<p>  </p> <p>In modern society, continuous light exposure and obesity are increasingly prevalent, especially in women of childbearing age. Circadian, metabolic, and reproductive systems have a complex, inter-regulated relationship. Thus, the disruption of one system likely impedes another. Excessive adiposity and circadian disruption alter normal behavior and physiology and disrupt the endocrine milieu. The overall goal of the studies described in this thesis was to develop and test a model system that could tease apart the influence of prepregnancy obesity and circadian disruption, as well as study the combined effects on female reproductive competence. </p> <p>The first study focuses on the prepregnancy period and aims to determine the effect of high fat diet feeding on diurnal eating pattern, body weight over the four-week period, the body composition at the end of the four-week period, hair corticosterone levels, and circadian fecal corticosterone patterns on female ICR mice. Five-week-old female ICR mice were randomly assigned to control (CON; 10% fat) or high fat (HF; 60%) diets and fed for four weeks to achieve adequate adiposity. During this four-week time period, mice had routine light exposure of 12h light and 12h dark. Feed was weighed at 0600 and 1745 Monday-Friday to determine diurnal feed intake. The mice were weighed on a weekly basis. After four weeks on respective diets, mice were anesthetized with isoflurane to measure crown-rump length to calculate BMI and hair was shaved for corticosterone extraction. Once mice recovered from anesthesia, body composition was measured with EchoMRI. After 1 week on diets, HF mice consumed more (P<0.05) during the day than CON mice, which is typically when mice are inactive. After two weeks on diets, HF mice weighed more (P<0.05) than CON, as well as had higher BMI and percent body fat (P<0.05) than CON after four weeks on diets. After four weeks on diets, HF mice had high hair corticosterone (P<0.05). Sampling feces over a 48h period at the end of the four weeks demonstrated that HF mice had elevated basal corticosterone, attenuated circadian rhythms, and a shift in corticosterone amplitude. The prepregnancy period demonstrated that high fat diets alone alter circadian eating pattern and corticosterone rhythms.</p> <p>The remainder of the study continued the dietary treatments assigned during the prepregnancy period, as well as implemented light conditions to create a 2Χ3 factorial study design. There were three light conditions: 12h light and 12h dark (LD), 24h dim light (L5), or 24h bright light (L100). Mice were moved into experimental light conditions after the observation of a vaginal plug or after 5 days with males. This portion of the study aimed to determine the effect of diet (CON or HF) and light exposure (LD, L5, or L100) on gestation length, number of pups born, milk composition, litter weight on postnatal day 12, as well as dam feed intake, hair corticosterone levels, and plasma prolactin. Continuous light exposure increased gestation length, with L5 (19.1 d ± 0.23) and L100 (18.9 d ± 0.21) having longer gestation lengths (P<0.05) than LD (18.1 d ± 0.25). Diet affected the number of pups born (P<0.05), with HF dams having fewer pups (9.99 ± 0.4) than CON (11.4 ± 0.4). Despite no difference in birth weight of standardized litters (n=8 pus/litter), litters of HF dams weighed more than CON by day 4 postnatal. The greater litter weight of HF dams continued until the end of the study on day 12 of lactation (P<0.05). Light had a tendency to increase litter weight (P=0.07). Diet, light, and stage of reproduction influenced dam feed intake (P<0.05). L100 dams had higher plasma prolactin, as well as final dam and mammary wet weights (P<0.05). Constant light exposure decreased ATP content in the mammary gland (P<0.05) and decreased milk lactose concentration (P<0.05). Pearson’s correlation analysis showed a positive relationship between mammary weight, fat pad weight, BMI, kcal of feed intake, and gestation length (P<0.05). In CON mice, hair corticosterone was negatively correlated with litter weight on lactation day 12. Liver weight was positively correlated with d 12 litter weight in HF mice. Together, these studies demonstrate that feeding high fat diets and continuous light alter maternal behavior and physiology, which may impact offspring health and development, however continuous light may not be the best approach to studying circadian disruption. Elevated maternal plasma prolactin and increased dam weight suggests a long day photoperiod was likely induced, thus potentially mitigating the circadian disruptive effects from constant light. Other model systems should be considered, such as using a chronic jet lag model that changes the light exposure every 3 d. </p>

The circadian rhythm is a rhythm which permeates all aspects of biological life and follows the hours of the sun. The pace of the rhythm is controlled by a collection of neurons in the hypothalamus, called the suprachiasmatic nucleus (SCN), whose signals affect rhythms throughout the body as can be seen in aspects of life from behavior down to oscillations of proteins in the cells. A disruption of this rhythm such as what happens during jet lag, where the rhythm of the SCN is out of synch with the rhythm of the rest of the body, is something that can have adverse effects on mental and physical health. To realign the SCN and the rhythm of the body, different methods and be implemented. This thesis investigated the effectiveness of glucocorticoids on re-aligning the rhythms of the body following a disruption through a meta-analysis and a qualitative review. The meta-analysis and review incorporated experiments from six articles investigating the hours of circadian rhythm shifts in the mouse model, after administering glucocorticoids. What was found was that the individual experiments presented results with high effect sizes; however, the direction of said effects was not uniform as the rhythms shifted in different directions. The lack of uniform direction caused no significant combined effect size to be found by this meta-analysis (MES=0.11 ± 0.06), showing that a statistical analysis based on hours shifted could not find a significant combined effect. The qualitative review, however, indicates that the administration of glucocorticoids shows an effect in re-entraining the rhythm of the peripheral parts of the body to that of the environmental cues and the SCN. Though no significant statistical effect was found in this analysis, the effect of glucocorticoids should not be discounted and could still prove a promising treatment for circadian disruptions, such as jet lag.

Alzheimer's disease (AD), as one of the most common neurodegenerative diseases, is characterized by the loss of neuronal dysfunction and death resulting in progressive cognitive impairment. The main histopathological hallmark of AD is the accumulation and deposition of misfolded Aβ peptide as amyloid plaques, however the precise role of Aβ toxicity in the disease pathogenesis is still unclear. Moreover, at early stages of the disease the important clinical features of the disorder, in addition to memory loss, are the disruptions of circadian rhythms and spatial disorientation. In the present work I first studied the role of Aβ toxicity by comparing the findings of genome-wide association studies in sporadic AD with the results of an RNAi screen in a transgenic C. elegans model of Aβ toxicity. The initial finding was that none of the human orthologues of these worm genes are associated with risk for sporadic Alzheimer’s disease, indicating that Aβ toxicity in the worm model may not be equivalent to sporadic AD. Nevertheless, comparing the first degree physical interactors (+1 interactome) of the GWAS and worm screen-derived gene products have uncovered 4 worm genes that have a +1 interactome overlap with the GWAS genes that is larger than one would expect by chance. Three of these genes form a chaperonin complex and the fourth gene codes for actin, a major substrate of the same chaperonin. Next I have evaluated the circadian disruptions in AD by developing a new system to simultaneously monitor the oscillations of the peripheral molecular clock and behavioural rhythms in single Drosophila. Experiments were undertaken on wild- type and Aβ-expressing flies. The results indicate the robustness of the peripheral clock is not correlated with the robustness of the circadian sleep and locomotor behaviours, indicating that the molecular clock does not directly drive behaviour. This is despite period length correlations that indicate that the underlying molecular mechanisms that generate both molecular and behavioural rhythms are the same. Rhythmicity in Aβ-expressing flies is worse than in controls. I further investigated the mechanism of spatial orientation in Drosophila. It was established that in the absence of visual stimuli the flies use self-motion cues to orientate themselves within the tubes and that in a Drosophila model of Aβ toxicity this control function is disrupted.

No description available.

No description available.