Intravenous gene transfer throughout the brain of infant Old World primates using AAV

Adeno-associated viruses (AAVs) can enable robust and safe gene delivery to the mammalian central nervous system (CNS). While the scientific community has developed numerous neurotropic AAV variants for systemic gene-transfer to the rodent brain, there are few AAVs that efficiently access the CNS of higher order primates. We describe here AAV.CAP-Mac, an engineered AAV variant that enables systemic, brain-wide gene delivery in infants of two Old World primate species--the rhesus macaque (Macaca mulatta) and the green monkey (Chlorocebus sabaeus). We identified CAP-Mac using a multi-species selection strategy, initially screening our library in the adult common marmoset (Callithrix jacchus) and narrowing our pool of test-variants for another round of selection in infant macaques. In individual characterization, CAP-Mac robustly transduces human neurons in vitro and Old World primate neurons in vivo, where it targets all lobes of cortex, the cerebellum, and multiple subcortical regions of disease relevance. We use CAP-Mac for Brainbow-like multicolor labeling of macaque neurons throughout the brain, enabling morphological reconstruction of both medium spiny neurons and cortical pyramidal cells. Because of its broad distribution throughout the brain and high neuronal efficiency in infant Old World primates compared to AAV9, CAP-Mac shows promise for researchers and clinicians alike to unlock novel, noninvasive access to the brain for efficient gene transfer.

Presence and potential distribution of malaria-infected New World primates of Costa Rica

Background In South and Central America, Plasmodium malariae/Plasmodium brasilianum, Plasmodium vivax, Plasmodium simium, and Plasmodium falciparum has been reported in New World primates (NWP). Specifically in Costa Rica, the presence of monkeys positive to P. malariae/P brasilianum has been identified in both captivity and in the wild. The aim of the present study was to determine the presence of P. brasilianum, P. falciparum, and P. vivax, and the potential distribution of these parasites-infecting NWP from Costa Rica. Methods The locations with PCR (Polymerase Chain Reaction) positive results and bioclimatic predictors were used to construct ecological niche models based on a modelling environment that uses the Maxent algorithm, named kuenm, capable to manage diverse settings to better estimate the potential distributions and uncertainty indices of the potential distribution. Results PCR analysis for the Plasmodium presence was conducted in 384 samples of four primates (Howler monkey [n = 130], White-face monkey [n = 132], Squirrel monkey [n = 50], and red spider monkey [n = 72]), from across Costa Rica. Three Plasmodium species were detected in all primate species (P. falciparum, P. malariae/P. brasilianum, and P. vivax). Overall, the infection prevalence was 8.9%, but each Plasmodium species ranged 2.1–3.4%. The niche model approach showed that the Pacific and the Atlantic coastal regions of Costa Rica presented suitable climatic conditions for parasite infections. However, the central pacific coast has a more trustable prediction for malaria in primates. Conclusions The results indicate that the regions with higher suitability for Plasmodium transmission in NWP coincide with regions where most human cases have been reported. These regions were also previously identified as areas with high suitability for vector species, suggesting that enzootic and epizootic cycles occur.

Activity pattern and habitat association of Assamese macaques Macaca assamensis McClelland, 1840 in Shivapuri Nagarjun National Park, Nepal

Assamese macaque Macaca assamensis McClelland, 1840 is one of the primate species with narrow distribution range and the least exploration. This study investigated the diurnal activity of Assamese macaque and association with the vegetation in Nagarjun Forest of Shivapuri Nagarjun National Park, Nepal. Behaviour sampling including Instantaneous sampling and Ad-libitum sampling (7:30 AM – 4:30 PM) along with vegetation survey (20 m × 20 m plots) were applied. The Raniban Barrack troop of Assamese macaque composed of 12 individuals was observed for a total of 225 hours to record the macaque’s diurnal activity. The troop spent 28% time in inactive, 25% in grooming, 23% in foraging, 23% in locomotion and 1% in fighting. Assamese macaque troop spent more time in Schima wallichii possessing 25.91%, 36.29% and 41.22% for foraging, locomotion and inactive respectively of the diurnal time. Altogether, 67 plant species (herbs, shrubs, trees and climbers) were documented from vegetation analysis. Schima wallichii and Ardisia macrocarpa were dominated the habitat. Paired t-test revealed significant difference in foraging (df = 24, P = 0.010) and inactive (df = 24, P = 0.003) between the morning and day observational phases. The findings of this study shed light on the food preference and microhabitat use by the protected Assamese macaque in Nepal that assists to formulate the management plans for the species.

Molecular liver fingerprint reflects the seasonal physiology of the grey mouse lemur (Microcebus murinus) during winter

Grey mouse lemurs (Microcebus murinus) are a primate species exhibiting strong physiological seasonality in response to environmental energetic constraint. They notably store large amounts of lipids during early winter (EW), which are thereafter mobilized during late winter (LW), when food availability is low. In addition, they develop glucose intolerance in LW only. To decipher how the hepatic mechanisms may support such metabolic flexibility, we analyzed the liver proteome of adult captive male mouse lemurs, which seasonal regulations of metabolism and reproduction are comparable to their wild counterparts, during the phases of either constitution or use of fat reserves. We highlight profound changes that reflect fat accretion in EW at the whole-body level, however, without triggering an ectopic storage of fat in the liver. Moreover, molecular regulations would be in line with the lowering of liver glucose utilization in LW, and thus with reduced tolerance to glucose. However, no major regulation was seen in insulin signaling/resistance pathways, which suggests that glucose intolerance does not reach a pathological stage. Finally, fat mobilization in LW appeared possibly linked to reactivation of the reproductive system and enhanced liver detoxification may reflect an anticipation to return to summer levels of food intake. Altogether, these results show that the physiology of mouse lemurs during winter relies on solid molecular foundations in liver processes to adapt fuel partitioning while avoiding reaching a pathological state despite large lipid fluxes. This work emphasizes how the mouse lemur is of primary interest for identifying molecular mechanisms relevant to biomedical field.

Distributed coding of duration in rodent prefrontal cortex during time reproduction

As we interact with the external world, we judge magnitudes from sensory information. The estimation of magnitudes has been characterized in primates, yet it is largely unexplored in non-primate species. Here we use time interval reproduction to study rodent behavior and its neural correlates in the context of magnitude estimation. We show that gerbils display primate-like magnitude estimation characteristics in time reproduction. Most prominently their behavioral responses show a systematic overestimation of small stimuli and an underestimation of large stimuli, often referred to as regression effect. We investigated the underlying neural mechanisms by recording from medial prefrontal cortex and show that the majority of neurons respond either during the measurement or the reproduction of a time interval. Cells that are active during both phases display distinct response patterns. We categorize the neural responses into multiple types and demonstrate that only populations with mixed responses can encode the bias of the regression effect. These results help unveil the organizing neural principles of time reproduction and perhaps magnitude estimation in general.

The retrocalcarine sulcus maps different retinotopic representations in macaques and humans

Primate cerebral cortex is highly convoluted with much of the cortical surface buried in sulcal folds. The origins of cortical folding and its functional relevance have been a major focus of systems and cognitive neuroscience, especially when considering stereotyped patterns of cortical folding that are shared across individuals within a primate species and across multiple species. However, foundational questions regarding organizing principles shared across species remain unanswered. Taking a cross-species comparative approach with a careful consideration of historical observations, we investigate cortical folding relative to primary visual cortex (area V1). We identify two macroanatomical structures—the retrocalcarine and external calcarine sulci—in 24 humans and 6 macaque monkeys. We show that within species, these sulci are identifiable in all individuals, fall on a similar part of the V1 retinotopic map, and thus, serve as anatomical landmarks predictive of functional organization. Yet, across species, the underlying eccentricity representations corresponding to these macroanatomical structures differ strikingly across humans and macaques. Thus, the correspondence between retinotopic representation and cortical folding for an evolutionarily old structure like V1 is species-specific and suggests potential differences in developmental and experiential constraints across primates.

Collective knowledge and the dynamics of culture in chimpanzees

Social learning in non-human primates has been studied experimentally for over 120 years, yet until the present century this was limited to what one individual learns from a single other. Evidence of group-wide traditions in the wild then highlighted the collective context for social learning, and broader ‘diffusion experiments’ have since demonstrated transmission at the community level. In the present article, we describe and set in comparative perspective three strands of our recent research that further explore the collective dimensions of culture and cumulative culture in chimpanzees. First, exposing small communities of chimpanzees to contexts incorporating increasingly challenging, but more rewarding tool use opportunities revealed solutions arising through the combination of different individuals' discoveries, spreading to become shared innovations. The second series of experiments yielded evidence of conformist changes from habitual techniques to alternatives displayed by a unanimous majority of others but implicating a form of quorum decision-making. Third, we found that between-group differences in social tolerance were associated with differential success in developing more complex tool use to exploit an increasingly inaccessible resource. We discuss the implications of this array of findings in the wider context of related studies of humans, other primates and non-primate species. This article is part of a discussion meeting issue ‘The emergence of collective knowledge and cumulative culture in animals, humans and machines’.

Age- and sex-related differences in baboon (Papio anubis) gray matter covariation

Age-related changes in cognition, brain morphology, and behavior are exhibited in several primate species. Baboons, like humans, naturally develop Alzheimer's disease-like pathology and cognitive declines with age and are an underutilized model for studies of aging. To determine age-related differences in gray matter covariation of 89 olive baboons (Papio anubis), we used source-based morphometry (SBM) to analyze data from magnetic resonance images. We hypothesized that we would find significant age effects in one or more SBM components, particularly those which include regions influenced by age in humans and other nonhuman primates (NHPs). A multivariate analysis of variance revealed that individual weighted gray matter covariation scores differed across the age classes. Elderly baboons contributed significantly less to gray matter covariation components including the brainstem, superior parietal cortex, thalamus, and pallidum compared to juveniles, and middle and superior frontal cortex compared to juveniles and young adults (p<0.05). Future studies should the relationship between the changes in gray matter covariation reported here and age-related cognitive decline.

SIVgsn-99CM71 Vpu employs different amino acids to antagonize human and greater spot-nosed monkey BST-2

Viral protein U (Vpu) is an accessory protein encoded by human immunodeficiency virus type 1 (HIV-1) and certain simian immunodeficiency virus (SIV) strains. Some of these viruses were reported to use Vpu to overcome restriction by BST-2 of their natural hosts. Our own recent report revealed that Vpu of SIVgsn-99CM71 (SIVgsn71) antagonizes human BST-2 through two AxxxxxxxW motifs (A 22 W 30 and A 25 W 33 ) whereas antagonizing BST-2 of its natural host, greater spot-nosed monkey (GSN), involved only A 22 W 30 motif. Here we show that residues A 22 , A 25 , W 30 , and W 33 of SIVgsn71 Vpu are all essential to antagonize human BST-2, while, neither single mutation of A 22 nor W 30 affected the ability to antagonize GSN BST-2. Similar to A 18 , which is located in the middle of the A 14 xxxxxxxW 22 motif in HIV-1 NL4-3 Vpu and is essential to antagonize human BST-2, A 29 , located in the middle of the A 25 W 33 motif of SIVgsn71 Vpu was found to be necessary for antagonizing human but not GSN BST-2. Further mutational analyses revealed that residues L 21 and K 32 of SIVgsn71 Vpu were also essential for antagonizing human BST-2. On the other hand, the ability of SIVgsn71 Vpu to target GSN BST-2 was unaffected by single amino acid substitutions but required multiple mutations to render SIVgsn71 Vpu inactive against GSN BST-2. These results suggest additional requirements for SIVgsn71 Vpu antagonizing human BST-2, implying evolution of the bst-2 gene under strong selective pressure. Importance Genes related to survival against life-threating pathogens are important determinants of natural selection in animal evolution. For instance, BST-2, a protein showing broad-spectrum antiviral activity, shows polymorphisms entailing different phenotypes even among primate species, suggesting that the bst-2 gene of primates has been subject to strong selective pressure during evolution. At the same time, viruses readily adapt to these evolutionary changes. Thus, we found that Vpu of an SIVgsn isolate (SIVgsn-99CM71) can target BST-2 from humans as well as from its natural host thus potentially facilitating zoonosis. Here we mapped residues in SIVgsn71 Vpu potentially contributing to cross-species transmission. We found that the requirements for targeting human BST-2 are distinct from and more complex than those for targeting GSN BST-2. Our results suggest that the human bst-2 gene might have evolved to acquire more restrictive phenotype than GSN bst-2 against viral proteins after being derived from their common ancestor.

AZFa Y Gene, DDX3Y, Evolved Novel Testis Transcript Variants in Primates with Proximal 3´UTR Polyadenylation for Germ Cell Specific Translation

Translational control is a major level of gene expression regulation in the male germ line. DDX3Y located in the AZFa region of the human Y chromosome encodes a conserved RNA helicase important for translational control at the G1-S phase of the cell cycle. In human, DDX3Y protein is expressed only in premeiotic male germ cells. In primates, DDX3Y evolved a second promoter producing novel testis-specific transcripts. Here, we show primate species-specific use of alternative polyadenylation (APA) sites for the testis-specific DDX3Y transcript variants. They have evolved first in the 3´UTRs of primate DDX3Y transcripts. A distal APA site is used for polyadenylation of DDX3Y testis transcripts in Callithrix jacchus; two proximal APAs in Macaca mulatta, in Pan trogloydates and in human. This shift corresponds with a significant increase of DDX3Y protein expression in the macaque testis and kidney tissue. In chimpanzee and human, shift to predominant use of the most proximal APA site is associated with translation of these DDX3Y transcripts in only premeiotic male germ cells. We therefore assume evolution of a positive selection process for functional DDX3Y testis transcripts in these primates to promote increase of their stability and balancing translation efficiency especially in the male germ line.