L'élucidation de la microcircuiterie liant les différentes composantes des ganglions de la base est d'une importance capitale afin d'améliorer notre compréhension de ce système neuronal hautement complexe impliqué notamment dans le contrôle de la motricité. C'est dans cette optique qu'ont été entrepris les travaux de recherche consolidés dans cet ouvrage qui rapporte des données neuroanatomiques nouvelles obtenues chez le singe cynomolgus {Macaca fascicularis) et le singe écureuil (Saimiri sciureus) à l'aide d'une technique de pointe permettant le marquage et la reconstruction tridimensionnelle complète de neurones individuels. L'injection par microiontophorèse d'un traceur antérograde, la biotine dextran aminé, dans le pallidum interne, le complexe centre médian/parafasciculaire du thalamus ainsi que le cortex moteur primaire, a permis de tracer en détail l'arborisation axonale des neurones composant ces structures. L'étude approfondie des neurones de projection du pallidum interne révèle que la majorité des axones pallidofuges sont fortement collatéralisés, un même neurone étant en mesure d'influencer à la fois le thalamus ventral, le complexe centre médian/parafasciculaire du thalamus ainsi que le noyau pédonculopontin du tegmentum mésencéphalique par le biais d'un jeu complexe de collatérales axonales. Il en est de même pour les neurones de projection du complexe thalamique centre médian/parafasciculaire dont le branchement axonal permet d'influencer individuellement et de façon variée, à la fois le cortex cérébral et le striatum. Nos travaux révèlent en plus que, contrairement à ce que l'on croyait, la projection corticostriée en provenance du cortex moteur primaire chez le primate n'est pas dédiée uniquement au striatum. En effet, la découverte de neurones corticaux projetant à la fois au striatum et vers le tronc cérébral via des collatérales axonales prouve que le cortex moteur primaire peut influencer le striatum de façon directe et indirecte. L'ensemble de ces résultats révèle que les ganglions de la base forment un réseau neuronal très vaste dont les éléments constitutifs possèdent un axone fortement collatéralisé. Ces données neuroanatomiques jettent un éclairage nouveau sur l'organisation anatomique et fonctionnelle des ganglions de la base chez le primate et doivent être prises en considération dans l'élaboration de nouvelles approches thérapeutiques visant à contrer les processus neurodégénératifs qui affectent les ganglions de la base, comme ceux associés aux maladies de Parkinson et de Huntington. / A better knowledge of the neural wiring that links the major components of the basai ganglia is essential to understand the complex spatiotemporel séquence of neural events that ensures the correct flow of cortical information through this set of subcortical structures involved in the control of motor behavior. The présent thesis reports novel neuroanatomical findings gathered in both Old World (cynomolgus; Macaca fascicularis) and New Word (squirrel monkey, Saimiri sciureus) primates using a state-of-the-art method allowing a complète labelling and three-dimension reconstruction of single neurons. Microiontophoretic injections of biotin dextran aminé, an anterograde neuronal tracer, in the internai pallidum, the centre médian/parafascicular thalamic complex and the primary motor cortex allowed a detailed description of projection neurons within thèse forebrain structures. Our data show that the majority of pallidal neurons are endowed with a highly collateralized axon that projects to the ventral tiers thalamic nuclei, the centre médian/parafascicular thalamic complex and the brainstem pedunculopontin tegmental nucleus. Our results also reveal that single centre médian or parafascicular neurons are able to influence in a multifarious fashion both the cérébral cortex and the striatum. Furthermore, we hâve shown that the corticostriatal projection arising from primary motor cortex is not dedicated solely to the striatum, in contrast to current belief. We found neurons that project to the striatum indirectly through a thin collatéral emitted by a thick long-range axon heading towards the brainstem, a finding that indicates that the primary motor cortex also has an indirect access to the primate striatum providing this structure with a copy of the neuronal information that is being sent to the brainstem and/or spinal cord. Altogether, thèse data indicate that the main components of basai ganglia in primates harbour différent types of projection neurons, each endowed with a highly collateralized axons. In the light of thèse findings, the basai ganglia can now be viewed as a widely distributed neuronal network, whose éléments are endowed with a highly patterned set of axon collaterals. The understanding of this finely tuned network is a prerequisite for the development of new therapeutic avenues for the treatment of basai ganglia disorders, such as Parkinson's disease and Huntington's chorea.

Les primates représentent un modèle animal idéal pour étudier la stéroïdogénèse puisqu'ils sécrètent, comme les humains, de grandes quantités de dehydroepiandrosterone (DHEA) et de DHEA-sulfate (DHEA-S). La transformation de DHEA et de DHEA-S en androgènes et estrogènes actifs dans les tissus périphériques cibles dépend du niveau de l'expression des diverses enzymes stéroïdogéniques dans chaque type de cellules. Afin de mieux comprendre la formation et l'inactivation périphériques des androgènes et des estrogènes chez le singe, nous avons isolé chez le singe Macaca fascicularis, les orthologues des enzymes humaines par PCR, en utilisant des oligonucléotides dégénérés. Nous avons étudié d'une façon quantitative, la distribution de l'ARN messager des enzymes principales de biosynthèse et de métabolisme pour les stéroïdes chez le singe de cynomolgus, avec la méthode de PCR en temps réel. Finalement, nous avons caractérisé l'activité enzymatique des enzymes clés chez le singe de cynomolgus, soit la 311-HSD, la 1713-HSD du type 12 et les membres de la famille d'AKR 1C (la 3a-HSD, le type 5 1713- HSD et la 20a-HSD). Notre étude montre qu'il existe une forme unique de 3P-HSD chez le Macaca fascicularis, tandis que chez l'humain 2 isoformes sont présents de façon spécifique au tissu. La quantification des niveaux d'expression de l'ARNm a montré que l'enzyme est fortement présent dans les tissus stéroïdogénique classiques et plusieurs tissus périphériques. Aussi, les résultats suggèrent qu'une défecience en 313-11SD, en plus de l'hyperplasie congénitale surrénalienne, des maladies secondaires liées à une insuffisance de métabolisme stéroïde dans les tissus périphériques tels que la peau, les glandes mammaires, la prostate, et le cerveau. Un fragment de la région codante cADN de la 17(3-HSD du type 12 a été isolé par RT-PCR dans l'ARNm de foie de Macaca fascicularis. En utilisant les cellules HEK-293 qui expriment la 1713-HSD type 12 de Macaca fascicularis par transfection stable, nous avons montré que l'enzyme catalyse efficacement et sélectivement la transformation d'El en E2. En plus, l'ARNm de la 17[3-HSD12 de Macaca fascicularis est exprimé de façon ubiquiste, avec les niveaux les plus élevés trouvés dans le cervelet, le rate, et la surrénale. Ces résultats suggèrent fortement que cette enzyme est impliqué dans la biosynthèse de l'estradiol à la suite de l'étape de la transformation de 4-androstène-3,17-dione en estrone par l'aromatase. En utilisant des amorces spécifiques, nous avons isolé les fragments d'ADN complémentaire encodant les membres de famille d'aldo-keto réductases (AKR1C) chez le singe Macaca fascicularis, soit la 3a-HSD, le type 5 17S-HSD et la 20a-HSD. L'identité de chaque clone a été déterminée par la caractérisation de l'activité de l'enzyme exprimée par transfection stable dans les cellules HEK-293. La comparaison des caractéristiques enzymatiques de la famille AKR1C de Macaca fascicularis avec celles des orthologues d'humain et de souris montre différentes spécificités de substrat entre les espèces. La quantification des niveaux d'expression l'ARNm de la famille AKR1C de Macaca fascicularis montre que 1) la 3a-HSD est spécifique pour le foie, 2) le type 5 170-HSD est principalement trouvé dans le rein et le foie, et 3) 20a-HSD est très fortement exprimée dans le rein, l'estomac et le foie. L'expression des enzymes est en accord avec les fonctions de ces enzymes. / Human and some other primates are unique in having adrenals that secrete large amounts of dehydroepiandrosterone (DHEA) and its sulfated derivative DHEA-sulfate (DHEA-S). The transformation of DHEA and DHEA-S into active androgens and /or estrogens in peripheral target tissues depends on the expression of the various steroidogenic and metabolizing enzymes in each cell type. Since monkeys produce high levels of circulating DHEA and DHEA-S like humans, they represent an ideal animal model for studying steroidogenesis in humans. To gain more knowledge about the peripheral formation and inactivation of androgens and estrogens in the monkey, we isolated the cynomolgus monkey (Macaca fascicularis) orthologs of human enzymes by PCR-based cloning using degenerate oligonucleotides. Each clone was verified by automated dideoxynucleotide DNA sequencing. We also examined quantitatively the distribution of mRNAs of key steroidogenic and steroid metabolizing enzymes in the Macaca fascicularis using RealTime PCR. Furthermore, we characterized the enzymatic activity of the key enzymes, namely 313-HSD, type 12 1713-11SD and the members of the AKR IC family, namely 3a-HSD, type 5 1711-HSD and 20a-HSD. A unique isoform of Macaca fascicularis 315-HSD has been isolated by RT-PCR. Phylogenetic analysis suggests that Macaca fascicularis 313-HSD is the ortholog of human type 2 313-HSD. In addition, this enzyme shows a similar affinity to both 3H-Preg and 3H-DHEA. The quantification of mRNA expression levels showed that the enzyme is widely presented in classic steroidogenic tissues and several peripheral tissues. Thus the results suggest that deficiencies in 313-HSD enzyme would cause, in addition to congenital adrenal hyperplasia, secondary diseases related to a deficiency of steroid metabolism in the peripheral tissues such as skin, mammary glands, prostate, and brain. A fragment of the encoding region of type 12 1713-HSD cDNA was isolated by RT-PCR in Macaca fascicularis liver mRNA. Using HEK-293 cells which stably express Macaca fascicularis type 12 1715-HSD, we found that the enzyme catalyzes efficiently and selectively the transformation of El into E2. In addition, Macaca fascicularis 1713- HSDI2 mRNA is broadly expressed in all tissues examined, with the highest levels found in the cerebellum, spleen, and adrenal. These results strongly suggested that this enzyme act as a partner of aromatase in the formation of active estrogen in various tissues. Using isoform-specific primers, the cDNA fragments of Macaca fascicularis AKRIC family members, namely 3a-HSD, type 5 170-HSD and 20a-HSD, have been isolated. The identity of each clone was determined by substrate specificities using HEK-293 cells stably expressing the enzymes. Comparison of the enzymatic characteristics of Macaca fascicularis AKRIC family with human and mouse orthologs shows different substrate specificities between species. Quantification of mRNA expression levels of Macaca fascicularis AKRIC family shows that 1) the 3a-HSD is liver specific, 2) the type 5 170- IISD is mainly found in the kidney and liver, and 3) 20a-HSD is very highly expressed in the kidney, stomach and liver. Such tissue-specific expression patterns are in agreement with the metabolism function of the enzymes.

Human Immunodeficiency Virus (HIV) infection mostly spreads by the mucosal route: sexual transmission is the dominant mode of transmission, responsible for between 85% and 90% of cases of infection worldwide. These epidemiological data indicate that semen is one of the major sources of HIV-1 transmission. Semen, like other bodily secretions involved in HIV sexual transmission, contains the virus as two forms: cell-free viral particles and cell-associated virus, mostly in infected leukocytes. Although cell-to-cell HIV transmission has been extensively described as more efficient, rapid and resistant to host immune responses, very few studies have investigated the role in vivo of infected leukocytes in virus mucosal transmission. One such study has been recently conducted in our lab, and demonstrated that SIV-infected splenocytes are able to transmit infection to female macaques after vaginal exposure. However, all these studies used immune cells from peripheral blood or lymphoid tissues, such as spleen, and none have investigated the capacity of infected leukocytes in semen to transmit the infection in vivo. Indeed, nature, phenotype and infectivity of HIV associated with semen leukocytes may be different from that of HIV from other sources.Therefore, the objectives of this work are, first, to study of semen leukocytes and their dynamics during SIVmac251 infection in detail, then to investigate seminal factors that may influence semen infectiousness, and finally to test semen leukocyte infectivity in vitro and in vivo, using a model of mucosal exposure in cynomolgus macaques.Macaque semen contains all the target cells for HIV/SIV: CD4+ T cells, macrophages and dendritic cells in lower proportions. Semen CD4+ T cells and macrophages display an activation, differenciation and expression of migration markers profile which is typical of mucosal leucocytes. SIV infection induces significant changes in their phenotype and dynamics. Both cell types can be productively infected and are found in the semen at all stages of infection. These observations suggest that semen CD4+ T cells and macrophages may be able to transmit infection after mucosal exposure.If the role of semen infected leukocytes in HIV/SIV mucosal transmission is confirmed in vivo, this mechanism will be important to consider for further preventive strategies design, like microbicides.

Object permanence is a cognitive ability, which allows individual to realize the existence of an object even it is not directly accessible to its senses. This ability is essential for successful using of complex cognitive operations. Object permanence is qualitatively and gradually change throughout the development of a child. Congruently, it is not developed to the same level in various species of animals. The aim of this study is to study object permanence in naive rhesus monkeys (Macaca mulatta), because there is still some uncertainty about the development of this ability in macaques. Our results show that the naive subjects do not have the highest stage of object permanence (and they do not use representative strategy to solve the tasks), however, other results of our team suggest that more experienced individuals are able to achieve the highest stage under certain circumstances. We show that experimental design used to test object permanence can be modified and used also for studying of other cognitive abilities. We test the preferences of macaque monkeys toward novel non-food stimuli. The reactions of different species of animals can vary. The reactions depend on the type of stimuli (food or non-food), but also on the ecology and ethology of the species. Age, sex and personality of the...

Le propos de ce travail de thèse est d’examiner le développement de la formation de catégories de visages, par l’étude des préférences visuelles des nourrissons dans la première année de vie. Nous avons cherché à préciser les mécanismes de formation des préférences visuelles en les intégrant dans le cadre théorique développé par Valentine (1991), le face-space. Nous avons proposé de lier ces préférences à la manière dont l’expérience perceptive des nourrissons avec différentes catégories de visages va structurer l’espace de représentation des visages. De manière générale, nous avons postulé que les nourrissons présenteront des préférences pour les visages proches de la tendance centrale (i.e., prototype) du face-space. Nous avons mis en évidence une tendance des nourrissons de 0 à 6 mois à présenter un biais pour des visages d’adultes par rapport à des visages de nourrissons (Etudes 1 et 2), les premiers correspondant à une catégorie de visages prépondérante de l’environnement des nourrissons, là où les seconds correspondent à une catégorie de visages peu rencontrée. Ce biais pour la familiarité s’est avéré disparaitre à 9 et 12 mois (Etude 3). Ces préférences liées à la familiarité pourraient être liées à une forme de fausse reconnaissance du visage des proches des nourrissons, issue de la surreprésentation de ces visages dans le quotidien des nourrissons. Ce pattern de préférences n’a en revanche pas été retrouvé lorsque des nourrissons de 3 à 12 mois ont été confrontés à des visages d’enfants ou de nourrissons (Etudes 4 et 5), les résultats montrant plutôt une préférence pour les visages les moins familiers, relativement à l’expérience des nourrissons. Nous avons ensuite étudié les capacités de catégorisation de nourrissons de 9 et 12 mois pour des visages de différentes catégories d’âges, i.e., adulte, enfant, nourrisson (Etude 6). Les nourrissons de 12 mois ont formé des catégories discrètes des visages d’adulte et de nourrissons d’une part, et d’enfants et de nourrissons d’autre part. Les nourrissons de 9 mois en revanche ont montré un pattern plus asymétrique en ce qu’ils ont formé une représentation des visages d’enfants excluant un nouveau visage de nourrisson, et une représentation des visages de nourrissons incluant un nouveau visage d’enfant. Les nourrissons ayant tous une expérience de la crèche, donc des visages de nourrissons, cette asymétrie pourrait être liée à une influence de la connaissance de cette catégorie de visage. Dans une dernière étude (Etude 7) nous avons cherché à montrer plus directement le lien entre préférences visuelles et proximité par rapport au prototype, chez des nourrissons humains de 12 mois et des nourrissons macaques de 3 mois (Macaca mulatta). La mise en évidence de préférences liées à la distance par rapport au prototype chez ces deux populations suggère la présence d’un mécanisme commun aux deux espèces conduisant à la formation de préférences visuelles pour les visages. / The purpose of this work is to examine of the development of face category formation using infants’ visual preferences. We investigated the mechanisms leading to differential face preferences by integrating them in the theoretical framework developed by Valentine (1991), the face-space. We proposed that the way perceptual experience shape the structure of the face-space is a determinant of infants’ face preferences. We postulated that faces close to the central tendency of the face-space (i.e., prototype) will be preferred. We first reported a bias to look more toward adult faces than infant faces from birth to 6 month of age (Studies 1 and 2). Adult faces correspond to a frequently encountered category while infant faces represent a less frequently encountered category. We also showed a downturn of this familiarity bias as infants grow older (Study 3). The preferences showed by younger infants might be linked to a form of false recognition of the caregivers’ faces, due to the massive exposure to these faces. This pattern of preferences was not found in 3-to 12-month-olds presented with child and infant faces (Studies 4 and 5). Conversely, infants showed a tendency to prefer the less familiar faces, depending on their perceptual experience. We then studied 9- and 12-month-olds’ abilities to form categories of faces differing by age, i.e., adult, child, and infant faces, (Study 6). Twelve-month-olds formed discrete categories of adult and infant faces in one hand, and of child and infants faces on the other hand. Nine month-olds showed an asymmetric pattern of behavior, forming categories of child faces that exclude a new infant face, and categories of infant faces that include a new child face. All these infants being exposed to infant faces via nursery, the asymmetry might stem from the influence of the knowledge of this category of faces. In the last study (Study 7), we tried to provide more direct evidences of the link between face preferences and the distance from the prototype in two different populations: 12-month-old human infants, and 3-month-old macaque infants (Macaca mulatta). Preferences for faces close to the prototype in both species suggest a common mechanism leading to face preferences.

Whilst there has been a recent increase in interest in using positive reinforcement training for laboratory-housed primates, there remains a reluctance to put into practice training programmes. Much of this reticence seems to stem from lack of expertise in the running of training programmes, and a perception that training requires a large time investment, with concurrent staff costs. The aim of this thesis was to provide practical recommendations for the use of training programmes in laboratories, providing primate users and carestaff with background information needed to successfully implement training programmes whilst improving the welfare of the animals in their care. Training was carried out with two species, cynomolgus macaques (Macaca fascicularis) and common marmosets (Callithrix jacchus) in three different research laboratories to ensure practicability was as wide ranging as possible. Training success and the time investment required were closely related to the primate's temperament, most notably an individual's willingness to interact with humans, in both common marmosets and cynomolgus macaques. Age and sex however had no effect on an individual's trainability. The training of common marmosets was more successful than that with cynomolgus macaques, possibly due to differences in early experience and socialisation. Positive reinforcement training helped both species to cope with the stress of cage change or cleaning, with the monkeys showing less anxiety-related behaviour following the training programme than before. Involving two trainers in the training process did not affect the speed at which common marmosets learned to cooperate with transport box training, but behavioural observations showed that initial training sessions with a new trainer led to animals experiencing some anxiety. This however was relatively transient. Whilst the training of common marmosets to cooperate with hand capture was possible, there seemed little benefit in doing so as the monkeys did not show a reduced behavioural or physiological stress response to trained capture as compared to hand capture prior to training. However strong evidence was found that following both training and positive human interactions the marmosets coped better with capture and stress was reduced. It is recommended that an increased use of early socialisation would benefit laboratory-housed primates, and would also help improve the success of training. Further, the time investment required shows that training is practicable in the laboratory for both species, and that positive reinforcement training is an important way of improving their welfare likely through reducing boredom and fear.

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Vision is computationally challenging because objects in the real world can change in size, position, viewpoint etc., and therefore cast a myriad images on the retina. Viewpoint changes are particularly challenging because new features can appear or disappear and existing features can be stretched or compressed. Even though humans are adept at recognizing objects across changes in viewpoint, the underlying neural representations are poorly understood. The goal of this thesis is to investigate viewpoint invariant object representations in the brain using recordings of single neurons in monkey visual cortex, and using behavioural experiments in humans. This thesis summarizes the results from a series of six experiments in which we recorded the responses of single neurons in the monkey inferior temporal cortex, an area critical for object recognition. In Experiment 1, we recorded neural responses to objects across two views and elucidated the dynamics of viewpoint invariance and the factors that modulate it. We observed a dramatic transition from view dependence in the early part of the neural response to view invariance in the later part. In Experiment 2, we investigated the effect of silhouetting and inversion on view invariance. In Experiment 3, we generalized our findings to multiple viewpoints and characterized view invariance for impoverished non-generic viewpoints and mirror views. In Experiment 4, we compared the magnitude and dynamics of viewpoint invariance with other known identity-preserving transformations such as size, position and rotation. In Experiment 5, we demonstrate that IT neurons potentially encode object features even after they rotate out of view. In Experiment 5, we demonstrate a generalization of view invariance, whereby neurons can decouple patterns across non-rigid surface changes. Taken together, our results reveal a dynamic picture of how view invariant representations are constructed in the brain to enable complex perceptual inferences.

The primate visual system is organised and wired in a topological manner. From the eye well into extrastriate visual cortex, a preserved spatial representation of the vi- sual world is maintained across many levels of processing. Diffusion-weighted imaging (DWI), together with probabilistic tractography, is a non-invasive technique for map- ping connectivity within the brain. In this thesis I probed the sensitivity and accuracy of DWI and probabilistic tractography by quantifying its capacity to detect topolog- ical connectivity in the post mortem macaque brain, between the lateral geniculate nucleus (LGN) and primary visual cortex (V1). The results were validated against electrophysiological and histological data from previous studies. Using the methodol- ogy developed in this thesis, it was possible to segment the LGN reliably into distinct subregions based on its structural connectivity to different parts of the visual field represented in V1. Quantitative differences in connectivity from magno- and parvo- cellular subcomponents of the LGN to different parts of V1 could be replicated with this method in post mortem brains. The topological corticocortical connectivity be- tween extrastriate visual area V5/MT and V1 could also be mapped in the post mortem macaque. In vivo DWI scans previously obtained from the same brains have lower resolution and signal-to-noise because of the shorter scan times. Nevertheless, in many cases, these yielded topological maps similar to the post mortem maps. These results indicate that the preserved topology of connection between LGN to V1, and V5/MT to V1, can be revealed using non-invasive measures of diffusion-weighted imaging and tractography in vivo. In a preliminary investigation using Human Connectome data obtained in vivo, I was not able to segment the retinotopic map in LGN based on con- nections to V1. This may be because information about the topological connectivity is not carried in the much lower resolution human diffusion data, or because of other methodological limitations. I also investigated the mechanisms of perceptual learning by developing a novel task-irrelevant perceptual learning paradigm designed to adapt neuronal elements early on in visual processing in a certain region of the visual field. There is evidence, although not clear-cut, to suggest that the paradigm elicits task- irrelevant perceptual learning, but that these effects only emerge when practice-related effects are accounted for. When orientation and location specific effects on perceptual performance are examined, the largest improvement occurs at the trained location, however, there is also significant improvement at one other 'untrained' location, and there is also a significant improvement in performance for a control group that did not receive any training at any location. The work highlights inherent difficulties in inves- tigating perceptual learning, which relate to the fact that learning likely takes place at both lower and higher levels of processing, however, the paradigm provides a good starting point for comprehensively investigating the complex mechanisms underlying perceptual learning.