Amnesia for Complex Naturalistic Scenes and for Objects Following Fornix Transection in the Rhesus Monkey

Rhesus monkeys ( Macaca mulatta ) were trained to discriminate among many complex naturalistic scenes. The scenes were still frames from a cinema film. They were presented as the discriminative stimuli in a concurrent discrimination learning task in which each discriminative stimulus was presented on one trial each day. Learning of this task was severely impaired by fornix transection. The same animals were also deficient in a similar concurrent discrimination learning task, with each discriminative stimulus presented on one trial each day, but with objects, not complex scenes, as the stimulus material. The impairment in object discrimination learning in the present experiment is attributable to an interaction of object discrimination learning with scene discrimination learning, and can be understood as an effect of interference in long-term memory. In contrast to these impairments in long-term memory, a test of within-session learning of complex scenes, in which the average interval between successive presentations of the same stimulus was <3 min, was performed without significant impairment by the fornix-transected animals. These results show that long-term memory for complex naturalistic scenes reveals analogues in the monkey of human episodic memory and its impairment in amnesia.     

The anti-arthritic and immunosuppressive effects of cyclosporin A on collagen-induced arthritis in the rhesus monkey.

The influence of cyclosporin A (CsA) on type II collagen-induced arthritis (CIA) in the rhesus monkey has been investigated. CsA was administered subcutaneously in a dose of 25 mg/kg per day during 9-18 days and additionally 12.5 mg/kg per day for 7 days. At this dosing regime no significant alterations of haematologic parameters were found, indicating that the toxicity of CsA was negligible. Administration of CsA after onset of arthritis had no beneficial effect, but when given between immunization and manifestation of clinical symptoms, CIA could be prevented completely. Moreover, these monkeys became resistant to the disease, because no arthritic activity could be observed upon a booster immunization with type II collagen (CII). The suppression of disease by CsA is reflected in reduced antibody levels to CII.     

Effects of maternal style on infant behavior in Japanese macaques (Macaca fuscata)

We assessed the association of maternal style and infant behavior of group-living Japanese macaques during the first year of infant development. We tested the hypothesis that different mothering styles were correlated with the behavioral repertoire of infants at three different developmental stages. We expected that infants of rejecting mothers would show a higher level of enterprise and that infants of protective mothers would be less interested in the external environment. We found evidence that maternal style affects infant behavior during the early developmental phase, but this influence becomes smaller as the infant grows older and approaches complete independence. Maternal protectiveness appears to have long-lasting effects on infant exploration as infants of protective mothers tended to be less attracted by the external environment. On the other hand, mater- nal rejection appears to have long-lasting effects on infant interaction with other group members as more rejected infants tended to initiate a significantly higher number of contacts with other juveniles and adults. These results suggest that both maternal rejection and maternal protectiveness play an important role in the independence of the offspring, in opposite directions. That is, rejection promotes independence whereas protectiveness delays it.     

Cryobiology of non-human primate oocytes

The responses to various stresses involved with cryopreserv-ationprotocols were investigated using non-human primate oocytes.Fluorescence microscopy was used to assess the status of theF-actin microfilament system of rhesus monkey oocytes afterexposure to different concentrations of glycerol. The F-actinorganization around the cortex and hi the transzonal processeswas modified by exposure to 1.0 or 2.0 M glycerol at ambienttemperature. These effects were reduced significantly when exposureto glycerol was combined with cooling to 0C. Cynomolgus monkeyoocytes were also subjected to hyperosmotic stress and observedfor morphological changes. An irregular shrinkage phenomenonwas observed with germinal vesicle or metaphase I but not metaphaseII (MIl) oocytes. The irregular shrinkage became uniform andspherical when the oocytes were pretreated with ethyleneglycol-bis-(3-aminoethylether)N, N, N', N' tetraacetic acid (EGTA) before exposure tohypertonic solution. Also, in-vitro-matured MIl oocytes fromcynomolgus monkeys were used to determine crucial biophysicalparameters for freezing primate oocytes. The permeability ofoocyte plasma membrane to water, Lpg, and its activation energy,E_LP, were determined between 0 and -12C in the absence of cryoprotectiveadditives. The Lpg was found to be 3.8 10–14 m3N/s andthe ELp was 141.5 kJ/mol. The pre-exponential kinetic and exponentialthermodynamic parameters of intracellular ice formation weredetermined to be 8108 m2/s and 2.2 109 K5 respectively. Bycombining models of water transport and intracellular ice formation,the cumulative fraction of oocytes with intracellular ice asa function of the cooling rate was also predicted, and it wasshown to correlate reasonably with experimental observations.     

MhcDRB-sequences from cynomolgus macaques (Macaca fascicularis) of different origin

Cynomolgus macaques are frequently used in biomedical research. However, in contrast to their closest relative, the rhesus macaque, little is known about their Mhc genes except for the DQB1 locus. In this study, 33 DRB-sequences belonging to 17 allelic lineages were detected in a total of 68 macaques, 58 originating from Mauritius and 10 from China. The majority of the sequences were detected in the few macaques from China, confirming the low degree of genetic variation in macaques from Mauritius. In summary, the DRB region in cynomolgus macaques is polymorphic. The sequences belong in general to the same allelic lineages as in their closest relative, the rhesus macaque. Two exon 2 DNA sequences were identical in both species and may represent a trans-species origin. In addition, protein sequences of members of the DRB*W1 lineage seem to be rather conserved in the three macaque species examined so far. Six DRB-haplotypes were detected in the macaques from Mauritius. While single DRB-alleles or some protein sequences seemed to be conserved among macaque species, we could not detect any evidence for a trans-species conservation of a complete DRB region. Overall, the data indicate that reorganization of the DRB region by recombination is a major force in creating diversity in cynomolgus macaques as it is in rhesus macaques.     

Permeability characteristics and osmotic sensitivity of rhesus monkey (Macaca mulatta) oocytes

BACKGROUND: Permeability characteristics and sensitivity to osmotic shock are principal parameters that are important to derive procedures for the successful cryopreservation of mammalian oocytes. METHODS AND RESULTS: The osmotically inactive volume of rhesus monkey oocytes was determined by measuring their volumes in the presence of hypertonic solutions of sucrose from 0.2 to 1.5 mol/l, compared with their volume in isotonic TALP-HEPES solution. Boyle-van't Hoff plots at infinite osmolality indicated that the non-osmotic volumes of immature and mature oocytes were 20 and 17% respectively. Osmotic responses of oocytes exposed to 1.0 mol/l solutions of glycerol, dimethylsulphoxide (DMSO) and ethylene glycol (EG) were determined. Rhesus monkey oocytes appeared to be less permeable to glycerol than to DMSO or to EG. Sensitivity of oocytes to osmotic shock was determined by exposing them to various solutions of EG (0.1 to 5.0 mol/l) and then abruptly diluting them into isotonic medium. Morphological survival, as measured by membrane integrity, of oocytes diluted out of EG depended significantly on the concentration of EG (P < 0.01). CONCLUSION: Determination of permeability characteristics and sensitivity to osmotic shock of rhesus oocytes will aid in the derivation of procedures for their cryopreservation.     

Specific detection of human coagulation factor IX in cynomolgus macaques

Summary.  After screening for species-specific antihuman factor (F)IX monoclonal antibodies, we found that antibody 3A6 did not bind to cynomolgus FIX. The 3A6 epitope was found to include Ala262 of human FIX. The 3A6 antibody was used as a catching antibody in an enzyme immunoassay (EIA) for specific detection of human FIX in cynomolgus macaque plasma. No significant increase of substrate hydrolysis was observed when EIA buffer containing cynomolgus macaque plasma was subjected to the 3A6-based EIA. Addition of up to 30% cynomolgus macaque plasma or canine plasma to the assay did not alter detection of human FIX. Three cynomolgus macaques were injected with human FIX (10 U kg⁻¹; i.v.) and the circulating human FIX was quantified in the macaque plasma. The FIX level in the circulation increased to 470 ± 37.6 ng mL⁻¹ at 1 h after the injection and gradually decreased to 1.79 ± 1.1 ng mL⁻¹ by day 5, which is approximately 0.06% of the normal human plasma FIX concentration. These data suggest that the cynomolgus macaque can be used as a primate model for studying hemophilia B gene therapy by transduction of macaque organs with vectors to express human FIX in vivo and detection of human FIX using the 3A6 monoclonal antibody.     

Adiposity and weight gain during pregnancy associate independently with behavior of infant rhesus monkeys (Macaca mulatta)

Growing evidence identifies maternal adiposity as a potentially modifiable risk factor for adverse neurodevelopment. This retrospective cohort analysis examined whether maternal prepregnancy adiposity and gestational weight gain were associated with behavioral outcomes in 173 rhesus macaque infants at the California National Primate Research Center. Dams conceived indoors, had uncomplicated pregnancies, delivered vaginally, and reared infants indoors. Infants underwent standardized biobehavioral analysis at 90–120 days of age from 3/2001–5/2015. Offspring of mothers with greater baseline adiposity or gestational weight gain exhibited a pattern of poor adaptability characterized by greater emotionality as the assessments proceeded, blunted affective response to a human intruder challenge, and reduced interest in novel stimuli which is associated with poorer social functioning later in life. They also had lower cortisol levels following dexamethasone suppression, perhaps a response to cortisol excess during gestation. These results amplify growing public health concerns implicating maternal adiposity in impaired fetal neurobehavioral programming.     

Factors shaping genetic variation in the MHC of natural non-human primate populations

Across a large distribution range, population-specific factors as well as pathogen-mediated selection may shape species genetic diversity in the major histocompatibility complex (MHC). We have studied genetic diversity and population differentiation in the MHC region of the Southeast Asian cynomolgus macaque (Macaca fascicularis fascicularis), a species with large and discontinuous range, in order to investigate the role of demography vs selection. Genetic variation was assessed at seven MHC microsatellites on 272 individuals from five populations (Indochina, Java, Borneo, Philippines, and Mauritius). A high genetic diversity was observed in all populations and the Philippines but also the Mauritius populations were the most genetically differentiated. The strength and extent of linkage disequilibrium (LD) (up to 4 Mb) varies across populations mainly because of demographic factors. In Indochina, the complete lack of LD could be the signature of ancient hybridization between cynomolgus and rhesus macaques in the Indochinese peninsula. With the additional support of seven autosomal microsatellites, tests for outlier loci based on intrapopulation diversity and interpopulation differentiation (using F-statistic) allowed to dissociate demographic from selective histories: (i) demographic history may itself explain levels of MHC variability in the Mauritius populations and (ii) positive selection could be responsible for the Philippines population differentiation, especially in the MHC class II region. Among various pathogens, Plasmodium knowlesi and Plasmodium coatneyi are two likely candidates to explain the higher frequency of some MHC haplotypes. Indeed, literature describes low parasitemia in the Philippines individuals, contrasting with fatal infections provoked by these parasites in other cynomolgus macaque populations.     

Population genetics of the ABO locus within the rhesus (Macaca mulatta) and cynomolgus (M. fascicularis) macaque hybrid zone

Knowledge of the macaque ABO blood group system has been critical in the development of nonhuman primates (NHPs) as a translational model. Serving not only as a useful homologue of the disease‐linked ABO system in humans, macaque ABO blood groups must be typed in colonies prior to performing experimental procedures requiring blood transfusion or transplantation. While the rates of blood type incompatibility and the distributions of A, B and AB blood groups are known in large samples of rhesus (Macaca mulatta) and cynomolgus (M. fascicularis) macaques, there is a dearth of blood type data from macaque populations occupying the rhesus‐cynomolgus hybrid zone in Southeast Asia. Using molecular phenotyping, we profiled ABO blood group distributions of 232 macaques from 10 populations in the hybrid zone and compared them to pure blood populations of the two species. We found that while these distributions are significantly different in most populations, there was a lack of differentiation between the hybrid and cynomolgus macaques as well as between the Thai and neighbouring populations. This supports a more expansive model of hybridization between rhesus and cynomolgus macaques than often proposed and highlights the increased need for consideration of population genetic structure in biomedical studies that employ macaques as animal models. Additionally, we report an enrichment of indeterminate blood types in the hybrid populations.