Cognitive decline is one of the most common symptoms from neuropathology as well as a part of natural aging. While there may be a number of factors that contribute to age-related cognitive decline, previous research has shed a light on the role of chronic hypertension. The effect of hypertension on cognitive decline through small vessel disease is referred to as Vascular Cognitive Impairment and Dementia (VCID). However, the exact molecular pathology behind VCID is not very well understood. Using a non-human primate model of hypertensive aging with the Macaca mulatta, (more commonly known as the Rhesus Macaque) this project builds on previous research implicating collagen IV as part of the cascade of molecular changes that occur in VCID. This project evaluated collagen IV thickness around blood vessels in the corpus callosum and cingulum bundle of normotensive and hypertensive monkeys. as well as determined vessel properties such as total vessel area and perimeter length to evaluate the relationship to scores from the subjects cognitive testing batteries. The results from this project will allow for an examination of the effects on hypertension on vascular properties and possible mechanisms for the development of cognitive impairments. Data collected from this research shows significant differences of collagen IV thickness in the Corpus Callosum between hypertensive and normotensive groups. Similarly, in the cingulum bundle we see that the difference between these groups in collagen IV thickness is trending towards significance. The relationship between average collagen IV densities, blood pressure at perfusion, and cognitive testing scores also showed trending relationships in both the cingulum bundle and the corpus callosum. These results demonstrate how prolonged hypertension can negatively influence cognitive abilities and implicates increases in collagen IV around small vessels in white matter as a significant factor in the molecular cascade which results in cognitive impairment.

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.

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.

京都大学 / 0048 / 新制・課程博士 / 博士(人間・環境学) / 甲第19903号 / 人博第789号 / 新制||人||190(附属図書館) / 28||人博||789(吉田南総合図書館) / 32980 / 京都大学大学院人間・環境学研究科相関環境学専攻 / (主査)准教授 三浦 智行, 教授 川本 卓男, 教授 宮下 英明 / 学位規則第4条第1項該当 / Doctor of Human and Environmental Studies / Kyoto University / DFAM

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.

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5 ABSTRACT Object permanence is a cognitive ability to perceive the continuous existence of objects, even if they cannot be directly observed, respectively perceived by other senses (Piaget 1954). In humans object permanence develops in 6 qualitatively different stages. By using a comparative approach, it was found that the last stage 6 of this ability also occurs in great apes, gibbons and some New World monkeys (capuchin, marmoset and tamarin). In this study, we conducted a study with a series of invisible displacements of an object, in which we investigated whether two rhesus macaques (Macaca mulatta) have fully developed the ability of object permanence and don't rely on simple alternative cognitive strategies, while solving the different tasks. With one test subject, we confirmed that he solved the tasks with stage 6 object permanence abilities. Although the second individual reached significant performance in some sessions, the overall results are ambiguous, because during the testing he had a tendency to use simple alternative strategies. Our study concludes that under certain circumstances macaques have the cognitive capacity for a fully developed ability of object permanence. Key words: Object permanence, rhesus macaque, invisible displacement, cognitive functions

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...

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