devoted to social activities by Assamese macaques (16.0%) than by rhesus macaques (33.7%). Assamese macaques were generally arboreal, with 94.0% of their activities in trees, whereas rhesus macaques were largely terrestrial, with 58.5% of their activities on the ground. These differences in food selection, home-range size, ranging and activity patterns, and habitat use suggest that Assamese and rhesus macaques reduce resource competition through resource partitioning to coexist in a landscape matrix.

The rhesus macaque is a prime model animal in neuroscience. A comprehensive transcriptomic and open chromatin atlas of the rhesus macaque brain is key to a deeper understanding of the brain. Here we characterize the transcriptome of 416 brain samples from 52 regions of 8 rhesus macaque brains. We identify gene modules associated with specific brain regions like the cerebral cortex, pituitary, and thalamus. In addition, we discover 9703 novel intergenic transcripts, including 1701 coding transcripts and 2845 lncRNAs. Most of the novel transcripts are only expressed in specific brain regions or cortical regions of specific individuals. We further survey the open chromatin regions in the hippocampal CA1 and several cerebral cortical regions of the rhesus macaque brain using ATAC-seq, revealing CA1- and cortex-specific open chromatin regions. Our results add to the growing body of knowledge regarding the baseline transcriptomic and open chromatin profiles in the brain of the rhesus macaque., Non-human primates share many features with humans and are an important animal model in neuroscience. Here, the authors present a comprehensive transcriptomic and open chromatin atlas of the rhesus macaque brain.

Rigorous behavioral studies made in human subjects have shown that small-eccentricity target displacements are associated with increased saccadic reaction times, but the reasons for this remain unclear. Before characterizing the neurophysiological foundations underlying this relationship between the spatial and temporal aspects of saccades, we tested the triggering of small saccades in the male rhesus macaque monkey. We also compared our results to those obtained in human subjects, both from the existing literature and through our own additional measurements. Using a variety of behavioral tasks exercising visual and nonvisual guidance of small saccades, we found that small saccades consistently require more time than larger saccades to be triggered in the nonhuman primate, even in the absence of any visual guidance and when valid advance information about the saccade landing position is available. We also found a strong asymmetry in the reaction times of small upper versus lower visual field visually guided saccades, a phenomenon that has not been described before for small saccades, even in humans. Following the suggestion that an eye movement is not initiated as long as the visuo-oculomotor system is within a state of balance, in which opposing commands counterbalance each other, we propose that the longer reaction times are a signature of enhanced times needed to create the symmetry-breaking condition that puts downstream premotor neurons into a push-pull regime necessary for rotating the eyeballs. Our results provide an important catalog of nonhuman primate oculomotor capabilities on the miniature scale, allowing concrete predictions on underlying neurophysiological mechanisms. NEW & NOTEWORTHY Leveraging a multitude of neurophysiological investigations in the rhesus macaque monkey, we generated and tested hypotheses about small-saccade latencies in this animal model. We found that small saccades always take longer, on average, than larger saccades to trigger, regardless of visual and cognitive context. Moreover, small downward saccades have the longest latencies overall. Our results provide an important documentation of oculomotor capabilities of an indispensable animal model for neuroscientific research in vision, cognition, and action.

The Chinese tree shrew (Tupaia belangeri chinensis) is a small mammal closely related to primates. It has a small body size, low maintenance cost, and a relatively short reproductive cycle, all of which has made it the ideal model for the study of a variety of human diseases. In this study, we compared the anatomy of the skin of the Chinese tree shrew with that of the rhesus macaque, mouse and human, with the intention of providing the basic data required for the creation of skin disease models using this animal. Paraffin sections, hematoxylin-eosin (H&E) staining, masson staining and immunohistochemical techniques were used to examine the dorsal skin structure of the Chinese tree shrew. The epidermis was shown to be composed of 1-2 layers of cells. There were hair follicles, sebaceous glands and sweat glands in the dermis and the subcutaneous tissue, with apocrine glands being more common than eccrine glands. Both Keratin5 (KRT5) and Keratin10 (KRT10) were expressed in the skin of the Chinese tree shrew, with a localization in the cytoplasm. Overall, the skin morphology and histology of the Chinese tree shrew was basically the same as that of the human. We propose that the Chinese tree shrew has a strong potential to be used for creating animal models to help elucidate the molecular mechanisms underlying a variety of skin diseases.

To understand a visual scene, the brain segregates figures from background by assigning borders to foreground objects. Neurons in primate visual cortex encode which object owns a border (border ownership), but the underlying circuitry is not understood. Here, we used multielectrode probes to record from border ownership-selective units in different layers in macaque visual area V4 to study the laminar organization and timing of border ownership selectivity. We find that border ownership selectivity occurs first in deep layer units, in contrast to spike latency for small stimuli in the classical receptive field. Units on the same penetration typically share the preferred side of border ownership, also across layers, similar to orientation preference. Units are often border ownership-selective for a range of border orientations, where the preferred sides of border ownership are systematically organized in visual space. Together our data reveal a columnar organization of border ownership in V4 where the earliest border ownership signals are not simply inherited from upstream areas, but computed by neurons in deep layers, and may thus be part of signals fed back to upstream cortical areas or the oculomotor system early after stimulus onset. The finding that preferred border ownership is clustered and can cover a wide range of spatially contiguous locations suggests that the asymmetric context integrated by these neurons is provided in a systematically clustered manner, possibly through corticocortical feedback and horizontal connections., eLife digest To understand a visual scene, the brain needs to identify objects and distinguish them from background. A border marks the transition from object to background, but to differentiate which side of the border belongs to the object and which to background, the brain must integrate information across space. An early signature of this computation is that brain cells signal which side of a border is ‘owned’ by an object, also known as border ownership. But how the brain computes border ownership remains unknown. The optic nerve is a cable-like group of nerve cells that transmits information from the eye to the brain’s visual processing areas and into the visual cortex. This flow of information is often described as traveling in a feedforward direction, away from the eyes to progressively more specialized areas in the visual cortex. However, there are also numerous feedback connections in the brain, running backward from more specialized to less specialized cortical areas. To better understand the role of these feedforward and feedback circuits in the visual processing of object borders, Franken and Reynolds made use of their stereotyped projection patterns across the cortex layers. Feedforward connections terminate in the middle layers of a cortical area, whereas feedback connections terminate in upper and lower layers. Since time is required for information to traverse the cortical layers, dissecting the timing of border ownership signals may reveal if border ownership is computed in a feedforward or feedback manner. To find out more, electrodes were used to record neural activity in the upper, middle and lower layers of the visual cortex of two rhesus monkeys as they were presented with a set of abstract scenes composed of simple shapes on a background. This revealed that cells signaling border ownership in deep layers of the cortex did so before the signals appeared in the middle layer. This suggests that feedback rather than feedforward is required to compute border ownership. Moreover, Franken and Reynolds found evidence that cells that prefer the same side of border ownership are clustered in columns, showing how these neural circuits are organized within the visual cortex. In summary, Franken and Reynolds found that the circuits of the primate brain that compute border ownership occur as columns, in which cells in deep layers signal border ownership first, suggesting that border ownership relies on feedback from more specialized areas. A better understanding of how feedback in the brain works to process visual information helps us appreciate what happens when these systems are impaired.

Primatologists, psychologists and neuroscientists have long hypothesized that primate behavior is highly structured. However, fully delineating that structure has been impossible due to the difficulties of precision behavioral tracking. Here we analyzed a dataset consisting of continuous measures of the 3D position of fifteen body landmarks from two male rhesus macaques (Macaca mulatta) performing three different tasks in a large unrestrained environment over many hours. Using an unsupervised embedding approach on the tracked joints, we identified commonly repeated pose patterns, which we call postures. We found that macaques’ behavior is characterized by 49 distinct identifiable postures, lasting an average of 0.6 seconds each. We found evidence that behavior is hierarchically organized, in that transitions between poses tend to occur within larger modules, which correspond to intuitively identifiably actions; these actions are in turn organized hierarchically. Our behavioral decomposition allows us to identify universal (cross-individual and cross-task) and unique (specific to each individual and task) principles of behavior. These results demonstrate the hierarchical nature of primate behavior and provide a method for the automated “ethogramming” of primate behavior.

Hierarchical temporal dynamics are a fundamental computational property of the brain; however, there are no whole-brain, noninvasive investigations into timescales of neural processing in animal models. To that end, we used the spatial resolution and sensitivity of ultrahigh field fMRI performed at 10.5 Tesla to probe timescales across the whole macaque brain. We uncovered within-species consistency between timescales estimated from fMRI and electrophysiology. Crucially, we extended existing electrophysiological hierarchies to whole brain topographies. Our results validate the complementary use of hemodynamic and electrophysiological intrinsic timescales, establishing a basis for future translational work. Further, with these results in hand, we were able to show that one facet of the high-dimensional functional connectivity topography of any region in the brain is closely related to hierarchical temporal dynamics. We demonstrated that intrinsic timescales are organized along spatial gradients that closely match functional connectivity gradient topographies across the whole brain. We conclude that intrinsic timescales are a unifying organizational principle of neural processing across the whole brain.Declaration of InterestsThe authors declare no competing interests.

Population receptive field (pRF) modeling is a popular fMRI method to map the retinotopic organization of the human brain. While fMRI-based pRF maps are qualitatively similar to invasively recorded single-cell receptive fields in animals, it remains unclear what neuronal signal they represent. We addressed this question in awake nonhuman primates comparing whole-brain fMRI and large-scale neurophysiological recordings in areas V1 and V4 of the visual cortex. We examined the fits of several pRF models based on the fMRI blood-oxygen-level-dependent (BOLD) signal, multi-unit spiking activity (MUA), and local field potential (LFP) power in different frequency bands. We found that pRFs derived from BOLD-fMRI were most similar to MUA-pRFs in V1 and V4, while pRFs based on LFP gamma power also gave a good approximation. fMRI-based pRFs thus reliably reflect neuronal receptive field properties in the primate brain. In addition to our results in V1 and V4, the whole-brain fMRI measurements revealed retinotopic tuning in many other cortical and subcortical areas with a consistent increase in pRF size with increasing eccentricity, as well as a retinotopically specific deactivation of default mode network nodes similar to previous observations in humans. ispartof: ELIFE vol:10 ispartof: location:England status: published

Macaque monkeys are widely used to study vision. In the traditional approach, monkeys are brought into a lab to perform visual tasks while they are restrained to obtain stable eye tracking and neural recordings. Here, we describe a novel environment to study visual cognition in a more natural setting as well as other natural and social behaviors. We designed a naturalistic environment with an integrated touchscreen workstation that enables high-quality eye tracking in unrestrained monkeys. We used this environment to train monkeys on a challenging same-different task. We also show that this environment can reveal interesting novel social behaviors. As proof of concept, we show that two naive monkeys were able to learn this complex task through a combination of socially observing trained monkeys and solo trial-and-error. We propose that such naturalistic environments can be used to rigorously study visual cognition as well as other natural and social behaviors in freely moving monkeys.

BACKGROUND Simian varicella virus (SVV) is a primate herpesvirus that causes a natural varicella-like disease in Old World monkeys and may cause epizootics in facilities housing nonhuman primates. SVV infection of nonhuman primates is used as an experimental model to investigate varicella pathogenesis and to develop antiviral strategies. METHODS An indirect enzyme-linked immunosorbent assay (ELISA) was developed to detect SVV antibodies in infected rhesus macaque monkeys. RESULTS An ELISA determined SVV antibody titers following experimental infection. SVV IgG was detected by day 14 post-infection and remained elevated for at least 84 days. CONCLUSIONS The SVV ELISA is a safe and rapid approach to confirm SVV seropositivity and to determine SVV antibody titers in naturally and experimentally SVV-infected monkeys. In addition to being a useful diagnostic assay to rapidly confirm acute disease or past SVV infection, the SVV ELISA is a valuable epidemiological tool to determine the incidence of SVV in non-human primate facilities.

Rhesus macaques are a common non-human primate model used in the evaluation of human monoclonal antibodies, molecules whose effector functions depend on a conserved N-linked glycan in the Fc region. This carbohydrate is a target of glycoengineering efforts aimed at altering antibody effector function by modulating the affinity of Fcγ receptors. For example, a reduction in the overall core fucose content is one such strategy that can increase antibody-mediated cellular cytotoxicity by increasing Fc-FcγRIIIa affinity. While the position of the Fc glycan is conserved in macaques, differences in the frequency of glycoforms and the use of an alternate monosaccharide in sialylated glycan species add a degree of uncertainty to the testing of glycoengineered human antibodies in rhesus macaques. Using a panel of 16 human IgG1 glycovariants, we measured the affinities of macaque FcγRs for differing glycoforms via surface plasmon resonance. Our results suggest that macaques are a tractable species in which to test the effects of antibody glycoengineering.

Zika virus (ZIKV) infection at the maternal-placental interface is associated with adverse pregnancy outcomes including fetal demise and pregnancy loss. To determine how infection impacts placental trophoblasts, we utilized rhesus macaque trophoblast stem cells (TSC) that can be differentiated into early gestation syncytiotrophoblasts (ST) and extravillous trophoblasts (EVT). TSCs and STs, but not EVTs, were highly permissive to productive infection with ZIKV strain DAK AR 41524. The impact of ZIKV on the cellular transcriptome showed that infection of TSCs and STs increased expression of immune related genes, including those involved in type I and type III interferon responses. ZIKV exposure altered extracellular vesicle (EV) protein, mRNA, and miRNA cargo, regardless of productive infection. These findings suggest that early gestation macaque TSCs and STs are permissive to ZIKV infection, and that EV analysis may provide a foundation for identifying non-invasive biomarkers of placental infection in a highly translational model.

The dynamic nature of the SIV population during disease progression in the SIV/macaque model of AIDS and the factors responsible for its behavior have not been documented, largely owing to the lack of sufficient spatial and temporal sampling of both viral and host data from SIV-infected animals. In this study, we detail Bayesian coalescent inference of the changing collective intra-host viral effective population size (Ne) from various tissues over the course of infection and its relationship with what we demonstrate is a continuously changing immune cell repertoire within the blood. Although the relative contribution of these factors varied among hosts and time points, the adaptive immune response best explained the overall periodic dynamic behavior of the effective virus population. Data exposing the nature of the relationship between the virus and immune cell populations revealed the plausibility of an eco-evolutionary mathematical model, which was able to mimic the large-scale oscillations in Ne through virus escape from relatively few, early immunodominant responses, followed by slower escape from several subdominant and weakened immune populations. The results of this study suggest that SIV diversity within the untreated host is governed by a predator-prey relationship, wherein differing phases of infection are the result of adaptation in response to varying immune responses. Previous investigations into viral population dynamics using sequence data have focused on single estimates of the effective viral population size (Ne) or point estimates over sparse sampling data to provide insight into the precise impact of immune selection on virus adaptive behavior. Herein, we describe the use of the coalescent phylogenetic frame- work to estimate the relative changes in Ne over time in order to quantify the relationship with empirical data on the dynamic immune composition of the host. This relationship has allowed us to expand on earlier simulations to build a predator-prey model that explains the deterministic behavior of the virus over the course of disease progression. We show that sequential viral adaptation can occur in response to phases of varying immune pressure, providing a broader picture of the viral response throughout the entire course of progression to AIDS.

Medical countermeasure development under the US Food and Drug Administration animal rule requires validated animal models of acute radiation effects. The key large animal model is the non-human primate, rhesus macaque. To date, only the rhesus macaque has been used for both critical supportive data and pivotal efficacy trials seeking US Food and Drug Administration approval. The potential for use of the rhesus for other high priority studies such as vaccine development underscores the need to identify another non-human primate model to account for the current lack of rhesus for medical countermeasure development. The cynomolgus macaque, Macaca fascicularis, has an existing database of medical countermeasure development against the hematopoietic acute radiation syndrome, as well as the use of radiation exposure protocols that mimic the likely nonuniform and heterogenous exposure consequent to a nuclear terrorist event. The review herein describes published studies of adult male cynomolgus macaques that used two exposure protocols-unilateral, nonuniform total-body irradiation and partial-body irradiation with bone marrow sparing-with the administration of subject-based medical management to assess mitigation against the hematopoietic acute radiation syndrome. These studies assessed the efficacy of cytokine combinations and cell-based therapy to mitigate acute radiation-induced myelosuppression. Both therapeutics were shown to mitigate the myelosuppression of the hematopoietic acute radiation syndrome. Additional studies being presented herein further defined the dose-dependent hematopoietic acute radiation syndrome of cynomolgus and rhesus macaques and a differential dose-dependent effect with young male and female cynomolgus macaques. The database supports the investigation of the cynomolgus macaque as a comparable non-human primate for efficacy testing under the US Food and Drug Administration animal rule. Critical gaps in knowledge required to validate the models and exposure protocols are also identified.

Contains fulltext : 237221.pdf (Publisher’s version ) (Open Access) The macaque middle superior temporal sulcus shares functional properties with the human temporoparietal junction supporting mentalizing. The ability to attribute thoughts to others, also called theory of mind (TOM), has been extensively studied in humans; however, its evolutionary origins have been challenged. Computationally, the basis of TOM has been interpreted within the predictive coding framework and associated with activity in the temporoparietal junction (TPJ). Here, we revealed, using a nonlinguistic task and functional magnetic resonance imaging, that activity in a region of the macaque middle superior temporal cortex was specifically modulated by the predictability of social situations. As in human TPJ, this region could be distinguished from other temporal regions involved in face processing. Our result suggests the existence of a precursor for the TOM ability in the last common ancestor of human and Old World monkeys. 11 p.

High-level characterizations of the primate cerebral cortex sit between two extremes: on one end the cortical mantle is seen as a mosaic of structurally and functionally unique areas, and on the other it is seen as a uniform six-layered structure in which functional differences are defined solely by extrinsic connections. Neither of these extremes captures the crucial neuroanatomical finding: that the cortex exhibits systematic gradations in architectonic structure. These gradations have been shown to predict cortico-cortical connectivity, which in turn suggests powerful ways to ground connectomics in anatomical structure, and by extension cortical function. A challenge to more widespread use of this concept is the labor-intensive and invasive nature of histological staining, which is the primary means of recognizing anatomical gradations. Here we show that a novel computational analysis technique can be used to derive a coarse-grained picture of cortical variation. For each of 78 cortical areas spanning the entire cortical mantle of the rhesus macaque, we created a high dimensional set of anatomical features derived from captured images of cortical tissue stained for myelin and SMI-32. The method involved semi-automated de-noising of images, and enabled comparison of brain areas without hand-labeling of features such as layer boundaries. We applied nonmetric multidimensional scaling (NMDS) to the dataset to visualize similarity among cortical areas. This analysis shows a systematic variation between weakly laminated (limbic) cortices and sharply laminated (eulaminate) cortices. We call this smooth continuum the ‘cortical spectrum’. We also show that this spectrum is visible within subsystems of the cortex: the occipital, parietal, temporal, motor, prefrontal, and insular cortices. We compared the NMDS-derived spectrum with a spectrum produced using T1- and T2-weighted magnetic resonance imaging (MRI) data derived from macaque, and found close agreement of the two coarse-graining methods. This evidence suggests that T1/T2 data, routinely obtained in human MRI studies, can be used as an effective proxy for data derived from high-resolution histological methods. More generally, this approach shows that the cortical spectrum is robust to the specific method used to compare cortical areas, and is therefore a powerful tool to understand the principles of organization of the primate cortex.

The Patch-seq approach is a powerful variation of the patch-clamp technique that allows for the combined electrophysiological, morphological, and transcriptomic characterization of individual neurons. To generate Patch-seq datasets at scale, we identified and refined key factors that contribute to the efficient collection of high-quality data. We developed patch-clamp electrophysiology software with analysis functions specifically designed to automate acquisition with online quality control. We recognized the importance of extracting the nucleus for transcriptomic success and maximizing membrane integrity during nucleus extraction for morphology success. The protocol is generalizable to different species and brain regions, as demonstrated by capturing multimodal data from human and macaque brain slices. The protocol, analysis and acquisition software are compiled at https://githubcom/AllenInstitute/patchseqtools. This resource can be used by individual labs to generate data across diverse mammalian species and that is compatible with large publicly available Patch-seq datasets.

DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey (Chlorocebus sabaeus), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, we developed two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes that gain methylation with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED and genes possessing the trimethylated H3K27 mark in their promoters. The epigenetic clocks are expected to be useful for anti-aging studies in vervets.

Non-human primates (NHPs) have played a vital role in fundamental, pre-clinical, and translational studies because of their high physiological and genetic similarity to humans. Here, we report a method to isolate primary hepatocytes from the livers of rhesus macaques (Macaca mulatta) after in situ whole liver perfusion. Isolated primary macaque hepatocytes (PMHs) were treated with various compounds known to have different pathways of genotoxicity/carcinogenicity and the resulting DNA damage was evaluated using the high-throughput CometChip assay. The comet data were quantified using benchmark dose (BMD) modeling and the BMD50 values for treatments of PMHs were compared with those generated from primary human hepatocytes (PHHs) in our previous study (Seo et al. Arch Toxicol 2020, 2207–2224). The results showed that despite varying CYP450 enzyme activities, PMHs had the same sensitivity and specificity as PHHs in detecting four indirect-acting (i.e., requiring metabolic activation) and seven direct-acting genotoxicants/carcinogens, as well as five non-carcinogens that are negative or equivocal for genotoxicity in vivo. The BMD50 estimates and their confidence intervals revealed species differences for DNA damage potency, especially for direct-acting compounds. The present study provides a practical method for maximizing the use of animal tissues by isolating primary hepatocytes from NHPs. Our data support the use of PMHs as a reliable surrogate of PHHs for evaluating the genotoxic hazards of chemical substances for humans.

This study was designed to (1) characterize the macronutrient composition of olive baboon (Papio anubis) milk, (2) compare baboon milk composition to that of rhesus macaques (Macaca mulatta), and (3) evaluate the association between the proportion of milk energy derived from protein and relative growth rate within anthropoid primates. A single milk sample was collected from each of eight lactating olive baboons ranging between 47- and 129-days postparturition and six rhesus macaques from 15- to 92-days living at the same institution under identical management conditions. Macronutrient composition (water, fat, protein sugar, and ash) was determined using standard techniques developed at the Nutrition Laboratory at the Smithsonian National Zoological Park. Baboon milk on average contained 86.0% ± 0.6% water, 4.7% ± 0.5% fat, 1.6% ± 0.04% protein, 7.3% ± 0.07% sugar, and 0.165% ± 0.007% ash. Baboon milk gross energy (GE) averaged 0.81 ± 0.04 kcal/g with 51.9% ± 2.6% from fat, 11.8% ± 0.7% from protein, and 36.2% ± 2.0% from sugar. Baboon milk demonstrated strong similarity to milk composition of the closely phylogenetically related rhesus macaque (86.1% ± 0.3% water, 4.1% ± 0.4% fat, 1.69% ± 0.05% protein, 7.71% ± 0.08% sugar, 0.19% ± 0.01% ash, and 0.78 kcal/g). There was no statistical difference between baboon and macaque milk in the proportions of energy from fat, sugar, and protein. Baboon milk can be described as a high sugar, moderate fat, and low protein milk with moderate energy density, which is consistent with their lactation strategy characterized by frequent, on-demand nursing and relatively slow life history compared to nonprimate mammal taxa. The milk energy from protein of both baboon and macaque (12.8% ± 0.3%) milk was intermediate between the protein milk energy of platyrrhine (19.3%-23.2%) and hominoid (8.9%-12.6%) primates, consistent with their relative growth rates also being intermediate. Compared to these cercopithecid monkeys, platyrrhine primates have both higher relative growth rates and higher milk energy from protein, while apes tend to be lower in both.

Cortical circuits are thought to contain a large number of cell types that coordinate to produce behavior. Currentin vivomethods rely on clustering of specified features of extracellular waveforms to identify putative cell types, but these capture only a small amount of variation. Here, we develop a new method (WaveMAP) that combines non-linear dimensionality reduction with graph clustering to identify putative cell types. We applyWaveMAPto extracellular waveforms recorded from dorsal premotor cortex of macaque monkeys performing a decision-making task. UsingWaveMAP, we robustly establish eight waveform clusters and show that these clusters recapitulate previously identified narrow- and broad-spiking types while revealing previously unknown diversity within these subtypes. The eight clusters exhibited distinct laminar distributions, characteristic firing rate patterns, and decision-related dynamics. Such insights were weaker when using feature-based approaches.WaveMAPtherefore provides a more nuanced understanding of the dynamics of cell types in cortical circuits.SignificanceHow different cell types sculpt activity patterns in brain areas associated with decision-making is a fundamentally unresolved problem in neuroscience. In monkeys, and other species where transgenic access is not yet possible, identifying physiological typesin vivorelies on only a few discrete user-specified features of extracellular waveforms to identify cell types. Here, we show that non-linear dimensionality reduction with graph clustering applied to the entire extracellular waveform can delineate many different putative cell types and does so in an interpretable manner. We show that this method reveals previously undocumented physiological, functional, and laminar diversity in the dorsal premotor cortex of monkeys, a key brain area implicated in decision-making.

Living near primate species has positive and negative outcomes for human communities. While most studies focus on understanding people's perceptions regarding the adverse consequences of interacting with primates, less is known about people's willingness to coexist with primates or reasons that may promote human-primate coexistence. We surveyed 794 people co-living with four different primate species-rhesus macaque Macaca mulatta, bonnet macaque Macaca radiata, lion-tailed macaque Macaca silenus, and Hanuman langur Semnopithecus dussumieri-in southern and western India to understand how people perceived the costs and benefits of coexistence. The results of our semi-structured interview study revealed that although tangible costs (i.e., financial losses from primate depredation) primarily drive people's stated tolerance for primate presence, intangible benefits from primates (i.e., their ecological, existence, sentience, and religious values) also critically affect attitudes towards coexistence. Amongst the four species, people associated rhesus macaques with the greatest costs and fewest benefits, lion-tailed macaques with the lowest costs, and bonnet macaques with the highest benefits. People preferred lion-tailed macaques and Hanuman langurs more than bonnet and rhesus macaques, and affection for a species shaped how people viewed costs accruing from the species. People's preferences for species were influenced by their existence, ecological, and sentience values more than their religious value. We suggest that intangible benefits influence people's fondness for a primate species and this, in turn, shapes how people perceive costs resulting from the species. Hence strengthening people's perceptions of the intangible benefits they receive from primate species will improve human tolerance for living near primates. We argue that there is a need to understand the context of human-primate conflicts beyond the cost aspects and focus on the benefits to improve human-primate coexistence.

There is an urgent need for effective therapeutic interventions against SARS-CoV-2, including new variants that continue to arise. Neutralizing monoclonal antibodies have shown promise in clinical studies. We investigated the therapeutic efficacy of a combination of two potent monoclonal antibodies, C135-LS and C144-LS that carry half-life extension mutations, in the rhesus macaque model of COVID-19. Twelve young adult macaques (three groups of four animals) were inoculated intranasally and intra-tracheally with a high dose of SARS-CoV-2 and 24 hours later, treated intravenously with a high (40 mg/kg) or low (12 mg/kg) dose of the C135-LS and C144-LS antibody combination, or a control monoclonal antibody. Animals were monitored for 7 days. Compared to the control animals, animals treated with either dose of the anti-SARS-CoV-2 antibodies showed similarly improved clinical scores, lower levels of virus replication in upper and lower respiratory tract, and significantly reduced interstitial pneumonia, as measured by comprehensive lung histology. In conclusion, this study provides proof-of-concept in support of further clinical development of these monoclonal antibodies against COVID-19 during early infection., Author summary Monoclonal antibodies that neutralize SARS-CoV-2 have shown promise in treating recently infected individuals who are at high risk of progression to severe COVID-19 disease. Although several monoclonal antibodies are currently being used in the clinic, there is an ongoing need to develop additional antibodies. The ideal monoclonal antibodies, or combinations, should be potent and durable, and maintain activity against emerging viral variants. In this study, we tested a combination of two potent monoclonal antibodies, C135-LS and C-144-LS, engineered to have long half-lives, in the macaque model of SARS-CoV-2 infection. Animals treated early after infection fared better than placebo-treated controls, manifesting fewer clinical signs, less virus replication in the respiratory tract, and reduced lung inflammation. These promising data support clinical testing of these monoclonal antibodies in humans and further development of similar antibody-based prophylactic and therapeutic strategies.

Temporal discounting captures both choice preferences and motivation for delayed rewards. While temporally discounted value for choice is represented in brain areas including the dorsolateral prefrontal cortex (DLPFC) and the striatum, the neural process of motivation for delayed rewards remains unidentified. Here we show that neuronal activity of the dorsal part of the primate caudate head (dCDh) — a striatal region receiving projection from the DLPFC — signals temporally discounted value essential for computing motivation for delayed rewards. Macaque monkeys performed an instrumental task, in which a visual cue indicated the forthcoming size and delay duration before reward. Single dCDh neurons represented the temporally discounted value without reflecting changes in the animal’s physiological state. Bilateral pharmacological or chemogenetic inactivation of dCDh specifically distorted a normal motivational performance based on the integration of reward size and delay. These results suggest a major contribution of dCDh to encoding a temporally discounted value, the integrated multidimensional information critical for formulating the motivation for action.

The inferior parietal lobule (IPL) is one of the most expanded cortical regions in humans relative to other primates. It is also among the most structurally and functionally asymmetric regions in the human cerebral cortex. Whether the structural and connectional asymmetries of IPL subdivisions differ across primate species and how this relates to functional asymmetries remain unclear. We identified IPL subregions that exhibited positive allometric in both hemispheres, scaling across rhesus macaque monkeys, chimpanzees, and humans. The patterns of IPL subregions asymmetry were similar in chimpanzees and humans, but no IPL asymmetries were evident in macaques. Among the comparative sample of primates, humans showed the most widespread asymmetric connections in the frontal, parietal, and temporal cortices, constituting leftward asymmetric networks that may provide an anatomical basis for language and tool use. Unique human asymmetric connectivity between the IPL and primary motor cortex might be related to handedness. These findings suggest that structural and connectional asymmetries may underlie hemispheric specialization of the human brain.

Digitized neuroanatomical atlases that can be overlaid onto functional data are crucial for localizing brain structures and analyzing functional networks identified by neuroimaging techniques. To aid in functional and structural data analysis, we have created a comprehensive parcellation of the rhesus macaque subcortex using a high-resolution ex vivo structural imaging scan. This anatomical scan and its parcellation were warped to the updated NIMH Macaque Template (NMT v2), an in vivo population template, where the parcellation was refined to produce the Subcortical Atlas of the Rhesus Macaque (SARM) with 210 primary regions-of-interest (ROIs). The subcortical parcellation and nomenclature reflect those of the 4th edition of the Rhesus Monkey Brain in Stereotaxic Coordinates ( Paxinos et al., in preparation ), rather than proposing yet another novel atlas. The primary ROIs are organized across six spatial hierarchical scales from small, fine-grained ROIs to broader composites of multiple ROIs, making the SARM suitable for analysis at different resolutions and allowing broader labeling of functional signals when more accurate localization is not possible. As an example application of this atlas, we have included a functional localizer for the dorsal lateral geniculate (DLG) nucleus in three macaques using a visual flickering checkerboard stimulus, identifying and quantifying significant fMRI activation in this atlas region. The SARM has been made openly available to the neuroimaging community and can easily be used with common MRI data processing software, such as AFNI, where the atlas has been embedded into the software alongside cortical macaque atlases.

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.

Calcium imaging is a powerful tool for recording from large populations of neurons in vivo. Imaging in rhesus macaque motor cortex can enable the discovery of fundamental principles of motor cortical function and can inform the design of next generation brain-computer interfaces (BCIs). Surface two-photon imaging, however, cannot presently access somatic calcium signals of neurons from all layers of macaque motor cortex due to photon scattering. Here, we demonstrate an implant and imaging system capable of chronic, motion-stabilized two-photon imaging of neuronal calcium signals from macaques engaged in a motor task. By imaging apical dendrites, we achieved optical access to large populations of deep and superficial cortical neurons across dorsal premotor (PMd) and gyral primary motor (M1) cortices. Dendritic signals from individual neurons displayed tuning for different directions of arm movement. Combining several technical advances, we developed an optical BCI (oBCI) driven by these dendritic signalswhich successfully decoded movement direction online. By fusing two-photon functional imaging with CLARITY volumetric imaging, we verified that many imaged dendrites which contributed to oBCI decoding originated from layer 5 output neurons, including a putative Betz cell. This approach establishes new opportunities for studying motor control and designing BCIs via two photon imaging., Surface two-photon imaging of the brain cannot access somatic calcium signals of neurons from deep layers of the macaque cortex. Here, the authors present an implant and imaging system for chronic motion-stabilized two-photon imaging of dendritic calcium signals to drive an optical brain-computer interface in macaques.

An hourglass cup-shape pattern of regulation at the molecular level was detected during the development of the primate brain. Specifically, a peak of temporally differentially expressed genes around the time of birth has been observed in the human brain. However, to what extend this peak of regulation exists among species has not been investigated in great detail. Here, by integrating multiple large-scale transcriptome data from rhesus macaques, we confirmed that a similar differential expression peak exists during the development of the macaque brain. We also found that a similar peak exists during the development of other organs, such as liver, testis, kidney and heart. Furthermore, we found that distinct pathways are regulated in the peak period of those organs. Our results highlight the importance of co-evolution of diverse organs during critical periods of perinatal development in primates.

Inhibitory interneurons are believed to realize critical gating functions in cortical circuits, but it has been difficult to ascertain the content of gated information for well characterized interneurons in primate cortex. Here, we address this question by characterizing putative interneurons in primate prefrontal and anterior cingulate cortex while monkeys engaged in attention demanding reversal learning. We find that subclasses of narrow spiking neurons have a relative suppressive effect on the local circuit indicating they are inhibitory interneurons. One of these interneuron subclasses showed prominent firing rate modulations and (35-45 Hz) gamma synchronous spiking during periods of uncertainty in both, lateral prefrontal cortex (LPFC) and in anterior cingulate cortex (ACC). In LPFC this interneuron subclass activated when the uncertainty of attention cues was resolved during flexible learning, whereas in ACC it fired and gamma-synchronized when outcomes were uncertain and prediction errors were high during learning. Computational modeling of this interneuron-specific gamma band activity in simple circuit motifs suggests it could reflect a soft winner-take-all gating of information having high degree of uncertainty. Together, these findings elucidate an electrophysiologically-characterized interneuron subclass in the primate, that forms gamma synchronous networks in two different areas when resolving uncertainty during adaptive goal-directed behavior.