Dissertations / Theses on the topic 'Rhesus macaque'

The corticospinal tract (CST), which carries commands from the cerebral cortex to the spinal cord, is vital to fine motor control. Spinal cord injury (SCI) often damages CST axons, causing loss of motor function, most notably in the hands and legs. Our preliminary work in rats suggests that CST circuitry is complex: neurons whose axons project to the lower cervical spinal cord, which directly controls hand function, also send axon collaterals to other locations in the nervous system and may engage parallel motor systems. To inform research into repair of SCI, we therefore aimed to map the entire projection pattern, or “connectome,” of such cervically-projecting CST axons. In this study, we mapped the corticospinal connectome of the Rhesus macaque - an animal model more similar to humans, and therefore more clinically relevant for examining SCI. Comparison of the Rhesus macaque and rat CST connectome, and extrapolation to the human CST connectome, may improve targeting of treatments and rehabilitation after human SCI. To selectively trace cervically-projecting CST motor axons, a virus encoding a Cre-recombinase-dependent tracer (AAV-DIO-gCOMET) was injected into the hand motor cortex, and a virus encoding Cre-recombinase (AAV-Cre) was injected into the C8 level of the spinal cord. In this intersectional approach, the gCOMET virus infects many neurons in the cortex, but gCOMET expression is not turned on unless the nucleus also contains Cre-recombinase, which must be retrogradely transported from axon terminals in the C8 spinal cord. Thus, gCOMET is only expressed in neurons that project to the C8 spinal cord, and it proceeds to fill the entire neuron, including all axon collaterals. Any gCOMET-labeled axon segments observed in other regions of the nervous system are therefore collaterals of cervically-projecting axons. gCOMET-positive axons were immunohistochemically labeled, and axon density was quantified using a fluorescence microscope and Fiji/ImageJ software. Specific regions of interest were chosen for analysis because of their known relevance in motor function in humans, and for comparison to results of a similar study in rats. Results in the first monkey have revealed both similarities and differences between the monkey and rodent CST connectome. Analyses of additional monkeys are ongoing. The final results will provide detailed information about differences between rodent and primate CST, will serve as a baseline for examining changes in the CST connectome after SCI, and will provide guidance for studies targeting treatment and functional recovery after SCI.

Many primate populations face the threat of extinction due to habitat loss, intensive agriculture, hunting for meat, the pet trade and/or use in traditional medicines. An alternative approach to in situ conservation includes gene banking and the use of assisted reproductive technologies (ART), such as oocyte in vitro maturation (IVM) and in vitro fertilization (IVF). Although many of these 'high-tech' solutions have not yet been proven viable for pragmatic wildlife conservation, basic research and development of these emerging tools can provide necessary information needed to optimize these techniques and institute ART as a routine practice in conservation efforts. A severely limiting factor in the successful application of ARTs is the availability of mature developmentally competent oocytes. Oocyte maturation involves many nuclear and cytoplasmic factors, which can be affected by maturation conditions and female age. In vitro maturation does not have the same success rate across species studied. In primates especially, IVM oocytes exhibit reduced developmental capacity upon fertilization when compared to in vivo matured (IVO) oocytes. This study aimed to investigate possible causes of reduced developmental capacity of primate IVM oocytes using the rhesus macaque (Macaca mulatta) as a model. Research efforts included investigation of ovarian senescence, oocyte karyotype and spindle morphology, and establishment of an optimal sperm cryopreservation protocol for use in IVF. Histological examination of the rhesus ovary demonstrated an age-related pattern of follicle depletion similar to that described in the human ovary. Oocyte karyotype analysis revealed a significant effect of IVM on the frequency of hyperhaploidy. In addition, immunostaining and confocal microscopy demonstrated a significant increase of anomalous chromosome congression on the oocyte metaphase II spindle equator in relation to IVM and donor female age. These results indicate that IVM can produce serious, if not lethal consequences for embryo development. This study presents baseline data on ovarian aging in the rhesus macaque and aspects of nuclear maturation during macaque IVM that may contribute to the design of primate oocyte recovery plans. Implementation of either of two sperm cryopreservation methods originally developed for rhesus and vervet monkeys will aid future investigation of the developmental capacity of IVM oocytes.

Beta defensins are multifunctional secreted short peptides rapidly evolving in mammals. They present antibacterial and antiviral action in many species and possess immune cell signal activity, constituting a link between innate and adaptive immunity. In humans the β-defensin region is known to be copy number variable (CNV) and contains seven genes repeated as a block, with a diploid copy number between 1 and 12 and an approximate repeat length of 240kb but the extent and nature of CNV in other mammals remains poorly known. The rhesus macaque (Macaca mulatta) is the most widespread non-human primate, hence constituting a good model to study adaptation and its divergence time from the human lineage (~25MYA) presents enough sequence diversity to investigate mechanisms of copy number variation and evolution. Its genome has been sequenced, although there is poor assembly quality in repeated segments such as the β-defensin region. This thesis studied the genomic architecture of the rhesus macaque β-defensin region using a variety of methods (aCGH, PCR-based methods, BAC library screening and cytogenetic approaches) with the aim of overcoming the limitations of the assembly and of determining the copy number distribution for this region. Evidences are here provided that only the region containing DEFB2L gene (orthologue to human DEFB4) is CNV, with a diploid copy number between 2 and 11, with a repeat size of 20kb, while the rest of the cluster shows no variation. This could represent a case where the same area prone to copy number variation evolved to present a different copy number unit structure in two different lineages, still converging in the same copy number distribution for the possible effect of similar functional constraints. Also, evidences of non-synonymous variations are shown for the DEFB2L gene, suggestive of the different evolutionary pattern followed by the rhesus macaque β-defensin region.

Numerous studies show that a low level of response to the intoxicating effects of alcohol is considered a risk factor for future alcoholism. However, assessing this sensitivity usually requires administering a controlled dose of alcohol, which has a number of inherent problems. Early observations in our lab suggest that the response to anesthetics that show cross tolerance with alcohol, like ketamine, are blunted in nonhuman primates at risk for high alcohol intake, and may be a viable measure of future alcohol consumption. This study was designed to test potential predictors of future alcohol consumption using the change in ketamine across repeated exposures (i.e., tolerance). In addition, potential mediating factors of alcohol consumption, including early temperament and behavior, were assessed. Subjects were 16 three-year-old, alcohol naïve rhesus macaque males raised by their biological mothers. Ketamine Exposure-Each subject was exposed to three 10.0 mg/kg intramuscular doses of ketamine. The time from injection to recovery from anesthetic was recorded for each dose, to be used as a measure of subject's sensitivity and developed tolerance. Alcohol Intake Assessment-Two weeks after the final ketamine dose, subjects were allowed ad libitum access to a palatable 8.4% alcohol solution for two-hours a day, five days a week, for six weeks. During the Two-Choice phase of testing, subjects were simultaneously given ad libitum access to the 8.4% alcohol solution and to a sweetened solution for two-hours a day, five days a week, for four weeks. Solution consumption was recorded daily and averaged across the weeks for each phase of alcohol testing. Temperament and Behavior-As infants, all subjects participated in a bio-behavioral assessment (BBA), when they were between 90 and 120 days of age. Data collected during the BBA on subjects' temperament (Vigilance, Gentleness, Confidence, and Nervousness) and Behavior (Activity and Emotionality) were used in analyses. Results showed a relationship between the tolerance developed between ketamine doses and average alcohol consumption during the Alcohol-Only phase (r = 0.61, R2 = 0.372, F (1,14) = 8.300, p = 0.012). Average alcohol consumption during the Alcohol-Only phase was also related to ratings of Confidence (r = 0.499, R2=0.249, F(1,14)=4.647, p = 0.049), Activity (Day 1: r = 0.503, R2 = 0.253, F(1,14) = 4.732, p = 0.047; Day 2: r = 0.455, R2 = 0.207, F(1,14) = 3.652, p = 0.077), and Emotionality (r = 0.466, R2 = 0.217, F(1,14) = 3.885, p=0.069). The results of this study suggest that change in ketamine recovery time and early life temperament and behaviors may be measures of future risk for alcohol abuse disorders. This data is limited by the small sample size and future study is necessary to further tease out the relationships between these variables and alcohol consumption.

La duplicació és el principal mecanisme de formació de nou material genètic i d'innovació funcional. Entendre com les duplicacions sorgeixen, evolucionen, co-evolucionen i engendren noves funcions és essencial. Aquesta tesi recull les meves contribucions a aquest objectiu. Investigo la recombinació responsable de la co-evolució dels duplicats: conversió gènica entre loci (IGC). Específicament, exploro com l'IGC i la recombinació per entrecreuament interactuen; com la dependència de l'IGC de la similitud entre duplicats influencia la seva co-evolució i com el col·lapse de duplicats en el muntatge de genomes altera proves estadístiques. També caracteritzo la diversitat de les duplicacions altament similars del genoma humà per aclarir els seus mecanismes de duplicació, moment d'aparició i contribució a la formació de nous gens. Finalment, descric les regions duplicades i variants en nombre de còpia del genoma del macaco rhesus i hi identifico diferències gèniques en nombre de còpies de rellevància funcional amb el genoma humà.<br>Duplication is the main mechanism for the formation of new genetic material and functional innovation. Understanding the way duplications arise, evolve, co-evolve and give rise to new functions is essential. In this thesis, I present my contributions to the pursuit of this goal. I investigate the recombination process driving the concerted evolution of duplicates: interlocus gene conversion (IGC). In particular, I explore how IGC and crossover interplay, how IGC dependence on sequence similarity between duplicates influences their concerted evolution, and how IGC and the collapse of duplications in genome assemblies alters test statistics. In addition, I characterize the diversity of highly similar duplications in the human genome to elucidate their duplication mechanisms, their time of appearance and their contribution to the formation of new genes. Finally, I describe the duplicated and copy-number variant regions in the rhesus macaque genome and identify therein gene copy-number differences of functional relevance with humans.

La premiere partie de ce travail decrit les niveaux d'attention chez le macaque rhesus pendant l'execution d'une tache visuo-motrice presentant divers degres de difficulte en laboratoire. L'analyse du comportement de l'animal correlee a celle de son electrocorticogramme (ecog) recueilli dans l'aire parietale posterieure (aire 5 de brodmann), par des electrodes implantees a demeure, a montre chez celui-ci des relations significatives des rythmes beta avec l'etat attentionnel de l'animal. L'attention diffuse vers l'environnement experimental a ete illustree par une dispersion des frequences, l'attention focalisee sur la tache qu'il effectue, par une concentration des frequences autour de 20-30 hz. Des enregistrements simultanes dans le cortex occipital a montre l'apparition de rythmes rapides visuels (autour de 18 hz) pendant la focalisation attentive et des rythmes dans la bande alpha (autour de 10 hz) correspondant a des stades de relaxation des sujets. Dans la deuxieme et la troisieme partie, nous avons applique cette methode ecog a l'etude des capacites d'attention et du sommeil chez 4 jeunes macaques rhesus avant, pendant et apres des vols spatiaux biocosmos dans lesquels les sujets sont leur propre temoin. L'analyse visuelle et automatisee des traces des premiers jours de vol ont temoigne d'une diminution considerable des taux de rythmes beta pendant l'execution d'une tache visuo-motrice accompagnee entre-autre d'une modification de la distribution de leurs frequences instantanees. Des rythmes lents ont ete notes pendant des phases importantes du test, signant un retrait d'attention. L'organisation structurale et temporelle du sommeil nocturne a ete egalement modifiee : augmentation des eveils et du sommeil leger, diminution du sommeil profond, augmentation du sommeil paradoxal, inversion de la distribution des taux nocturnes de sommeil lent et profond. Apres quelques jours, le sujet est redevenu plus attentif bien que les rythmes lents aient regresse lentement. Pendant la nuit, le sommeil paradoxal a diminue. Differentes hypotheses ont ete proposees pour expliquer ces troubles attentionnels et hypniques, en particulier l'effet conjugue de la microgravite et d'une tension emotionnelle.

Epstein-Barr virus (EBV) is associated with a number of human diseases and does not have a vaccine. It is believed that neutralizing antibodies are an important immune effector for an EBV vaccine, but it is unknown whether serum neutralizing antibodies can alter EBV infection through the oral mucosa. The studies presented in this dissertation were designed 1) to adapt the rhesus macaque animal model to allow testing of neutralizing antibodies in a biologically relevant system and 2) to better define the neutralizing antibody response of EBV infected humans. Infection of rhesus macaques with the EBV related lymphocryptovirus, rhLCV, provides an accurate model system for studying EBV, but there were two hurdles that needed to be overcome before neutralizing antibodies could be tested in this model. First, there are no neutralizing antibodies specific to rhLCV and we found that a potent EBV neutralizing antibody, 72A1, did not cross-neutralize rhLCV. Second, murine monoclonal antibodies are inherently immunogenic in macaques and induce anti-antibody responses that limit their utility. To create a virus sensitive to 72A1 neutralization, the major membrane glycoprotein of rhLCV with replaced with EBV gp350. The data presented here show that this chimeric virus can use EBV gp350 to support entry into macaque cells in vitro and following oral inoculation of rhesus macaques. To reduce the immunogenicity of the murine antibodies, “rhesusized” antibody variants were generated and shown to retain antigen specificity. The combination of this novel, chimeric virus and the “rhesusized” antibodies will now allow testing of neutralizing antibodies in the macaque model. Although multiple EBV glycoproteins have been shown to induce neutralizing antibodies in mice, studies of the human neutralizing antibody response have been narrowly focused on a single antibody binding epitope on gp350. Here we show that antibodies binding to this epitope do not represent all EBV neutralizing activity in human sera. Additionally, these data suggest that the neutralizing response is much broader than appreciated, with multiple glycoproteins inducing EBV neutralizing antibodies. Accurately defining the repertoire of viral glycoproteins targeted by human neutralizing antibodies can inform us of the naturally immunogenic proteins that may make good vaccine immunogens.<br>Biology, Molecular and Cellular

Thesis (M.A.)--Boston University<br>Sleep fragmentation and disturbances of normal circadian rhythms are inherent in the aging human population. The rhesus macaque (Mucaca mulatta) exhibits similar disruption in sleep patterns and is a useful model to study these disturbances. Orexin is an excitatory neuropeptide that has been implicated in the regulation of wakefulness and alertness. Specifically, it has projections from its neuronal bodies in the lateral and perifornical hypothalamus to various forebrain and brainstem regions that control arousal state. One of the regions of high innervation by these orexigenic neurons is the thalamus. This study used a semi-quantitative means to determine if there are age dependent changes in Orexin innervation in the thalamus. There was a general trend of decreasing axon density when analyzed with a novel semi-quantitative method (r = -0.515, p = 0.024, df = 17) and approached significance when assessed with a previously published method (r = -0.454, p = 0.0509, df = 17), indicating a decrease with age. Additionally, there was no significant decrease in unilateral bouton counts iii when examined with age using either method. Although the findings in this study point to an age-related decrease in axon terminals, further research should examine the total orexigenic positive content in the thalamus to explain why bouton counts do not seem to change.

La determination de la sequence nucleotidique du sivmac a montre que ce virus presente l'organisation genomique caracteristique d'un lentivirus, et qu'il est remarquablement proche du hiv-2, avec lequel il partage une homologie nucleotidique de 75%. La proximite genetique du sivmac et du hiv-2 suggere une parente evolutive entre ces deux virus et pose la question d'une origine simienne pour les virus du sida humain. Le gene d'enveloppe du sivmac presente la caracteristique d'etre tronque par un codon non-sens de la partie codant pour le domaine cytoplasmique de l'enveloppe. Lorsque le codon non-sens tag a ete remplace par un codon glutamine cag, le virus a presente une capacite de replication reduite en lignee lymphoide. Un phenomene de contre-selection de l'expression du domaine cytoplasmique a ete mis en evidence in vitro. Par contre, l'analyse par pcr a revele que, chez les macaques infectes, le domaine cytoplasmique est exprime, suggerant que cette region est necessaire au developpement de l'infection in vivo. Dans la derniere partie du travail, nous avons etudie les etapes precoces de l'encephalopathie induite par le siv. L'infection du systeme nerveux central s'est revelee etre un evenement precoce, le virus pouvant etre detecte par hybridation in situ des le 7#e jour suivant l'inoculation. Les infiltrats monocytaires representent la principale source de virus dans le snc. Nous avons observe une activation des macrophages et des cellules microgliales, ce qui suggere l'existence d'un mecanisme immunopathologique pouvant favoriser la dissemination initiale du virus dans le snc

Thesis (Ph. D.) -- University of Maryland, College Park, 2007.<br>Thesis research directed by: Animal Sciences. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.

Natural killer (NK) cells can kill virus-infected cells without prior antigenic exposure, and are therefore important for controlling viral replication prior to the onset of adaptive immune responses. Primate NK cells express activating and inhibitory killer-cell immunoglobulin-like receptors (KIRs) that bind to specific major histocompatibility complex (MHC) class I molecules. The importance of KIR interactions with MHC class I in human immunodeficiency virus (HIV) pathogenesis is demonstrated by the association of select KIR and MHC class I genotypes with delayed progression to acquired immunodeficiency syndrome (AIDS).

Le travail realise a porte sur l'etude du macaque rhesus infecte par le virus d'immunodeficience simienne (siv) comme modele de l'infection humaine par le virus d'immunodeficience humaine (hiv). En effet, l'infection par siv des macaques presente une forte analogie avec l'infection humaine par hiv, en terme d'evolution virologique et clinique. Nous avons valide ce modele en terme de reponses immunes cellulaires. Ce modele represente donc un outil de choix pour les etudes physiopathologiques afin de comprendre les mecanismes conduisant au deficit immunitaire et pour les etudes vaccinales

Nos travaux ont ete orientes vers l'etude des modifications des genes nef et env qui peuvent moduler la virulence des lentivirus de primates, les virus de l'immunodeficience humaine (vih) et simienne (siv). Nous nous sommes servis de deux modeles : l'infection de macaques rhesus par le siv ou par des virus chimeres siv-vih (shiv) porteurs des proteines d'enveloppe de virus vih-1 x4 ou r5. L'evolution clinique observee chez des macaques inocules avec un siv attenue nous a incite a caracteriser les virus afin de rechercher les modifications associees a l'augmentation de virulence. Notre analyse s'est concentree sur l'analyse du gene nef en raison de son importance pour le pouvoir pathogene des lentivirus de primates. Nous montrons que l'extremite carboxy terminale de nef confere au sivmac un avantage replicatif in vivo. Dans une seconde etude, notre objectif a ete d'augmenter la virulence d'un virus chimere siv-vih, le shivsbg. Le pouvoir pathogene extreme du sivsmmpbj14 etant associe a la presence d'une tyrosine dans l'extremite n-terminale de nef, nous avons insere cette mutation dans le genome du shivsbg et caracterise les proprietes replicatives du virus mute in vitro, puis in vivo chez des macaques. Devant l'absence de virulence extreme, nous avons caracterise les souches virales et identifie les alterations de nef qui pourraient etre responsables de cette propriete. Une troisieme partie a consiste a obtenir un shiv porteur de l'enveloppe de l'isolat primaire vih-1 bx08 et capable de reproduire, chez le macaque, l'infection humaine a vih. Les vih-1 r5 sont transmis majoritairement et constituent les virus principaux contre lesquels la vaccination doit proteger. Des virus d'epreuves semblables aux isolats vih r5 sont indispensables pour reproduire l'exposition aux souches virales circulantes et permettre d'evaluer chez l'animal la protection conferee par les candidats vaccins.

Rhesus macaques represent a valuable model in biomedical research and in development of vaccines and therapeutics. Due to the lack of reagents, the general properties of IgG and corresponding cellular receptors (FcγR) in this species are poorly characterized. We engineered recombinant IgGs containing each of the four rhesus macaque heavy constant region (CH) subclasses. To define FcγRs that mediate IgGs, we identified and characterized three FcγR classes, and generated recombinant cDNA constructs. cDNA IgH constructs were created by fusing – by sequence overlap extension PCRs – a gene segment encoding the murine variable heavy domain specific for the hapten NIP, an established specificity system for assessing antibody effector functions, with rhesus macaque CH fragments. The complete IgH constructs were transfected into J558L cells, a murine IgH-lost myeloma cell line expressing anti-NIP light chain. Secretion of engineered IgGs was determined by ELISAs using NIP-BSA and anti-monkey IgG-specific antibodies. Molecular cloning methods were applied to identify and clone FcγR genes, and recombinant FcγR cDNA constructs were created by the recombinant DNA method. Four engineered IgH cDNA constructs were successfully created. Recombinant IgGs, in the intact Ig form and retaining the original anti-NIP specificity, were successfully produced. Compared to those in humans, FcγRs in rhesus macaques share high homology, yet also feature a relatively high level of intra-species polymorphism and possess different N-linked glycosylation patterns. FcγR constructs and expression vectors were successfully generated. The chimeric recombinant IgGs are powerful tools for defining IgG functional properties and studying CH structure/function relationship. These molecules can also be used as immunogens for generation of antibodies capable of unequivocally detecting individual IgG subclasses. The findings on FcγRs validate rhesus macaques as a model for studying antibody responses, and underscore the need to take into account of the genetic heterogeneity. The FcγR constructs and vectors serve as a tool for further studies of IgG/FcγR interactions. We also reported here our findings from a separate study that the main female hormone, 17β-estradiol, is capable of restoring antibody responses to an influenza vaccine in a postmenopausal mouse model, suggesting that immunogenicity and efficacy of influenza vaccines should be evaluated in postmenopausal women.

Thesis (M.S.) -- University of Maryland, College Park, 2006.<br>Thesis research directed by: Dept. of Nutrition and Food Science. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.

This research address the problem of inferring, through Radio-Frequency Identification (RFID) tracking data, the graph structures underlying social interactions in a group of rhesus macaques (a species of monkey). These social interactions are considered as independent affiliative and dominative components and are characterized by a variety of visual and auditory displays and gestures. Social structure in a group is an important indicator of its members’ relative level of access to resources and has interesting implications for an individual’s health. Automatic inference of the social structure in an animal group enables a number of important capabilities, including: 1. A verifiable measure of how the social structure is affected by an intervention such as a change in the environment, or the introduction of another animal, and 2. A potentially significant reduction in person hours normally used for assessing these changes. The behaviors of interest in the context of this research are those definable using the macaques’ spatial (x,y,z) position and motion inside an enclosure. Periods of time spent in close proximity with other group members are considered to be events of passive interaction and are used in the calculation of an Affiliation Matrix. This represents the strength of undirected interaction or tie-strength between individual animals. Dominance is a directed relation that is quantified using a heuristic for the detection of withdrawal and displacement behaviors. The results of an analysis based on these approaches for a group of 6 male monkeys that were tracked over a period of 60 days at the Yerkes Primate Research Center are presented in this Thesis.

Rhesus macaques are a widely used animal model of human diseases and related immune responses. Fc receptors (FcRs) mediate the interaction between antibody molecules and innate killing mechanisms, consequently eliminating the pathogen. In rhesus macaques, FcRs are highly polymorphic. To evaluate the potential influence of FcgR polymorphisms on the interaction with antibody molecules, we performed in silico analysis using SIFT, Provean, nsSNPAnalyzer, I-Mutant, MuSTAB and iPTREE-STAB web servers. V20G in FcγRI, I137K in FcγRII and I233V in FcγRIII were further analyzed structurally using FOLD-X, AMMP and Chimera to calculate changes in folding and interaction energy and for structure visualization. Results from our analysis suggest that the selected variations destabilize protein structure. Additionally, Q32R increases the binding affinity of FcγRI, whereas A131T decreases the binding affinity of FcγRII towards IgG1. Together, our results indicate that these substitutions might influence effector and regulatory mechanisms resulting from antibody/FcR interactions.

Dans un premier temps nous avons voulu determiner le role in vivo des reponses t cd8+ cytotoxiques (ctl) dans le modele macaque rhesus/siv grace a un suivi longitudinal de 2 ans de 2 cohortes de 12 macaques, une infectee par le siv, l'autre vaccinee par un melange de lipopeptides comprenant 7 sequences issues des proteines nef et gag puis infectee par le siv. Nous avons pu montrer que la presence de reponses ctl etait inversement correlee a la viremie cellulaire, et que la reponse cytotoxique avait un role benefique sur l'evolution clinique des animaux puisqu'elle etait associee a une phase asymptomatique de plus longue duree. Ensuite, afin d'etudier le devenir des reponses ctl chez les macaques vaccines apres infection, nous avons immunise 4 autres macaques par les memes lipopeptides. Chez 2 macaques la reponse ctl induite etait dirigee contre un seul et meme epitope de la proteine nef et cette reponse monospecifique etait perdue au 5 e m e mois. L'analyse des sequences provirales de nef chez les 2 macaques a montre que il y avait eu la selection d'un variant viral minoritaire moins immunogene, puis l'apparition d'un mutant d'echappement. Un autre macaque ne presentait pas de ctl ni apres immunisation ni apres infection et a evolue rapidement vers un sida. Le quatrieme macaque qui possedait des ctl bispecifiques a montre lui aussi la selection de variants et l'apparition de mutants d'echappement mais avec un controle majeur de la charge virale et une periode asymptomatique plus longue. Afin d'obtenir des reponses ctl polyspecifiques nous avons ajoute un epitope cd4 a notre preparation vaccinale, pouvant induire une forte reponse t auxiliaire : le peptide 830-846 de l'anatoxine tetanique. Huit autres macaques ont ete immunises avec la tt puis avec les 8 lipopeptides dans une nouvelle formulation vaccinale de micelles mixtes. Nous avons mis en evidence une reponse ctl chez 7 macaques sur 8 et chez 2 d'entre eux ces reponses etaient polyspecifiques dirigees contre 4 a 6 peptides de nef et/ou de gag et etaient correlees avec la presence d'une reponse th cd4+ anti-peptide tt 830-846 de type th1 (secretion d'ifn-). Apres le test d'inoculation d'epreuve les macaques n'ont pas ete proteges contre l'infection, neanmoins, a partir du 3 e m e mois, le macaque ayant des ctl diriges contre 6 epitopes a une viremie cellulaire et plasmatique indetectables.

Evidence suggests that certain genotypic variants associated with novelty-seeking and aggressiveness, such as the 7-repeat dopamine D4 receptor variant (DRD4-7R), short (s) allele of the serotonin transporter (5-HTT), and the low-activity variant of the MAOa promoter (MAOa-L), are more prevalent in human groups that radiated out of Africa than human groups that remained in Africa. Rhesus macaques (Macaca mulatta), like humans, are a widespread species of primates that needed to adapt to different regional environments with one group, Indian-derived rhesus macaques, largely occupying predictable and resource-rich environments, while the other group, the Chinese-derived rhesus macaques, has come to occupy less predictable and resource-abundant environments. Rhesus macaques possess orthologues of these trait-related genes, making it possible to compare the frequency of genotypes associated with these traits between members of two strains. DNA was obtained from N=212 rhesus macaques (n=54 Chinese-derived, n=158 Indian-derived) and genotyped for DRD4 (n=98), 5-HTT (n=190), and MAOA (n=97). Analyses showed that Chinese-derived subjects exhibited higher frequencies of the DRD4-7R and 5-HTT-s-allele when compared to Indian-derived subjects. There were no strain differences in MAOA-L genotype groupings, but the Chinese-derived subjects exhibited a more frequent high-activity (MAOA-H-6R) allele when compared to the Indian-derived subjects. The results suggest that the Chinese-derived rhesus macaques possess a higher frequency of alleles associated with novelty-seeking, impulsivity, and aggressiveness compared to their Indian-derived peers and that those genotypically-mediated traits may have beneficial to both humans and rhesus macaques as they spread into novel and unfamiliar environments.

Mu-opioid receptor (MOR) agonists are effective agents for pain management, but are also limited by a number of undesirable effects. One approach to enhance the therapeutic effects and minimize the undesirable effects of MOR agonists may be to combine MOR agonists with an adjunct targeting a different receptor system. This targeted medical approach, known as “combination therapy”, aims to augment the desired effects of the MOR agonist (i.e. antinociception) and/or diminish the undesirable deleterious side effects of the MOR agonist. This dissertation investigated the utility of this approach in an assay of thermal nociception and schedule-controlled responding in male rhesus monkeys with three aims. One aim determined the utility of N-methyl D-aspartate (NMDA) receptor antagonists to selectively enhance MOR agonist antinociception. A second identified the pharmacological determinants of antinociceptive interactions between a nociceptin opioid peptide (NOP) receptor agonist and MOR agonists. A third aim investigated the potential for fixed-proportion mixtures of a competitive MOR antagonist and MOR agonist to manipulate antinociceptive efficacy. Experimental results did not support the utility of NMDA antagonists as adjuncts to selectively enhance MOR agonist antinociception. Furthermore, the antinociceptive interactions between a NOP agonist and MOR agonists were modest and occurred under a narrow range of conditions. Finally, fixed proportion MOR antagonist-agonist mixtures were effective in manipulating antinociceptive in vivo efficacy. In conclusion, this dissertation does not provide strong empirical evidence that a combination therapy approach will result in clinically effective and selective enhancement of MOR agonist analgesia. The dissertation concludes with proposed strategies and novel preclinical methods to enhance preclinical-to-clinical translation of effective candidate analgesics.

B virus diagnosis presents a challenge largely complicated by the asymptomatic infection of rhesus macaques, and extremely pathogenic fatal infections in humans. Humoral detection of antibodies is generally performed using whole virus antigen for which preparation requires strict biosafety measures and specialized BSL-4 facilities. As an alternative to utilizing B virus antigen, we describe the production of a truncated form of B virus envelope glycoprotein D, gD 287, in a baculovirus expression system, and evaluate its diagnostic potential as an antigen in recombinant ELISA. After purification and characterization, gD 287 was tested using 22 negative and 72 positive macaque sera samples previously classified using the traditional method. We find that sensitivity and specificity of the recombinant ELISA are dependent on antibody titer of tested serum and gD 287 shows good to excellent predictive potential for identification of positive sera with titers higher than 500.

Detecting and interpreting sensory events, and remembering those events in in the service of future actions, forms the foundation of all behavior. Each of these pillars of the so-called "perception-action cycle" have been topics of extensive inquiry throughout recorded history, with philosophical foundations provided by early BCE and CE periods (especially during the Classic and Renaissance eras) leading to intensive empirical study in the twentieth and twenty-first centuries. Such experiments have described detailed (but incomplete) behavioral functions reflecting perception and memory, and have begun to unravel the extraordinarily complex substrates of these functions in the nervous system. The current dissertation was motivated by these findings, with the goal of meaningfully extending our understanding of such processes through a multi-experiment approach spanning the behavioral and neurophysiological levels. The focus of these experiments is on short-term memory (STM), though as we shall see, STM is ultimately inseparable from sensory perception and is directly or indirectly associated with guidance of motor responses. It thus provides a nexus between the sensory inputs and motor outputs that describe interactions between the organism and environment. In Chapter 2, previous findings from nonhuman primate literature describing relatively poor performance for auditory compared to visual or tactile STM inspired similar comparisons among modalities in humans. In both STM and recognition memory paradigms, accuracy is shown to be lowest for the auditory modality, suggesting commonalities among primate species. Chapters 3-5 examined STM processing in nonhuman primates at the behavioral and neurophysiological levels. In Chapter 3, a systematic investigation of memory errors produced by recycling memoranda across trials (proactive interference) is provided for the understudied auditory modality in monkeys. Such errors were ameliorated (but not completely eliminated) by increasing the proportions of unique memoranda presented within a session, and by separating successive trials by greater time intervals. In Chapter 4, previous results revealing a human memory advantage for audiovisual events (compared to unimodal auditory or visual events) inspired a similar comparison in monkeys using a concurrent auditory, visual, and audiovisual STM task. Here, the primary results conformed to a priori expectations, with superior performance observed on audiovisual trials compared to either unimodal trial type. Surprisingly, two of three subjects exhibited superior unimodal performance on auditory trials. This result contrasts with previous results in nonhuman primates, but can be interpreted in light of these subjects' extensive prior experience with unimodal auditory STM tasks. In Chapter 5, the same subjects performed the concurrent audiovisual STM task while activity of single cells and local cell populations was recorded within prefrontal cortex (PFC), a region known to exhibit multisensory integrative and memory functions. The results indicate that both of these functions converge within PFC, down to the level of individual cells, as evidenced by audiovisual integrative responses within mnemonic processes such as delay-related changes in activity and detection of repeated versus different sensory cues. Further, a disproportionate number of the recorded units exhibited such mnemonic processes on audiovisual trials, a finding that corresponds to the superior behavioral performance on these trials. Taken together, these findings reinforce the important role of PFC in STM and multisensory integration. They further strengthen the evidence that "memory" is not a unitary phenomenon, but can be seen as the outcome of processing within and among multiple subsystems, with substantial areas of overlap and separation across modalities. Finally, cross-species comparisons reveal substantial similarities in memory processing between humans and nonhuman primates, suggesting shared evolutionary heritage of systems underlying the perception-action cycle.

In the present study, electrophysiological and behavioral effects of compromised Gama-Aminobutyric Acid (GABAergic) transmission were investigated in adult Rhesus macaque monkeys (N=2). GABAergic transmission was perturbed in the putamen by administration of a GABAa receptor antagonist, gabazine (10 and 500 μM), via a microdialysis-local field potential (MD-LFP) probe. Resultant changes in striatal local field potentials (LFPs) were measured as an assay of synchrony. Gabazine perfusion evoked discrete large amplitude spikes in LFPs in all subjects, and the frequency and shape of individual spikes were concentration-dependent. Pre-treatment with the GABAa receptor agonist, muscimol (100 μM) blocked the gabazine-induced events, confirming a role for GABAa receptors in the effects. Behavioral manifestations of gabazine treatment were observed only at the maximum concentration. Unusual facial movements suggested aberrant electrical activity was propagated from striatum to motor cortex, perhaps via reentrant circuits. These results support a role for GABAergic transmission in segregation of striatal circuits.

Facilities housing non-human primates are required to make provisions for their psychological wellbeing, which may include monitoring animals for signs of decreased wellbeing such as the presence of abnormal behaviors or alopecia. By analyzing archival behavioral data collected by the Behavior Management Unit at the Yerkes National Primate Research Center (YNPRC), I aimed to identify behavioral predictors of self-wounding and alopecia and to evaluate the effectiveness of current treatments in reducing abnormal behavior and alopecia in rhesus macaques (Macaca mulatta). The behaviors of self-biting and hair plucking (conditional logistic regression, p < .05) as well as floating limb and self-oral behaviors (Mantel-Haenszel chi-square tests, p < .05) were identified as behavioral predictors of self-wounding. Fear behaviors were associated with an increased risk of developing alopecia (Mantel-Haenszel chi square, p < .05). An inverse relationship was found between alopecia and stereotypic locomotor behaviors such as pacing, with animals who displayed these behaviors being less likely to develop significant hair loss (conditional logistic regression, p < .05). Overall, the type of treatment provided (e.g., additional foraging opportunities, the provision of toys, or the provision of visual barriers) did not predict improvement in levels of abnormal behavior or alopecia (logistic regression, p > .05). The results of these analyses add to the literature on self-wounding and alopecia and will allow refinement of the quantitative behavioral monitoring system at YNPRC such that more at-risk animals can be identified and treated prior to the development of abnormal or harmful behaviors.

Le macaque rhésus infecté par le virus de l’immunodéficience simienne (SIV) fait l’objet de nombreuses études en tant que modèle de la pathogenèse induite par le virus de l’immunodéficience humaine de type 1 (VIH-1). Il existe deux sous-espèces de macaque rhésus définies notamment d’après leur origine géographique. Le macaque rhésus indien montre une progression pathologique particulièrement rapide, caractérisée par une déplétion massive de la population lymphocytaire T CD4+ intestinale les jours suivant l’infection. Cette déplétion a été associée à la translocation des bactéries commensales à travers l’épithélium intestinal en phase chronique. En revanche, chez le macaque rhésus chinois la vitesse de développement de la maladie est comparable à celle des patients infectés par le VIH-1. En périphérie, les données virales et immunologiques sont également plus proches de ce qui est documenté chez l’Homme infecté. Toutefois, la cinétique de dégradation de la muqueuse intestinale les jours suivant l’infection reste peu explorée dans ce modèle. Dans un premier temps, mes travaux de doctorat ont permis de confirmer la dissémination rapide du SIV dans le tractus gastro-intestinal du macaque rhésus d’origine chinoise. L’intestin grêle, notamment l’iléon, est la cible d’une réplication virale soutenue et très précoce. Malgré une réplication virale intense, le nombre de lymphocytes T CD4+ dans la muqueuse de l’iléon reste constant durant les deux premières semaines suivant l’infection par le virus dans ce modèle. Nous observons en revanche une augmentation conséquente du nombre de cellules T cytotoxiques et de macrophages, suggérant la mise en place d’une forte réponse immune in situ. Nous démontrons que l’augmentation du nombre de ces cellules et le maintien du nombre de lymphocytes T CD4+ dans la muqueuse iléale sont certainement liés, du moins en partie, au recrutement de cellules circulantes. En effet, nous décrivons pour la première fois une augmentation significative de l’expression de nombreuses chimiokines par cette muqueuse dès les premiers jours suivant l’infection. En parallèle nous décrivons, dans le sang périphérique, une diminution transitoire du nombre de lymphocytes T CD4+ et CD8+. Enfin, nous avons décelé une augmentation de l’expression d’interleukine 7 (IL-7) après infection. Cette augmentation, spécifiquement observée dans la muqueuse de l’intestin grêle, est corrélée à l’expression des chimiokines. Ces résultats apportent de nouveaux éléments sur la contribution de l’IL-7 dans la régulation de l’expression des chimiokines par la muqueuse intestinale suite à l’infection par le SIV. L’ensemble de nos résultats démontre que la population de lymphocytes T CD4+ de l’intestin grêle est préservée au cours de l’infection aiguë par le SIV chez le macaque rhésus chinois. En parallèle, l’exacerbation de l’expression locale de chimiokines laisse supposer une relocalisation des cellules du système immunitaire vers la muqueuse intestinale. Ces migrations pourraient avoir des effets délétères pour l’hôte en apportant de nouvelles cibles nourrissant la réplication virale. A l’opposé, le recrutement localisé de cellules immunitaires clés pour le déclenchement des réponses antivirales innées et adaptatives pourrait limiter la réplication du virus. Il est donc crucial de mieux définir l’impact de ce recrutement sur l’immunité muqueuse et la progression de la maladie. Nos découvertes apportent également de nouveaux arguments en faveur de l’utilisation du macaque rhésus d’origine chinoise en tant que modèle de choix pour l’étude de la physiopathologie de l’infection humaine par le VIH-1<br>As a model to study type 1 human immunodeficiency virus (HIV-1) pathogenesis, rhesus macaques infected with the simian immunodeficiency virus (SIV) are under extensive investigation. Two subspecies of rhesus macaques have been defined, based on a different geographic origin. Indian rhesus macaques exhibit a rapid disease progression and acute infection is characterized by a massive CD4 T-cell loss in the intestinal mucosa. This was associated to the translocation of bacterial products through the gut epithelium during the chronic stage. Contrary to the animals of Indian origin, the pathogenesis of Chinese rhesus macaques infected with SIV is similar to HIV-1 infected patients. Viral and immunological settings in periphery are also closer to what is described in infected humans. However, the kinetics of mucosal disruption is poorly documented in this model. As a first step, I confirmed the rapid SIV dissemination in the gastro-intestinal tract of Chinese rhesus macaques. The small intestine, in particular the ileum, undergoes an early and high viral replication. Despite this high viral load, the numbers of CD4+ T cells in the ileum mucosa remains unchanged during the first two weeks following infection in this model. On the other hand, we noticed a substantial augmentation of cytotoxic T-cell numbers and macrophages, suggesting the establishment in situ of a strong immune response. We demonstrated that this augmentation of CD8+ T cells and macrophages together with the maintenance of helper T-cell numbers in the ileum mucosa are most probably related, at least in part, to the recruitment of circulating cells. Indeed, we describe for the first time a significant augmentation of numerous chemokine expressions by this mucosa the first days post-infection. At the same time, we described a transient diminution of CD4+ and CD8+ T-cell numbers in the blood. Finally, we detected a significant upregulation of interleukine 7 (IL-7) expression after SIV infection. This increase, specifically observed in the small intestine mucosa, is correlated to chemokine expressions. These results highlight new evidences on IL-7 contribution in the regulation of chemokines expression following SIV infection. All together, our results revealed the preservation of CD4+ T cell population in the small intestine mucosa during the acute phase of SIV infection in Chinese rhesus macaques. Furthermore, the exacerbation of local chemokine expressions let us think that immune cells are relocated to the intestinal mucosa the first days after infection. These migrations could have deleterious effects to the host, bringing new targets for viral replication. On the other side, this localized recruitment of immune cells that are key players in intestinal immunity could restrict the replication of the virus. Consequently, it is of major importance to better define the impact of immune cells trafficking on intestinal mucosa integrity and disease progression. Our findings bring new arguments in favor of Chinese rhesus macaque as a suitable model to study HIV-1 pathogenesis

L'infection experimentale du macaque par le sivmac constitue le meilleur modele animal de l'infection humaine par le vih. En effet, le siv est genetiquement apparente au vih, il presente le meme tropisme cellulaire et induit en quelques mois une pathologie semblable au sida. Ce modele constitue donc un bon outil pour mieux comprendre la physiopathologie de l'infection par le vih, et l'essai de preparations vaccinales nous avons examine des parametres immunitaires et la charge virale au cours des etapes precoces suivant l'infection par le virus pathogene sivmac251 et le virus sivmac251deltanef attenue par deletion du gene nef. Dans le contexte d'une infection par le virus pathogene, nous avons montre : (1) la charge virale initiale est peu dependante de la dose d'inoculum ; (2) l'infection est suivie d'un pic de production d'ifn-a qui precede mais n'est pas capable de limiter le pic de replication initiale ; (3) la production de la plupart des cytokines est stimulee apres infection et nous n'avons pas pu mettre en evidence de profil particulier associe a l'efficacite du controle de la replication virale ; toutefois (4) une association a pu etre etablie entre le niveau d'ifn-g et niveau de l'antigenemie p27 circulante, suggerant un effet benefique de l'ifn-g ; (5) l'efficacite de la resorbtion de la charge virale initiale est un facteur predictif de l'evolution ulterieure. Dans une optique vaccinale, nous avons egalement infecte des singes par le virus attenue sivmac251deltanef dont une parti a ete ensuite soumis a une inoculation d'epreuve avec le virus pathogene sivmac251. A ce jour, la seule preparation vaccinale reellement efficace est basee sur l'utilisation d'un virus vivant attenue par inactivation du gene nef. Nous avons montre chez ces animaux que : (1) l'infection par le virus attenue induit une charge virale beaucoup plus faible que le virus pathogene chez les animaux naifs ; (2) les animaux n'ont pas developpe de pathologie apres cinq annees d'observation ; (3) les animaux vaccines ne sont pas totalement proteges contre l'infection par le virus d'epreuve potentiellement pathogene, bien que ces animaux n'aient pas developpe de pathologie cinq annees apres l'inoculation d'epreuve.

L'interleukine 7 (IL-7) est une cytokine indispensable au développement et à l'homéostasie des lymphocytes T. Le récepteur à l'IL-7 (IL-7R) est composé de la chaîne alpha (ou CD127) partagée avec le récepteur au TSLP et de la chaîne commune gamma c (ou CD132) partagée avec plusieurs récepteurs de cytokines gamma. L'expression de son récepteur a été décrite dans les lymphocytes T, mais n'a pas été clairement démontrée dans les cellules présentatrices d'antigène (CPA). Cependant, l'expression de CD127 et des récepteurs aux cytokines gamma ont été décrits sur ces cellules suggérant l'expression d'un IL-7R fonctionnel par les CPA. De façon intéressante, la chaîne CD127 existe également sous différentes formes solubles (CD127s) résultant d'épissages alternatifs de l'ARN messager. Toutefois, l'expression et la régulation de l'expression des isoformes de CD127 ont été peu étudiées dans les CPA. Par ailleurs, des polymorphismes du gène CD127 ont été identifiés et associés à une forte concentration plasmatique de la forme soluble CD127s ∆6 chez l'Homme et à une plus forte susceptibilité de développer des maladies auto-immunes. Certains de ces polymorphismes ont également été associés à une évolution plus rapide vers le stade SIDA chez les patients HIV. Enfin, sa capacité à lier l'IL-7 suggère un rôle important de cette forme soluble dans la régulation de la réponse à l'IL-7 en agissant sur sa biodisponibilité. Cependant, l'expression de CD127s plasmatique est très controversée chez les patients HIV en phase chronique. De plus, son expression n'est pas connue dans les organes infectés et n'a jamais été décrite en phase aiguë de l'infection. Enfin, son origine et sa fonction ne sont pas encore élucidées. La quantification spécifique de CD127s ∆6 par RT-qPCR chez le macaque rhésus sain révèle une expression minoritaire de CD127s ∆6 dans les PBMC, faible dans les intestins, plus importante dans les ganglions et encore plus importante dans les poumons. De façon plus précise, cette étude met en évidence sur cellules isolées du sang et de la rate de singes sains, une faible expression de CD127 par les monocytes caractérisée néanmoins par une représentation majeure de la forme soluble contrairement aux lymphocytes T. Ces résultats ont été confirmés par la suite in vitro dans 2 populations immunitaires majoritaires des poumons : les macrophages alvéolaires primaires (MA) issus de lavages broncho-alvéolaires (LBA) de macaque rhésus sains et les cellules épithéliales pulmonaires (CEP) humaines de la lignée NCI-H226. Dans une deuxième partie, la quantification spécifique de CD127s ∆6 par RT-qPCR dans les organes (ganglions et poumons) et le dosage de la protéine CD127s plasmatique en phase aiguë de l'infection SIVmac251 révèlent une augmentation significative de son expression dans les poumons aux temps J7, J10 et J14 post infection et de sa concentration plasmatique à J10 chez les singes infectés. Enfin dans une dernière partie, la charge virale et l'IL-7 endogène ont également été mesurées chez les singes infectés afin de mieux comprendre les mécanismes de régulation de l'expression de CD127s ∆6 au cours de l'infection par le SIVmac251. De façon surprenante, aucune corrélation n'a été trouvée entre l'expression de CD127s ∆6 et la charge virale ou l'expression d'IL-7 endogène chez les singes infectés et les singes sains après injection d'une dose pharmacologique d'IL-7. Ces données suggèrent un effet indirect de l'IL-7 et du virus sur l'expression de CD127s ∆6 et un rôle des facteurs de l'inflammation dans la régulation de son expression. Dans l'objectif de mieux définir ces mécanismes de régulation, les transcrits codant pour la forme soluble ont été quantifiés dans les MA et les CEP in vitro après 6H de stimulation ou non sous IL-7 ou TSLP (ligands de CD127) seul ou couplé au TNFα (cytokine pro inflammatoire). (...)<br>Interleukin-7 (IL-7) is a crucial cytokine for T-cell development and peripheral T-cell homeostasis. The IL-7 receptor (IL-7R) is composed by the alpha chain (or CD127) shared with the TSLP receptor and the common gamma chain (or CD132) shared with several receptors of gamma cytokines. IL-7R expression was described in T lymphocytes but was not clearly demonstrated in antigen presenting cells (APC). However, CD127 chain and gamma cytokine receptors were described in these cells suggesting a functional IL-7R expression in APC. Interestingly, the CD127 chain also exists under various soluble forms (CD127s) resulting in alternative splicing of CD127 mRNA. However, the expression and the regulation of CD127 isoforms expression have been barely studied in APC. Moreover, polymorphisms in CD127 gene were identified and associated with a strong plasmatic concentration of the soluble form CD127s ∆6 in Humans and a stronger susceptibility to develop autoimmune diseases. Some of these polymorphisms are also associated with a faster evolution to the AIDS stage for HIV patients. Finally, the capacity of this soluble form to bound IL-7 suggests an important role of CD127s ∆6 to regulate IL-7 response by acting on his availability. However, the plasmatic CD127s expression is very controversial in HIV patients in chronic phase of infection. Moreover it expression was not known in infected organs and has never been described in acute phase of infection. Finally, nobody defines its origin and its function yet. The specific quantification of CD127s ∆6 by RT-qPCR revealed a minority expression of CD127s ∆6 in PBMC, weak in gut, more important in ganglions and even more in lung. More precisely, this study highlight on isolated cells from healthy monkey’s blood and spleen, a weak expression of CD127 by monocytes characterized by a majority expression of the soluble form contrary to T lymphocytes. Afterwards, we confirmed these results in vitro in two major immune populations in lung: in primary alveolar macrophages (AM) isolated from broncho-alveolar lavages (BAL) from healthy rhesus monkey and in the NCI-H226 lineage of human lung epithelial cells (LEC). In a second part, the specific quantification of CD127s Δ6 by RT-qPCR in organs (ganglions and lung) and the determination of the CD127s plasmatic protein at the acute phase of SIVmac251 infection revealed a significant up-regulation of this expression in lung in times D7, D10 and D14 post infection and its plasmatic concentration at D10 in infected monkeys. Finally, in the last part, we also quantified the viral load and IL-7 expression from infected monkeys to understand mechanisms implicated in regulation of CD127 expression during SIVmac251 infection. Surprisingly, we found none correlation between CD127s ∆6 expression and viral load or IL-7 expression from infected monkeys and healthy monkeys after injection of a pharmacological dose of IL-7. These data suggest an indirect effect of IL-7 and virus on CD127s ∆6 expression and a role of inflammation factors in regulation of his expression. In order to better define these mechanisms of regulation, the transcripts coding for the soluble form were quantified on AM and LEC in vitro after 6H of stimulation with or without IL-7 or TSLP (ligands of CD127) alone or combined with TNFα (pro inflammatory cytokine). Surprisingly, contrary to T lymphocytes, IL-7 do not induces down regulation of CD127 expression on AM and LEC. Nevertheless, CD127s ∆6 expression is upregulated upon TNFα by AM in a dose dependent manner. Moreover, the costimulation (IL-7 + TNFα) induces CD127s ∆6 expression by LEC revealing a synergic effect of IL-7 and TNFα. Finally the polarization of macrophages derived from human monocytes (hMDM) show that activated state of macrophages impact not only expression but also regulation of CD127 expression by these cytokines. (...)

A travers trois études, cette thèse vise à explorer les micro-fondations cognitives de l'économie. Dans une première étude, j'examine le rôle de l'information dans la coordination sur un moyen d'échange unique, c'est-à-dire l'émergence d'une monnaie. En s'appuyant sur les modèles de prospection monétaire (Kiyotaki &amp; Wright, 1989, et Iwai, 1996), l'objectif de cette étude est de remettre en question l'hypothèse selon laquelle une information exhaustive est une condition nécessaire à l'émergence d'une monnaie. Dans une deuxième étude, j'aborde le rôle de l'information dans une situation de concurrence duopolistique. À l'aide d'un modèle à la Hotelling (1929), nous vérifions l'hypothèse selon laquelle la variation de la quantité d'information accessible aux consommateurs influe sur la dynamique du marché. Dans une troisième étude, je m'intéresse à la prise de décision dans le risque chez le macaque rhésus. Prenant appui sur la théorie des perspectives (Kahneman &amp; Tversky, 1989, 1992), l'objectif principal est d'examiner dans quelle mesure les macaques font preuve d'un traitement asymétrique des gains et des pertes similaire à celui des humains<br>Through three studies, this thesis aims to explore the cognitive micro-foundations of economics. In a first study, I investigate the role of the information for coordination on a unique medium of exchange, that is to say money emergence. Relying on the search theoretical models (Kiyotaki &amp; Wright, 1989, and Iwai, 1996), the goal of this study is to challenge the assumption that an exhaustive information is a necessary condition for money emergence. In a second study, I tackle the role of the information in duopoly competition. Using a model a-la-Hotelling (1929), we test the hypothesis that varying the amount of information available by consumers substantially impacts market’s dynamics. In a third study, I am interested in decision-making under risk in rhesus monkeys. Based on the prospect theory (Kahneman &amp; Tversky, 1989, 1992), the main purpose is to assess to what extent macaques exhibit an asymmetric treatment of gains and losses similar to that of humans

Thesis (Ph. D.)--University of Oregon, 2008.<br>Typescript. Includes vita and abstract. Includes bibliographical references (leaves 181-195). Also available online in ProQuest, free to University of Oregon users.

<p>Among rhesus macaques, bi-directional aggression may occur between animals with shifting or ambiguous ranks, or between those whose relative ranks are well established. Factors that influence the latter case (here termed "insubordinate aggression") are not well understood. These factors are of interest because insubordinate aggression may be associated with stability in dominance relationships, and stability in dominance relationships is critically related to group stability. We hypothesized that in well-established female dominance relationships, the likelihood of insubordination during conflicts is influenced by characteristics of both opponents. Multivariate analysis of 11,591 dyadic conflicts among females in six captive rhesus groups shows that dyadic and individual characteristics related to weight, rank, age, and access to social support affect the likelihood of insubordinate aggression. As expected, insubordinate aggression is less likely to occur among dyads with high disparity in weight. The effects of age, rank, and access to social support are more complex. Increasing subordinate age is associated with increased modulation of insubordinate aggression according to opponent age. Age-based deference, i.e. suppression of insubordination associated with opponent age, decreases with increasing age of the lower-ranking opponent. Similarly, dyadic rank disparity has different effects on insubordination rate according to the age of the subordinate opponent. As females age, their likelihood of insubordination is less dependent on the degree to which they are outranked by their opponent. Also, the lower-ranking opponent's level of social support significantly affects her likelihood of insubordination, but the dominant animal's level of social support does not affect her likelihood of receiving insubordination. We predicted that for the lower-ranking opponent, having many maternal kin would promote insubordinate behavior, whereas for the higher-ranking opponent, having many maternal kin would inhibit insubordination. However, our results show that the dominant's matriline size has no effect on her likelihood of receiving insubordination. Further, matriline size has the opposite of the predicted effect for subordinates--subordinates with many maternal kin are significantly less likely to be insubordinate than those with few kin. We propose some possible explanations for this, which will require further investigation. Taken together, this research suggests that females gauge their degree of deference to dominants based on their own characteristics relative to their opponent's, taking into account size, age and weight differences as well as their own access to social support. Features of subordinate animals emerge as more important than those of dominants in determining the likelihood of insubordinate aggression in dyadic conflicts. Understanding determinants of insubordination will contribute to management practices aimed at maintenance of group stability, as the ultimate act of insubordinate aggression, social overthrow, poses a major welfare and management problem.

Der Einfluß der mütterlichen Verwandtschaft auf das soziale Verhalten ist eingehend für viele Primatenarten untersucht worden, es ist jedoch schwierig die Bedeutung der Verwandtenselektion auf die Evolution von sozialem Verhalten zu bewerten, wenn Studien auf die mütterliche Verwandtschaft begrenzt sind und die väterliche Verwandtschaft dabei völlig ignorieren. Das Ziel der vorliegenden Dissertation war die Untersuchung des Ausmaßes der väterlichen Verwandtschaft und ihr Einfluß auf die sozialen Beziehungen zwischen adulten Weibchen in einer freilebenden Gruppe von Rhesusaffen (Macaca mulatta) auf der Insel Cayo Santiago. Die wichtigsten Resultate können folgendermaßen zusammengefaßt werden: Erstens, zur Beurteilung des Ausmaßes der väterlichen Verwandtschaft wurde die Vaterschaft der zwischen 1993 und 1998 geborenen Kindern der Studiengruppe bestimmt. Die Resultate zeigten, dass die Reproduktion der Männchen innerhalb der Untersuchungszeit nicht gleich verteilt war, einige wenige Männchen zeugten viele Nachkommen, aber die Mehrzahl der potentiellen Väter reproduzierten sich gar nicht oder nur wenig. Dies führte zu einer Verwandtschaftsstruktur in der fast alle im Untersuchungszeitraum geborenen Kinder mindestens ein väterliches Halbgeschwister mit geringer Altersdifferenz hatten, d.h. entweder im selben Alter (74%) oder maximal zwei Jahre jünger oder älter als es selbst (15%). Wenn auch bei anderen Primatenarten die Reproduktion auf einige wenige Männchen beschränkt ist, dann sollte die Bedeutung der väterlichen Verwandtschaft für Primaten neu bewertet werden. Eine der wichtigsten Konsequenzen der ungleichen Reproduktion der Männchen wäre nämlich, dass viele Individuen mehr väterliche, als mütterliche Halbgeschwister in ihrem Leben haben. Zweitens, um den Einfluß der väterlichen Verwandtschaft auf die sozialen Beziehungen unter adulten Weibchen zu bewerten, wurden affiliative und aggressive Interaktionen von 34 Fokusweibchen und ihren sozialen Partnern beobachtet, die entweder ihre mütterlichen Halbschwestern, ihre väterlichen Halbschwestern oder nichtverwandte Weibchen waren. Die vorliegende Untersuchung bestätigte, dass mütterliche Halbschwestern die engsten affiliativen Beziehungen haben. Das wahrscheinlich wichtigste Resultat dieser Studie ist der Befund, dass adulte Weibchen deutlich häufiger affiliativ mit ihren väterlichen Halbschwestern als mit Nichtverwandten interagierten. Die Erkennung der väterlichen Halbschwestern war deutlicher unter Weibchen gleichen Alters als unter Weibchen unterschiedlichen Alters, wobei die affiliativen Interaktionen mit zunehmender Altersdifferenz (gemessen in Jahren) abnahmen. Dies deutet darauf hin, dass Altersnähe einen zusätzlichen regulierenden Einfluß auf affiliatives Verhalten hatte. Beweise dafür, dass sich väterliche Verwandte erkennen können, sind nur in Bezug auf affiliative Interaktionen, nicht aber auf dyadische Aggression gefunden worden, was eine kontextabhängige Verwandtenerkennung annehmen läßt. Drittens, bei der Einbeziehung weiterer Verwandtschaftskategorien zeigten die Daten, dass mütterliche Verwandte auch bei konstant gehaltenem Verwandtschaftsgrad deutlich gegenüber väterlichen Verwandten bevorzugt wurden. Dies weist darauf hin, dass die mütterliche Verwandtschaft in der untersuchten Gruppe einen größeren Einfluß auf die sozialen Beziehungen adulter Rhesusaffenweibchen hatte als die väterliche Verwandtschaft. Affiliative sowie aggressive Interaktionen nahmen mit sinkendem Verwandtschaftsgrad ab, aber entfernte Verwandte unterschieden einander immer noch von Nichtverwandten, was der Existenz einer Verwandschaftsschwelle widerspricht. Viertens, schließlich wurde die väterliche Verwandtschaft in Bezug auf Koalitionsbildungen untersucht. Eine Koalition wird gebildet, wenn ein Individuum in ein laufenden Konflikt zwischen zwei Kontrahenten eingreift, um eine Partei gegen die andere zu unterstützen. Weibliche Rhesusaffen unterstützten am häufigsten ihre mütterliche Halbschwestern. Außerdem unterstützten sie Nichtverwandte gleichen Alters häufiger als Nichtverwandte unterschiedlichen Alters. Weibchen unterstützten ihre väterlichen Halbschwestern nicht häufiger als Nichtverwandte, aber die Daten könnten auf einen indirekten Beweis der väterlichen Verwandtenerkennung hinweisen, da Weibchen dazu tendierten gegen ihre väterlichen Halbschwestern seltener zu intervenieren als gegen Nichtverwandte. Dieser Befund könnte durch die Tatsache bedingt sein, dass väterliche Halbschwestern sehr unterschiedliche Dominanzränge einnehmen können, währenddessen mütterliche Halbschwestern immer benachbarte Dominanzränge haben, was zur Folge hat, dass ein rangtiefes Weibchen ihrer väterlichen Halbschwester nicht wirklich helfen kann, da sie ein viel höheres Vergeltungsrisiko auf sich nimmt, wenn sie in einen Konflikt zwischen zwei ranghöhere Kontrahenten interveniert. Als einen Kompromiß könnten Weibchen statt dessen vermeiden gegen ihre väterlichen Halbschwestern zu intervenieren, was darauf hindeuten könnte, dass individuelle Zwänge bezüglich der eigenen Konkurrenzfähigkeit eine bedeutende Rolle bei der Koalitionsbildung spielen. Mütterliche und väterliche Halbschwestern zeigten zudem einen stärkeren Trend zu "reciprocity" und "interchange" als Nichtverwandte und gaben einander einen höheren Anteil an kostenintensiven Unterstützungen. Schließlich unterstreichen die Ergebnisse dieser Studie deutlich, dass Vertrautheit zwischen Individuen durch frühkindliche Bindungen mindestens auf zwei Wegen erfolgen kann: (i) Mütter vermitteln Vertrautheit zwischen ihren Kindern (die mütterliche Halbgeschwister sind) aufgrund der durch die Laktation bedingten engen Mutter-Kind Bindung und (ii) Altersnähe vermittelt mehr Vertrautheit zwischen Altersgenossen (die entweder väterliche Halbgeschwister oder Nichtverwandte sind), die wichtige Lebensabschnitte wie z.B. Kindheit, Menstruationsbeginn, Schwangerschaft oder Mutterschaft zu ähnlichen Zeiten durchlaufen, während Weibchen unterschiedlichen Alters dies nicht tun. In jedem Fall brauchen väterliche Halbgeschwister neben der Vertrautheit zu ihren Altersgenossen noch einen zusätzlichen Mechanismus wie z.B. das "phenotype matching" um innerhalb ihrer Altersgenossen wirklich zwischen väterlichen Halbgeschwistern und Nichtverwandten zu unterscheiden.<br>The impact of maternal kinship on social behaviour has been studied in detail for many primate species, but it is difficult to assess the importance of kin selection in shaping the evolution of social behaviour when studies are limited to maternal kin, completely ignoring paternal kinship. This thesis aimed to investigate the extent of paternal kinship and its impact on the social relationships among adult females in one group of free-ranging rhesus macaques (Macaca mulatta) living on the island of Cayo Santiago. The main findings can be summarised as follows: Firstly, in order to access the extent of paternal kinship, paternity has been analysed for all infants of the study group born between 1993 and 1998. Results revealed that male reproduction was highly skewed over the study period as few males have sired a high number of offspring, but the majority of potential sires have sired no or few offspring. This created a kinship structure in which nearly all animals born during the study period had at least one paternal half-sibling in close age proximity, i.e., either of the same age (74%) or within a two-year age difference of themselves (15%). Assuming that male reproductive success is also skewed in other primate species, then the importance of paternal kinship in primate societies should be re-emphasised. One of the most important consequences of male reproductive skew is that many individuals will have more paternal than maternal half-siblings during their life time. Secondly, in order to access the impact of paternal kinship on the social relationships among adult females, focal data on affiliation and aggression have been collected on 34 adult females with respect to their social partners who were either their maternal half-sisters, paternal half-sisters or unrelated females. The present study confirmed that the closest affiliative relationships characterise maternal half-sisters. Probably the most important result of this study was the finding that adult females were significantly more affiliative with their paternal half-sisters than with their non-kin. The recognition of paternal sisters was more pronounced among females of the same age than among females of different age, with a decrease in affiliation as the exact age difference (measured in years) increased among paternal half-sisters. This indicates that age proximity had an additional regulatory effect upon affiliative behaviour. However, evidence for paternal kin discrimination was only found with respect to affiliation, but not with respect to dyadic aggression suggesting context-dependent kin discrimination. Thirdly, when more kin categories were included in the analysis, adult females showed a strong bias towards maternal kin in comparison to paternal kin. This bias towards maternal kin when the degree of relatedness was held constantly suggests, that maternal kinship had a larger impact on the social relationships among adult female rhesus macaques than paternal kinship at least in the study group. Both affiliation and aggression declined with decreasing degrees of relatedness, but distant kin still differentiated each other from non-kin contradicting the existence of a relatedness threshold. Fourthly, paternal kinship was finally investigated with respect to coalition formation. A coalition is formed when an individual intervenes in an ongoing conflict between two opponents in order to support one party against the other. Female rhesus macaques intervened most often on behalf of their maternal half-sisters. In addition, unrelated female peers supported each other more often than unrelated female non-peers. Females did not support their paternal half-sisters more often than non-kin, but data may indicate indirect evidence for paternal kin discrimination as females tended to target their paternal half-sisters less often than non-kin. This finding might be due to the fact, that paternal half-sisters can be very different in rank, while maternal half-sisters are of adjacent rank, implying that a low-ranking female cannot provide actual help to her paternal half-sisters, as she may risk a higher probability of retaliation when intervening in a conflict between two higher-ranking opponents. As a compromise, females may instead avoid to target their paternal half-sisters, suggesting that constraints to an individuals own competitive ability play an important role in coalition formation. Maternal and paternal half-sisters showed a stronger trend in reciprocity and interchange than non-kin and also provided a higher proportion of costly interventions towards each other. Finally, the results of the present study strongly suggest that familiarity among individuals can arise through association in early development by at least two alternatives: (i) mothers mediating familiarity among their offspring (which are maternal half-siblings) caused by the close mother-offspring relationship during lactation and (ii) age proximity is mediating familiarity among age mates (including both paternal related and unrelated peers) as peers go through important life history stages such as infancy, menarche, pregnancy or motherhood at similar times while females of different age do not. In any case, paternal half-siblings additionally need a mechanism such as phenotype matching to discriminate paternal half-siblings from non-kin even within their peer group.

Group living primates utilise a number of characteristic post-conflict behaviours as a means of regulating the impact of escalated intragroup disputes. Although immature group members are typically implicated in disproportionate levels of aggression in many cercopithecine taxa, the conflict management abilities of young animals remain relatively unstudied as most previous investigations have focused solely upon adults or pooled data across age classes. This study therefore utilised a cross-sectional design to examine the immediate consequences of aggressive confrontations and the patterning of both affiliative and agonistic post-conflict interactions with former opponents and previously uninvolved bystanders, in free-ranging immature rhesus macaques (Macaca mulatta) at Cayo Santiago, Puerto Rico. Subjects of both sexes (n = 108) and between 1 and 4 years of age were drawn from two social groups, upon which 451 pairs of 10-minute post-conflict and matched-control observations were collected over a 10 month period in 1996. These data were supplemented by 10-minute post-conflict intervals extracted from an additional 432 hours of continuous focal observations conducted upon a balanced subset of 36 juveniles, together with a total of 549 group-wide scan samples concentrating upon affiliative behaviour. Involvement in aggression was found to have both social and ecological costs for former victims, which were subject to elevated rates of subsequent threats and attacks in the minutes following a conflict, a period in which they also spent more time in locomotion and less time upon feeding. Nevertheless the behaviour of aggressors was also affected, as contestants in both roles exhibited some degree of post-conflict elevation in self- (e.g. scratching) and object-directed activities (e.g. gnawing or manipulating) likely to be indicative of tension or anxiety, although these increases were often more pronounced in the recipient as opposed to the perpetrator of aggression. Affiliative reunions between former adversaries in the wake of aggression were demonstrable in even the youngest subject cohort and the patterning of these "reconciliatory" events was similar to that documented in previous work on adult macaques, with the context of the preceding conflict (over food versus of no discernible cause) and the quality of relationship between the protagonists (whether close kin or favoured affiliates, or not) significantly reducing or elevating, respectively, the likelihood that a reunion would take place. In the former case, variation in conciliatory tendency was also paralleled by a difference in the degree to which rates of self-scratching were elevated under post-conflict conditions, whilst in the latter case it was not - confrontations between close associates produced levels of scratching no higher than those after a dispute between less favoured affiliates. Immature subjects were also more likely to interact with certain other partner classes under post-conflict as opposed to baseline conditions. For example, there was a pronounced increase in affiliative contacts between former coalition partners following polyadic conflicts, these overtures typically being instigated by the beneficiary of support. Affinitive interactions between both aggressors and victims and previously urtinvolved bystanders were also significantly elevated, being preferentially directed toward the contestant's close relatives and those of its opponent; the latter type of interaction appeared more frequent in the youngest subjects and partner selection was not merely a side-effect of proximity to members of the opponent's family. The degree to which kinship between former opponents, or with bystanders, influenced the likelihood of post-conflict affiliation was greater in female subjects, but the sexes behaved similarly in all other respects. Significant differences in behaviour between birth cohorts were also largely absent, although older immatures were more likely to "redirect" aggression toward third parties when victimised. These attacks against bystanders in the wake of conflicts were exhibited by both aggressors and victims, although aggressive responses were more likely when in the latter role. It is suggested that redirection by former victims may function predominantly as a signal to other group members, as these aggressive events were particularly likely to take place within view of former opponents and were associated with a high incidence of vocal threats; furthermore, redirection was associated with a significant reduction in the amount of aggression the subject subsequently received from others. Immature rhesus macaques therefore appear to possess a rich repertoire of post-conflict behaviour, in many ways resembling that reported in previous studies based upon mixed-age subject samples. However, relatively small size and on average low rank may place greater constraints upon the behaviour of juvenile group members, which therefore may need to reach a certain age or size before fully expressing their potential. Further work is now needed to ducidatc the functional cons~quences for immature contestants of the patterns of post-conflict hehaviour documented. partIcularly those involving partners other than the former opponent.

The study of lateralisation has taken several forms ranging from investigating morphological asymmetries to research on lateralised motor and perceptual functions with many studies successfully evidencing lateralisation in a variety of species. This study, featuring three species (olive baboons, rhesus macaques, and spotted hyaenas) investigated visual field biases with the aim of determining whether emotional valence underpins these biases whilst also considering the influence of a number of other factors such as emotional intensity, age, sex, rank, and, for the first time, oestrus cycles (olive baboons only). This study aimed to establish whether Campbell’s (1982) Right Hemisphere Hypothesis or Silberman & Weingartner’s (1986) Valence Hypothesis offered the more valid theory for the lateralisation of emotion by considering interactions across the full spectrum of emotion – a question the almost exclusive investigation of negatively affective scenarios by previous studies has been unable to answer. Furthermore, this study provided a new methodology for investigating behavioural lateralisation by suggesting that separating the visual spectrum into five fields (extreme left, mid left, centre, mid right and extreme right) allows a more accurate insight into the lateralisation of visual perception than the traditional hemifield model. Finally, a more conservative method is proposed for analysing behavioural data in future studies from this field and suggests that these methods provide a more accurate representation of the lateralisation of emotion than those previously employed. A population-level left side bias was found for the spotted hyaenas, thus providing the first evidence of significantly lateralised behaviour in a large carnivore and, for this species at least, lending some support to Campbell’s (1982) Right Hemisphere hypothesis but as population-level biases were not found for either of the other species it may be premature to suggest this support is unequivocal. Significant age effects were found in two species as adult olive baboons and spotted hyaenas were both found to express significant left side biases. Spotted hyaenas were also found to express significant left side biases for females, dominant individuals, high intensity interactions, and sexual valence interactions whilst olive baboons expressed a significant left side bias during negative valence behaviours but no significant lateral biases were found in any context for rhesus macaques. In olive baboons behaviours performed by males and those of a low intensity were found to occur more frequently in the mid and central visual fields and neutral valence behaviours were less occurrent in the extreme visual fields whilst in spotted hyaenas sexual, positive and negative valence behaviours were significantly less centralised than neutral valence behaviours. Non-oestrus adult female olive baboons were significantly more strongly lateralised than in-oestrus females, thus suggesting an influence of sex hormones upon lateralisation that may also have been apparent from the hyaena data, particularly regarding the significant lateral biases observed for females and dominant individuals. Finally, this thesis discusses a number of methodological issues that were encountered during this study and provides recommendations for future research in this field. Namely, this thesis provides an updated method for calculating laterality bias that is much more suitable for species with binocular vision and details a novel method of assessing visual field preferences by considering central and peripheral visual fields as separate entities. Furthermore, this thesis suggests that the weighted method designed and implemented for this study provides a much more accurate methodological foundation for analyses which avoids the caveats that may have affected previous research and thus provides a considerably more robust template that should be encouraged for any similar subsequent studies.

This thesis presents the development and application of methods to assess cognitive markers of emotion and psychological wellbeing in a species of nonhuman primate, the rhesus macaque (Macaca mulatta). In humans, vulnerability to emotional disorders such as anxiety and depression is characterized by particular cognitive profiles, known as cognitive biases. For example, anxious people automatically attend to threat-relevant information, interpret ambiguous information negatively, and have negative expectations of future events. In this thesis, I first describe two treatments that were used prior to cognitive testing to induce positive and negative shifts in inferred affective state in the monkeys (enrichment and a health-check, respectively) and discuss the impact of these treatments on the monkeys’ behaviour and physiology (Chapters 2 and 3). In the first cognitive study (Chapter 4), I present a method that uses eye-gaze to assess the extent to which threatening (versus non-threatening) stimuli capture visual spatial attention when two stimuli are presented at different locations. In the second study (Chapter 5), I present a simple operant touch-screen task to assess the extent to which a threatening distractor stimulus captures attention and impairs performance on an ongoing task when presented at the same location as the taskrelevant stimulus. In the third study (Chapter 6), I present a Go/NoGo touchscreen task to assess judgements about the reward value of ambiguous stimuli. In all of these studies, the two treatments led to different cognitive profiles in the monkeys. Monkeys showed a) automatic capture of attention by threatening stimuli, which was followed by avoidance following the health-check, but not Post-enrichment; b) impaired task performance when a threatening distractor stimulus was presented Post-health-check, and improved performance on these trials Post-enrichment; and c) a more negative judgement about the reward value of ambiguous stimuli Post-health-check versus Post-enrichment. I discuss these cognitive biases in light of available data from humans, and recent work with nonhuman animals. These data indicate that furthering our understanding of primate and other animal psychological wellbeing, may be achieved through the development of measures of cognitive bias, such as those presented here.

Natal dispersal may have considerable social, ecological and evolutionary consequences. While speciesspecific dispersal strategies have received much attention, individual variation in dispersal decisions and its fitness consequences remain poorly understood. We investigated causes and consequences of natal dispersal age in rhesus macaques (Macaca mulatta), a species with male dispersal. Using long-term demographic and genetic data from a semi-free ranging population on Cayo Santiago, Puerto Rico, we analysed how the social environment such as maternal family, group and population characteristics affected the age at which males leave their natal group. While natal dispersal age was unrelated to most measures of group or population structure, our study confirmed earlier findings that sons of high-ranking mothers dispersed later than sons of low-ranking ones. Natal dispersal age did not affect males\\\' subsequent survival, but males dispersing later were more likely to reproduce. Late dispersers were likely to start reproducing while still residing in their natal group, frequently produced extra-group offspring before natal dispersal and subsequently dispersed to the group in which they had fathered offspring more likely than expected. Hence, the timing of natal dispersal was affected by maternal rank and influenced male reproduction, which, in turn affected which group males dispersed to.

Auditory recognition memory in non-human primates is not well understood. Monkeys have difficulty acquiring auditory memory tasks, and limited capability maintaining auditory information over memory delays, relative to studies of visual memory. Neural substrates of auditory discrimination and recognition memory depend on superior temporal gyrus (STG), instead of rhinal cortex necessary for visual memory (Fritz et al., 2005). The current project assessed behavioral and neural correlates of auditory processing and memory function in monkeys, particularly focusing on the dorsal temporal pole (dTP), the rostral portion of STG. Chapter 2 examined recognition memory of monkeys under influences of various sound types. In a delayed matching-to-sample (DMTS) task, rhesus monkeys were trained to determine if two sounds, separated by a 5-second delay, were same (match trials) or different (nonmatch trials). Results demonstrated monkey vocalizations served as better cues than other sound types for auditory memory performance. Memory improvements may be due to familiarity and biological significance of con-specific sounds, analogous to using facial stimuli during visual tasks. Chapter 3 examined neuronal activity of dTP, when two monkeys performed an auditory DTMS task and listened to sound stimuli. Population encoding of sample stimuli in dTP was closely associated with memory accuracy. Moreover, a suppression effect on identical sounds was present, similar to processing in the ventral visual processing stream, inferior temporal cortex (ITC) and ventral temporal pole (vTP). Delay-related activity of dTP was weak, limited and short-lived, in contrast to visual studies reporting sustained activity over memory delays in ITC, vTP and prefrontal cortex. The findings provide preliminary evidence on why monkeys show limited memory capability, compared to visual memory, for auditory information. Neurons of dTP were sound-selective, and mainly evoked by one to four discrete stimuli only. Sound types and simple acoustic properties of sound stimuli cannot completely account for response profiles of dTP neurons. The findings suggest dTP is a higher order auditory area, and receives information from various auditory areas along STG. Dorsal temporal pole fits into proposals of neural networks for auditory processing, in which a hierarchical organization of information flow exists within the primate auditory nervous system.

The face holds a central role in both human and nonhuman primate social interactions, through the communication of feelings and intentions via facial expressions and by acting as a means of recognising individuals. Humans, however, also employ their faces in mate attraction and assessment, an area that has received little attention in nonhuman primates. Many researchers have proposed that human aesthetic judgments of facial attractiveness have a biological basis, and these preferences have evolved via sexual selection processes during human evolution. The use of the face in attractiveness assessments need not be limited to humans. Rather, there is good reason to suggest that this may also apply to other nonhuman primates, based on homologies in the way in which primates use their faces, and on evidence that the face is a site of sexual selection for many primate species. It was the aim of this thesis to explore whether facial traits may also play a role in judgements of attractiveness in a nonhuman primate, the rhesus macaque( Macaca mulatta), in an effort to understand whether humans are unique in utilising the face as a mechanism of mate assessment. Three factors that are reported to influence facial attractiveness in humans are facial symmetry, sexual dimorphism, and averageness. To assess whether they also play a role in nonhuman primates, a series of experiments were conducted where digital images of adult male and female rhesus macaque faces were altered for these features. Opposite-sexed images were then displayed to adult males and females in a captive setting. Eye gaze measures were utilised to assess visual preference for, and the relative importance of, these traits. These experiments yielded mixed results. Increasing facial symmetry of opposite-sexed conspecifics positively influenced the dependent gaze measures employed here. Manipulating degree of facial sexual dimorphism had little influence on the visual gaze of either sex. Facial averageness positively influenced visual preferences for opposite-sexed conspecifics among both sexes, although increasing degree of averageness did not. The last topic to be explored was facial colouration. Rhesus macaques like, various other species of anthropoid primates, possess facial displays of red secondary sexual colouration. As above, animals viewed digitally altered pale and red versions of opposite-sexed conspecifics. Although females displayed preferences for red male faces, males displayed no clear preferences based on female facial colour. This raises the possibility that male and female facial colour may serve different roles in intraspecific signaling. While it cannot be concluded that visual preferences are indeed indicative of real-life preferences, the results do indicate that animals are not indifferent to variations in conspecific facial features. The present findings have important implications regarding the evolution of facial attractiveness, as they provide the first experimental evidence suggesting that facial features may serve as a mechanism for mate selection across primate taxa and that both human and nonhuman primates may employ similar criteria to appraise facial attractiveness.

Operant conditioning using positive reinforcement techniques has been used extensively in the management of nonhuman primates in both zoological and laboratory settings. Based on a large body of previous research that demonstrates the utility of such techniques in reducing stress, abnormal behavior, and aggression, this research project was intended to develop and test the usefulness of habituation and counter-conditioning techniques in reducing the fear-responses of singly-housed male rhesus macaques living in the laboratory environment. Additionally, we investigated the variable of temperament as it relates to the reduction of fear-responsivity and overall training success. Based on a Wilcoxon Matched-Pairs Sign Test, we found that animals exposed to desensitization training were significantly likely to show a reduction in the rate at which they engaged in cringing toward humans (exact significance = .016, one-tailed, N ties = 6), cringing in general (exact significance = .016, one-tailed, N ties = 6), and in stress-related behaviors (exact significance = .016, one-tailed, N ties = 6). Animals exposed to basic husbandry training or exposed to no training at all were not significantly likely to show a reduction in the rates of these behaviors. When these same behaviors were analyzed in terms of duration of behavior, desensitization-exposed animals were significantly likely to show reduction in the amount of time spent cringing toward humans (exact significance = .016, one-tailed, N ties = 6), but not in cringing behaviors in general or in stress-related behaviors. Neither the husbandry-exposed group nor the group exposed to no training showed a significant number of subjects exhibiting a reduction in duration of any of these behaviors. Additionally, initial temperament assessments were found to significantly predict the relative ability of subjects exposed to training to acquire trained behaviors such that animals generally ranked as more inhibited in terms of temperament also ranked as slower learners based on a Wilcoxon Matched-Pairs Signed-Ranks test, z = -.316, p = .752 (two-tailed). Results of this study could enhance both laboratory animal welfare and laboratory animal research, and could be a first step in developing techniques for reducing fearful behavior in rhesus monkeys in the laboratory environment.

Les strategies vaccinales developpees pour lutter contre les virus de l'immunodeficience humaine (hiv-1 et hiv-2) responsables du sida utilisent principalement les glycoproteines (gp) d'enveloppe du hiv. Nous avons choisi de presenter de maniere optimale certains epitopes de ces proteines a la surface d'un antigene deja utilise chez l'homme, la particule d'antigene de surface du virus de l'hepatite b (aghbs). Nous avons etudie la reponse immunitaire obtenue apres immunisation de macaques par des particules hybrides v3/aghbs qui presentent le principal epitope de neutralisation de la gp120 d'enveloppe de hiv-1. Les macaques immunises ont developpe des anticorps persistants contre les deux parties de l'antigene hybride (aghbs et hiv-1), capables de neutraliser hiv-1 apres rappel, ainsi qu'une reponse cellulaire proliferative et cytotoxique specifique. Pour evaluer l'efficacite de ce prototype de vaccin lors d'une epreuve virulente, nous avons transpose ce systeme au virus de l'immunodeficience du singe (siv) puisque ce virus est capable d'infecter le macaque et d'induire une maladie similaire au sida de l'homme. Un epitope a potentiel neutralisant dans le domaine variable v2 de la gp140 d'enveloppe de siv a ete recemment mis en evidence. Nous avons construit des particules hybrides v2 siv/aghbs et nous avons immunise des macaques rhesus en utilisant un protocole comportant des injections de gp140 de siv presentee par un virus vaccine recombinant et des rappels par les particules v2/aghbs. Malgre le developpement d'anticorps neutralisants de siv dont une partie etaient diriges contre la region v2, les macaques immunises contre siv n'ont pas ete proteges de l'infection lors d'une epreuve virulente par siv et ont meme presente une viremie plus elevee que les singes controles. Cette facilitation de l'infection, si elle etait confirmee, poserait le probleme de l'utilisation de vaccins bases sur l'enveloppe virale dans la prophylaxie du sida simien