All human lives start with pregnancy. A pathological pregnancy can be physically, mentally, and financially detrimental to newborns and families. Preterm labor and birth (PTB) is one of the most serious pathological conditions associated with pregnancy. PTB affects 10% of global births and is the leading cause of death in children under five years of age. Multiple etiologies are identified for causing PTB and three major reproductive tissues are involved: the uterus, the cervix, and the feto–maternal interface. Throughout pregnancy, these reproductive tissues change in response to various signals, a process called remodeling. Timely and appropriate remodeling of these tissues is needed for a healthy pregnancy. One central element of remodeling is a change in tissues’ mechanical properties, the focus of this work. This dissertation investigates the mechanical environment of pregnancy by characterizing the remodeling of three reproductive tissues of primates (humans and Rhesus macaque monkeys) and computationally simulating pregnancy physiology. I combine comprehensive mechanical testing with digital image correlation (DIC) to capture the material behavior of reproductive tissues, characterize the architecture of these tissues’ fiber networks by optical coherence tomography (OCT), implement a microstructurally-inspired constitutive mate- rial model, conduct inverse finite element analysis (IFEA) to quantify observed remodeling, and finally use finite element analysis (FEA) to simulate pregnancy anatomy and physiology. Results presented here demonstrate that the non-human primate (NHP) cervix, human uterus, and NHP feto–maternal interface all undergo remodeling during pregnancy and experience com- plex stress conditions. In general, the NHP cervix becomes softer and more extensible, with distinct stages. While the ground substance compressibility stays approximately the same throughout gestation, the fiber network steadily becomes more extensible, though rapidly becomes less stiff and more dispersed during the second trimester. The human uterus late in gestation is softer and more extensible compared to its NP state; most of its remodeling involves changes to fiber network extensibility and architecture. The NHP feto–maternal interface adhesion strength reaches a peak early in the third trimester. Lastly, I generated preliminary subject-specific finite element models of NHP by using a workflow developed for human data. By doing this, the complex stress and stretch conditions that reproductive tissues undergo during pregnancy can be visualized. Future work advancing our understanding of pregnancy and women’s health should include the characterization of the time-dependent properties of reproductive tissues, investigation of the relationship between quantitative ultrasound measurements and tissues’ mechanical properties, and improvements to the current FEA workflow.

The normal aging process in humans is characterized by a number of hallmark changes including decreased white matter volume in the brain and accompanying cognitive decline. This is in contrast to neurodegenerative aging processes which involve acute pathology which results in neuronal cell death. Studying non-degenerative normal aging in humans can be difficult because of the high prevalence of neurodegenerative diseases in the population and other potentially confounding effects. Rhesus monkeys are an excellent model organism for the study of normal aging, as their aging process has been demonstrated to involve diminished white matter volume, but they do not suffer from neurodegenerative diseases such as Alzheimer's. In this study we seek to quantify levels of myelin degradation using confocal microscopy in regions of interest where it has been previously demonstrated that loss of white matter integrity results in lower levels of cognitive function across different treatment groups including aging monkeys, calorie restricted monkeys, and controls for calorie restricted monkeys. These areas include prefrontal white matter which is vital to executive function, the hippocampus which is integral to memory consolidation and the learning process, and finally the anterior, middle, and posterior cingulum bundle. The cingulum bundle contains a diverse variety of projections between cortical and subcortical regions, including but not limited to projections to and from the cingulate cortex which has been demonstrated to be vital for emotional processing, the limbic system, and a wide spectrum of other functions. We aim to quantify white matter degradation in these regions by using immunofluorescent tagging for healthy myelin basic protein (MBP) and degraded myelin basic protein (dMBP) and by measuring the colocalization between the two. For prefrontal white matter and hippocampus, we did not find significant differences in myelin degradation across treatment groups. In the cingulum bundle, however, we did find a significant effect of treatment on overall myelin damage throughout the bundle, and in particular we determined that there was a significant difference in colocalization in the anterior cingulum bundle between aging monkeys and control calorie restricted monkeys. Analysis of behavioral testing data yielded surprising results as we were unable to find a strong correlation between our measure for myelin degradation, and level of cognitive impairment. Our results indicate that there are likely differences in regional vulnerability to age related myelin damage across different white matter regions of the brain, however we would like to expand on this study to gain a more accurate understanding of how loss of white matter volume is distributed through the brain and the impact that has on cognitive outcomes.

Oocyte quality plays a critical role in establishment of pregnancies, embryo development, implantation and the health of offspring. The oocyte provides maternal factors necessary for the initial development of its embryo during the period of transcriptional silence. Despite the consistent increase in number of couples seeking assisted reproductive treatments, oocyte quality still remains as an obstacle in successful fertility treatments and the mechanisms governing the quality of oocyte are poorly understood. Among various factors that may potentially affect the quality of oocyte, the acquisition of oocyte developmental competence seems to mainly occur during the final stage of oocyte maturation. The correct temporal regulation of series of molecular events and the proper exchange of signals with surrounding follicular environment during this critical period will ensure the developmental competence of oocyte and its subsequent embryo. In order to identify molecular factors affecting oocyte quality, I have compared oocytes and cumulus cells of different qualities at a molecular level. I present in this thesis the pathways and molecules that may determine the developmental competence of oocyte as well as candidate molecular markers of oocyte and embryo quality. A cDNA microarray analysis was performed, comparing the transcriptomes of rhesus monkey MII oocytes of different qualities, high quality VVM oocytes and poor quality IVM oocytes. A small set of 59 Oocyte quality plays a critical role in establishment of pregnancies, embryo development, implantation and the health of offspring. The oocyte provides maternal factors necessary for the initial development of its embryo during the period of transcriptional silence. Despite the consistent increase in number of couples seeking assisted reproductive treatments, oocyte quality still remains as an obstacle in successful fertility treatments and the mechanisms governing the quality of oocyte are poorly understood. Among various factors that may potentially affect the quality of oocyte, the acquisition of oocyte developmental competence seems to mainly occur during the final stage of oocyte maturation. The correct temporal regulation of series of molecular events and the proper exchange of signals with surrounding follicular environment during this critical period will ensure the developmental competence of oocyte and its subsequent embryo. In order to identify molecular factors affecting oo was identified as differentially expressed between the two types of oocytes. These mRNAs are involved in steroid metabolism, cell-cell interactions, cellular homeostasis, cell adhesion, mRNA stability and translation. In addition, the overexpression of several imprinted genes in IVM oocytes were detected, indicating a possible loss of correct epigenetic programming during IVM. These results indicate that normal oocyte-somatic cell interactions may be disrupted during IVM and the interruptions of these interactions during the final phase of oocyte maturation may be the prime cause of reduced developmental competence of IVM oocytes. To elucidate oocyte quality factors linked to the cumulus cell phenotype, the transcriptomes of two types of rhesus monkey cumulus cells, IVM and VVM, were compared using a cDNA microarray analysis. In contrast to a relatively small difference between IVM and VVM oocytes, a large number of genes were differentially expressed between IVM and VVM rhesus cumulus cells. Moreover, a much larger number of differential mRNA expressions were observed comparing the transitions from pre-maturation cumulus cells to the IVM and VVM cumulus cells. The results from these array comparisons indicated that the cumulus cells may fail to achieve successfully normal gene regulation during IVM and thus make a remarkable amount of changes in gene expression to compensate for the loss. Numerous genes involved in lipid metabolism are incorrectly regulated during IVM, and the synthesis of sex hormones appears not suppressed during IVM. In addition, a panel of 24 cumulus cell markers of oocyte quality was identified. Genetic effects on oocyte quality were explored by comparing transcriptomes of oocytes obtained from two different inbred mouse strains, B6 and D2, and F1 hybrid. A clustering analysis and statistical tests showed that the transcriptome of F1 oocytes is more similar to the B6 transcriptome than to the D2 at both GV and MII stages. Also, comparison analyses of GV stage oocyte transcriptomes with MII oocyte transcriptomes from three different mouse strains indicated that the number of overdominance genes at the MII stage is bigger than the number of overdominance genes at the GV stage. In order to investigate how the genes gain the overdominance during the GV to MII transition, overdominance genes were categorized according to their mRNA expression patterns at GV and MII stages. The results showed that more than 80% of overdominance genes belong to one of the four major transition groups. The further evaluation of changes in array intensities from GV to MII stage transition revealed that F1 oocytes and inbred strain oocytes differentially regulate the mRNA abundance during oocyte maturation and that the differential regulation of mRNA abundance by the F1 genotype is responsible for the increase of the number of overdominance genes during maturation from GV stage to MII stage. A mRNA sequence analysis indicated that the gain of overdominant low in F1 mRNA expression pattern during maturation may be regulated by 3'UTR motif elements. The number of dominance genes also increase during GV to MII transition. At both GV and MII stages, there are more genes with B6 dominant mRNA expression pattern than those with D2 dominance pattern. Lipid metabolism, small molecule biochemistry and cell death are biofunctions overrepresented in both dominance and overdominance genes. In addition, `blebbing' was identified as a biofunction significantly downregulated in the F1 and B6 MII eggs, indicating that the cellular function may be involved in oocyte maturation. / Molecular Biology and Genetics / Accompanied by one .pdf file: YLEE_SupplementalTables.pdf

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.

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.

Papio ursinus are dietary generalists that exploit a diverse repertoire of food resources. This study explored the foraging strategies of a group of Papio ursinus and the foraging differences between subgroups classified by age and sex. Food resource preference, nutritional properties of food resources, and nutritional demands were examined to test the hypotheses that the foraging strategies exhibited by the subgroups would differ and that food selection is driven by nutritional demands. Adult females and juveniles were found to seek out food resources higher in proteins, while adult males were found to prefer food resources higher in carbohydrates. The findings support the alternative hypotheses and suggest that nutritional pressures are the best predictor of foraging optimization. A pilot study, involving the observation of a provisioned group of Macaca mulatta, that proved elemental to the formulation of the research design employed in the study of Papio ursinus, is also described.

Comparative research on event memory has typically focused on the binding of spatial and temporal information in memory, but much less is known about how animals remember information about the source of their memories (i.e., whether the event is something they performed themselves or whether they observed it). The purpose of the present study was to examine how rhesus monkeys (n = 8) and 3- to 4- year-old children (n = 20) remember this information along with other relevant event features (object identity, spatial location, temporal properties and contextual features) in working memory. In Experiment 1, rhesus monkeys completed five different delayed matching-to-sample tasks to assess independent encoding of these five event components. In Experiment 2, the monkeys either performed or observed an event and then had to respond to a randomly selected pair of memory tests used in the previous experiment. In Experiment 3, children were presented with the same memory task, but were given a brief demonstration to learn how to perform the task. Both children and monkeys responded to these tests using photos and shapes (for the identity and spatial tests) and icons (for the temporal, agency and context tests). The monkeys demonstrated significantly above-chance performance on the identity, spatial, temporal and agency tasks. The children were above chance on the one component the monkeys had difficulty with (context), but conversely demonstrated difficulty on the temporal memory test. There was evidence of feature integration in both monkeys and children. Specifically, the children were significantly more likely to respond correctly to the second memory test if they had also been correct on the first memory test. Two of five rhesus monkeys also showed this effect, indicating that for these individuals, the features were integrated in working memory. Implications of this research are discussed in relation to self-awareness and episodic memory research in children and nonhuman species.

Comparative research on event memory has typically focused on the binding of spatial and temporal information in memory, but much less is known about how animals remember information about the source of their memories (i.e., whether the event is something they performed themselves or whether they observed it). The purpose of the present study was to examine how rhesus monkeys (n = 8) and 3- to 4- year-old children (n = 20) remember this information along with other relevant event features (object identity, spatial location, temporal properties and contextual features) in working memory. In Experiment 1, rhesus monkeys completed five different delayed matching-to-sample tasks to assess independent encoding of these five event components. In Experiment 2, the monkeys either performed or observed an event and then had to respond to a randomly selected pair of memory tests used in the previous experiment. In Experiment 3, children were presented with the same memory task, but were given a brief demonstration to learn how to perform the task. Both children and monkeys responded to these tests using photos and shapes (for the identity and spatial tests) and icons (for the temporal, agency and context tests). The monkeys demonstrated significantly above-chance performance on the identity, spatial, temporal and agency tasks. The children were above chance on the one component the monkeys had difficulty with (context), but conversely demonstrated difficulty on the temporal memory test. There was evidence of feature integration in both monkeys and children. Specifically, the children were significantly more likely to respond correctly to the second memory test if they had also been correct on the first memory test. Two of five rhesus monkeys also showed this effect, indicating that for these individuals, the features were integrated in working memory. Implications of this research are discussed in relation to self-awareness and episodic memory research in children and nonhuman species.

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Self-injurious behavior (SIB) is a complex phenotype that occurs with an increasing prevalence of about 7-34% in humans and 10-12% in non-human primates (NHPs). This study evaluated the efficacy of probiotic Lactobacillus reuteri as a treatment for self-injurious behavior (SIB) and sleep disruption in rhesus macaques. The treatment was proposed to alleviate mild self-biting, sleep disruption, and reduce chronically elevated hypothalamic-pituitary-adrenocortical (HPA) axis activity, all hallmark features of monkeys with this condition. The probiotic preparation included two strains of L. reuteri (L. reuteri ATCC PTA 6475 & L. reuteri DSM 17938) containing on average 200 million colony forming units per chewable tablet. The study was conducted on 14 rhesus macaque monkeys (9 males) housed at the University of Massachusetts Amherst. To our knowledge this is the first time that a Lactobacillus strain has been used as a treatment for SIB in rhesus macaques. This study utilizes motion-activated infrared camera technology, modified enzyme-immunosorbent-assays (EIAs) techniques to measure hair cortisol concentrations, and daily behavioral observations to provide an overall assessment of the behavioral, physiological, and sleep associated implications of probiotic treatment on SIB and control non-human primates (NHPs). Administration of L reuteri modestly decreased biting behavior in monkeys with SIB (F(2,12) = 5.64, p= 0.02) and showed overall decrease in nighttime activity across all subjects but did not normalize SIB to nonSIB values. Hair cortisol values are pending. These findings and the findings of previous work further strengthen the argument for probiotics as an efficacious treatment for SIB behavior.