Mammalian reproduction is vulnerable to psychological and physiological stress. This research focuses on the psychophysiological mechanisms that lead to the disruption of pregnancy by the failure of implantation of fertilized ova into the uterine walls. The underlying hormonal mechanisms of implantation failure are not well understood. It is known that many environmental events have a substantial impact on hormonal dynamics in mammals. These environmentally induced hormonal changes can disrupt implantation. This thesis focuses on the hormonal dynamics of female mice that lose their pregnancy when exposed to a novel male during the implantation period (the Bruce effect). In Study 1, a repeatable and reliable Bruce effect was established by indirectly exposing inseminated females during the implantation period to novel males housed above them separated by a wire grid floor. Separating the animals allowed for the independent study of the chemical transmission from male to female, and the physiological transduction within the female. The findings from this study suggest that females must come in direct contact with the excretions of the stimulus novel males. The more excretions the females encounter, the greater the chance is of pregnancy disruption. The Bruce effect is known to be dependent on androgens in the stimulus males, since castration eliminates their capacity to disrupt pregnancy. Study 2 showed that surgically removing the androgen-dependent preputial glands from the stimulus males does not diminish their capacity to disrupt pregnancy. Study 3 showed that administering 17β-estradiol to castrated males can restore their capacity to disrupt pregnancy. This suggests that 17β-estradiol as well as testosterone is involved in the chemical transmission of the Bruce effect. It has been hypothesized that 17β-estradiol is elevated in females that fail to implant in the presence of a novel male. Administering an antibody specific to 17β-estradiol to females during their implantation period can lower the hypothesized increase in 17β-estradiol and implantation takes place despite the exposure to novel males. Finally, in Study 4 testosterone, 17β-estradiol and its major metabolites the estrone conjugates were quantified in females' urine and feces while exposed to novel males during implantation. It was found that testosterone and 17β-estradiol were significantly elevated in females that failed to implant while exposed to novel males. In conclusion, this line of research reveals a potential role of steroids in novel male induced pregnancy disruptions in mice. Elevated testosterone and 17β-estradiol are shown to be related to the prevention of implantation in mice. These hormonal dynamics may be partially responsible for the physiological transduction of the Bruce effect. / Thesis / Doctor of Philosophy (PhD)

Yes / Over the past few decades, the number of women having their first babies over the age of thirty-five in most developed societies has steadily increased. Concerns have been raised over this trend amidst warnings of both the increased risk of fertility problems and health risks to mother and child. Despite this, research into the timing of pregnancy in the context of decreasing fertility has been somewhat neglected, with research typically framed in biomedical rather than social terms. However, this area merits closer attention given the contradictory nature of societal messages that simultaneously encourage women to pursue careers and enhance lifestyle, whilst warning of ‘risks’ of infertility and problems in ‘delaying’ motherhood. This article is based on a small-scale qualitative study that uses data drawn from eleven in-depth interviews with ‘older mothers’ about their transition to motherhood. The data was thematically analysed. We found that the women drew upon risk discourses around decreasing fertility and advancing maternal age, and that these discourses impacted on their decisions about the timing of their pregnancies. Some mothers felt that they started trying to conceive at ‘non-ideal’ times, owing to expectations they held about decreasing fertility. We suggest that the impact of contradictory societal messages around the timing of motherhood need to be more clearly considered for their potential effects on the timing of pregnancy and note how this topic brings the personal, and, by implication, the societal, into conflict with the (narrated) biological.

Yes

The incidence of malformed newborns is higher in human pregnancies complicated by diabetes mellitus, as compared to non-diabetic pregnancies. Neural tube and cardiac defects predominate among the fetal malformations induced by hyperglycemia. Non-specific maternal immune stimulation is protective in mice against birth malformations caused by chemical or physical teratogens, or by maternal diabetes mellitus. Insulin dependent diabetes was induced in ICR females to study the late gestation fetal heart by morphometric analysis. Diabetic females treated with Freund's compete adjuvant (FCA) or interferon-gamma (IFNγ) were also generated to elucidate potential positive effects of maternal immune stimulation during the diabetic pregnancy by morphometric analysis and pathologic scoring. Insulin-dependent CD1 females were generated to analyze late gestation fetal myocardial apoptosis by flow cytometric analysis and by real time-polymerase chain reaction (RT-PCR) analysis of a panel of 5 genes involved in apoptosis/proliferation (Bcl-2, P53, Caspase3, Caspase9 and PkC-e). The morphometric analysis of fetal hearts revealed visibly obvious dilation of ventricular chambers and outflow channel of the left ventricle, and reduction of total myocardial ventricular area in late gestation fetuses, as predominant changes seen in the offspring of diabetic dams. Pathologic scoring revealed that maternal immune stimulation, particularly with FCA, in part alleviated fetal heart changes of cavitary dilation and myocardial reduction. Increased rate of apoptosis/necrosis in the fetal myocardium in late gestation during the diabetic pregnancy was evidenced by flow cytometric analysis. Particularly there was a significant increase in percentage of early apoptotic cells in the fetal myocardium detected by cell markers annexin V and propidium iodide. There was also a significant increase in percentage of late apoptotic/necrotic fetal myocardial cells in the diabetic group compared to the control group. These results suggest that maternal treatment with FCA may in part protect the heart from high hyperglycemia by reducing the number of myocardial cells undergoing apoptosis and necrosis. The RT-PCR analysis revealed subtle changes in gene expression for all the genes except Bcl-2. A paradoxical and dramatic up-regulation of this anti-apoptotic gene was observed in late gestation fetal myocardium from the insulin-dependent hyperglycemic groups. Possibly, this could be a mechanism to protect the fetal myocardial cell from the chronic exposure to a severe hyperglycemic insult and consequent apoptosis. In conclusion, maternal insulin-dependent diabetes caused morphological changes in the late gestation fetal heart. Such changes were in part related to dysregulation of myocardial apoptosis. Maternal immune stimulation with FCA improved fetal heart morphology, by a mechanism that may in part relate to normalizing fetal myocardial apoptosis. / Ph. D.

Weight, height, skinfold thicknesses, circumference measurements, and 72-hour food records were collected from pregnant women (N=51) at four-week intervals between the 12th and 40th weeks of gestation. Subjects were divided Into two groups according to percent standard prepregnant weight for height: overweight > 110% (N=17) and normal weight < 110% (N=28). Changes In weight, skinfold thicknesses and circumference measurements were similar between the two groups during the third trimester (weeks 28 to 40 of gestation). Significant increases in weight (1.58 kg per four weeks) and waist circumference and significant decreases in calf and abdominal skinfold thicknesses are reported. When the second and third trimesters (weeks 12 to 40 of gestation) were considered mean weight gain was 1 .87 kg per four-week interval. Overweight gravidas demonstrated a significantly greater decrease in abdominal skinfold thickness than normal-weight gravidas. The patterns of change over the second and third trimesters were different between the two groups for abdominal, knee, and calf skinfold thickness, hips and thigh circumference, body fat, and percent body fat. Caloric and macronutrient consumption was similar between groups and did not change throughout the second the two and third trimesters. Maternal weight gain was significantly associated with infant birth weight in both groups. / M.S.

Seventy five mature and 520 prepuberal Dublin Disease Resistant rats were utilized to study the effects of exogenous hormones upon various reproductive phenomena. Ovulation was induced in 45 day old females by means of PMS and HCG. Progesterone (1.5, 2.5, 3.5, 5.0, or 10.0 mg) was dissolved in peanut oil and administered subcutaneously daily from day 2 to day 20 post coitus. Estradiol (0.2 mcg) was dissolved in peanut oil and administered subcutaneously on day 3 post coitus. Control rats received oil only. / Ph. D.

There has been little scientific evidence to suggest that abstinence-only-until-marriage education programs are effective in preventing or reducing teenage pregnancy and sexually transmitted disease. There is also little scientific evidence to suggest that comprehensive sex education programs are as or more effective in preventing or reducing teenage pregnancy and sexually transmitted disease than their abstinence-only counterpart. The following study compares the teenage pregnancy and sexually transmitted disease rates among minors in Virginia that participate in abstinence-only programs with rates among minors participating in comprehensive sex education programs. I hypothesize that counties implementing comprehensive sex education programs in schools will typically have lower pregnancy and sexually transmitted disease rates among minors than counties implementing abstinence-only education programs. I test these hypotheses with data on the 16 Virginia counties and county equivalents which could be verified as having either comprehensive or abstinence-only sex education programs in public schools during 1998-2003. The data confirm the hypotheses. On average, comprehensive program counties showed greater declines in pregnancy rates among females aged 15-17 than abstinence-only program counties. Comprehensive counties experienced declines in Chlamydia and Gonorrhea rates among males and females aged 15-17, whereas abstinence-only counties' Gonorrhea and Chlamydia rates increased. These findings underscore the need for statewide -- indeed, nationwide -- public reporting of school systems' sex education program types to permit a more thorough comparison and evaluation of program outcomes. In the meantime, these results challenge Virginia advocates of abstinence-only education programs to empirically defend their claims. / Master of Science

Maternal overweight and obesity (i.e., excess adiposity) are risk factors for adverse pregnancy outcomes and long-term maternal and offspring health impairments that are rooted in placental dysfunction. Factors contributing to placental dysfunction in pregnancies affected by excess adiposity are not fully understood. We hypothesized that impaired remodelling of uterine spiral arteries and enhanced inflammatory signalling at the placental interface related to compositional and functional differences in uterine macrophage and natural killer (NK) cells in early pregnancy would contribute to placental hypoxia and impaired vascular maturation. We tested this hypothesis using a mouse model of periconceptional high-fat, high-sucrose (HFHS) diet-induced excess adiposity. In Chapter 3, we found that HFHS placental tissues were hypoxic and exhibited histological features of malperfusion and inflammation in late gestation. This was accompanied by elevated circulating fetal endocrine and inflammatory mediators. In Chapter 4, we show that diet-induced excess adiposity does not impair spiral artery transformation at mid-gestation but does promote angiogenic and inflammatory shifts related to decidual macrophage and NK cell populations that might contribute to later placental malperfusion. In Chapter 5, we examined the cell-type-specific impacts of excess adiposity using single-cell gene expression analysis. We found that immune and stromal cell populations from HFHS uterine tissues exhibit pro-fibrotic, pro-thrombotic, and potentially immuno-suppressive gene expression changes immediately following embryo implantation. This coincided with immunophenotypic changes in blood monocytes and neutrophils that might be indicative of low-level systemic vascular injury. Overall, our findings indicate that diet-induced excess adiposity can compromise placental perfusion in the absence of impaired spiral artery remodelling. Altered recruitment and activity of uterine immune cells driven by conditions surrounding excess adiposity likely participate in disrupted uteroplacental perfusion, inflammation, and suboptimal placental function. These data provide new insights into the cellular and molecular mechanisms underlying placental dysfunction in pregnancies affected by overweight and obesity. / Thesis / Doctor of Philosophy (PhD)

Fear and anxiety are fundamental emotional states that are critical for survival. These states are characterized by a variety of coordinated responses, including behavioral and autonomic changes, that need to be properly integrated. For the past decades, most studies have separated the behavioral and autonomic elements, generating a gap in understanding their integrative nature. In this thesis, a framework analysis is presented that allows for the integration of cardiac, behavioral, and neuronal readouts in freely moving mice during different emotional states. Furthermore, a growing body of evidence demonstrates that a vital component of these states is the physiological report of bodily states, or interoception, which allows for quick adaptation to changing situations. A set of distinctive interoceptive pathways has been described from the periphery to the brainstem; however, the circuits that process and integrate cardiac interoceptive signals in higher orders are poorly understood. The midbrain periaqueductal gray (PAG) is a region crucially involved in defensive states through its modulation of both, cardiac and behavioral components. Preliminary studies demonstrate an anatomical connection between the major cardiac interoception brainstem area, the nucleus of the solitary tract, and the PAG; however, the functional characterization and the specific neuronal substrates responsible for interoception in this area have not been described. An interesting particularity of the PAG is that the ventro-lateral subcolumn is the highest order of the neuraxis where inhibitory neurons that express the glycine can be found. In the lower brainstem and spinal cord, glycinergic inhibitory neurons have demonstrated a role in processing sensory and autonomic signals from the periphery, raising the question of whether the PAG glycinergic neurons could be involved in integrating cardiac interoceptive signals as part of a defensive state. In this thesis, using virally mediated trans-synaptic retrograde tracing, I showed that glycinergic PAG neurons receive inputs from cardiac regulatory areas in the brainstem and project massively to forebrain and midbrain regions. By employing advanced techniques such as deep brain calcium imaging with a miniaturized microscope and optogenetics, this study provides compelling evidence for the involvement of glycinergic PAG neurons in controlling heart rate and maintaining cardiac macrostate dynamics within physiological levels. The results of the optogenetic manipulation further revealed that a change in the heart rate macrostate caused by the glycinergic PAG neurons leads to anxiety-like behaviors, providing further evidence for the role of these neurons in regulating defensive states. Overall, by unraveling the neural circuitry underlying interoception in the PAG, our study paves the way to better understand fear and anxiety disorders. / Furcht und Angst sind grundlegende emotionale Zustände, die für das Überleben entscheidend sind. Diese Zustände sind durch eine Vielzahl von koordinierten Reaktionen gekennzeichnet, darunter auch Verhaltensänderungen und autonome Veränderungen, die richtig integriert werden müssen. In den letzten Jahrzehnten haben die meisten Studien die verhaltensbezogenen und autonomen Elemente getrennt, was zu einer Lücke im Verständnis ihrer integrativen Natur führte. In dieser Arbeit wird eine Rahmenanalyse vorgestellt, die die Integration von kardialen, verhaltensbezogenen und neuronalen Messwerten bei sich frei bewegenden Mäusen während verschiedener emotionaler Zustände ermöglicht. Darüber hinaus gibt es immer mehr Belege dafür, dass eine wichtige Komponente dieser Zustände die physiologische Rückmeldung von Körperzuständen an das Gehirn, die sog. Interozeption ist, die eine schnelle Anpassung an sich ändernde Situationen ermöglicht. Es wurde eine Reihe von ausgeprägten interozeptiven Bahnen von der Peripherie bis zum Hirnstamm beschrieben. Jedoch sind die Schaltkreise, die kardiale interozeptive Signale in höherer Ordnung verarbeiten und integrieren, kaum bekannt. Das periaquäduktale Grau des Mittelhirns (PAG) ist eine Region, die sich entscheidend an Verteidigungszuständen beteiligt ist und deren Modulation sowohl kardiale als auch verhaltensbezogene Signale beeinflusst. Vorläufige Studien zeigen eine anatomische Verbindung zwischen dem wichtigsten kardialen Interozeptionsbereich des Hirnstamms, dem Nucleus tractus solitarius, und dem PAG; die funktionelle Charakterisierung und die spezifischen neuronalen Substrate, die für die Interozeption in diesem Bereich verantwortlich sind, sind bislang jedoch nicht beschrieben worden. Eine interessante Besonderheit des PAG ist, dass die ventro-laterale Subkolumne die höchste Ordnung der Hirnachse mit hemmenden glyzinergen Zellkörpern aufweist. Im Hirnstamm und im Rückenmark haben diese hemmenden Neuronen eine Rolle bei der Verarbeitung sensorischer und autonomer Signale aus der Peripherie gezeigt, was die Frage aufwirft, ob die glyzinergen Neuronen des PAG an der Integration kardialer interozeptiver Signale als Teil eines Verteidigungszustandes beteiligt sein könnten. In dieser Arbeit habe ich mit Hilfe von viral vermitteltem trans-synaptischem retrograden Tracing gezeigt, dass glyzinerge PAG-Neuronen Inputs von kardialen Regulationsbereichen im Hirnstamm erhalten und massiv in Vorder- und Mittelhirnregionen projizieren. Durch den Einsatz fortschrittlicher Techniken, wie z. B. Tiefenhirn- Kalziumbildgebung mit einem miniaturisierten Mikroskop und Optogenetik, liefert diese Studie überzeugende Beweise für die Beteiligung glyzinerger PAG-Neuronen an der Kontrolle der Herzfrequenz und der Aufrechterhaltung der kardialen Makrostate-Dynamik innerhalb physiologischer Grenzen. Die Ergebnisse der optogenetischen Manipulationen zeigten außerdem, dass eine durch die glyzinergen PAG-Neuronen verursachte Veränderung des Makrostates der Herzfrequenz zu angstähnlichem Verhalten führt, was einen weiteren Beweis für die Rolle dieser Neuronen bei Furcht und Angst darstellt. Insgesamt ebnet unsere Studie durch die Entschlüsselung der neuronalen Schaltkreise, die der Interozeption im PAG zugrunde liegen, den Weg zu einem besseren Verständnis von Angst und Angststörungen.

Thesis (M.S.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2999-01-01