Thesis (Ph. D.)--State University of New York at Binghamton, Dept. of Psychology, 2005. / Includes bibliographical references.

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2007. / Title from first page of PDF file (viewed June 11, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 108-123).

Thesis (Ph. D.)--University of California, San Diego, 2007. / Title from first page of PDF file (viewed June 8, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 169-188).

L'habénula (Hb) est une petite structure cérébrale impliquée dans le contrôle des monoamines dont l’horloge circadienne est peu caractérisée. Ces travaux ont permis de prouver que l’Hb exprimait des gènes horloges en condition constante et qu’une déficience dans ces gènes altérait son horloge. De plus, l’Hb possède une horloge robuste qui oscille ex vivo sans l’entraînement du noyau suprachiasmatique (SCN) et même en présence de lumière constante qui affecte l’activité locomotrice et diminue l’amplitude des oscillations du SCN. Cependant, les oscillateurs de l’Hb se retrouvent désynchronisés en obscurité constante. Enfin, nous avons mis en évidence de potentiels synchronisateurs : quatre molécules affectent l’horloge dans l’Hb (dopamine, noradrénaline, vasopressine et orexine). Cette caractérisation de l’Hb pourra amener dans le futur à mieux comprendre son implication dans des maladies psychiatriques mêlant rythmes et monoamines comme la dépression ou l’addiction. / The habenula (Hb) is a key nucleus for monoamine control with circadian properties. However, its clockwork is not fully characterized. In this thesis, we confirm that the Hb harbors a molecular circadian clock which can be disrupted by mutations of clock genes. Furthermore, we showed that the Hb clock was still rhythmic even without the suprachiasmatic nucleus (SCN) or in constant light condition which disrupts locomotor activity rhythms and SCN oscillations. However, Hb oscillators (in the caudal and rostral part) are uncoupled in constant darkness condition. In the last part of the study, we determined the potential internal synchronizators. The results indicated that at least four molecules (dopamine, noradrenaline, vasopressin and orexin) affect the Hb circadian properties (period, amplitude). The characterization of the Hb clock will give us a better understanding of its involvement in psychiatric diseases combining rhythms and monoamine alteration like depression or addiction.

The suprachiasmatic nucleus (SCN) of the hypothalamus is the master mammalian pacemaker, co-ordinating the multitude of cell-autonomous circadian oscillators across the body to ensure internal synchrony, as well as maintaining an adaptive phase relationship with the light-dark cycle via projections from the retina. Intercellular communication between SCN clock neurons synchronises their oscillations, resulting in coherent output signals to the periphery. Vasoactive intestinal peptide (VIP), a neuropeptide expressed in the retinorecipient ventrolateral region of the SCN, is vital to this circuit-level co-ordination by signalling to its cognate VPAC2 receptor. In addition, VIP is important for the integration of light input into the SCN oscillation. The aims of the work presented in this thesis were to determine the roles of the VIP and VPAC2 cells in controlling circadian rhythmicity, and to elucidate the mechanisms of VIP signalling that underpin these roles. The first two experimental chapters utilise intersectional genetics and viral transduction to address separable roles for the VIP and VPAC2 cell populations. By diphtheria toxin-mediated cell ablation, or by adjusting cell-autonomous periodicity or rhythmicity specifically in these cell populations, I have identified that the VPAC2 cells are important for period setting and rhythmicity of both the SCN ex vivo and mouse behaviour in vivo, while the VIP cells play a vital role in behavioural rhythmicity and phase coherence across the SCN. The next two chapters use application of VIP to SCN slices to address mechanisms of phase-resetting through pharmacological manipulation and microarray analysis. I find that VIP has long lasting effects on all major circadian parameters of the SCN slice oscillation at both the cellular and circuit levels, and that it achieves this through a diversity of molecular pathways, in particular through cAMP/Ca2+ response elements within gene promoters. The final chapter focuses primarily on DUSP4, a negative regulator of the MAP kinase pathway that I have demonstrated to be upregulated by VIP. Here I demonstrate that DUSP4 affects the steady-state period of SCN slices, as well as influences phase shifting characteristics of both slices and mice. To conclude, the work presented here furthers our knowledge of neuropeptidergic communication in mammalian pacemaking. I have undertaken extensive characterisation of the molecular mechanisms through which the VIP neuropeptide influences SCN oscillators, and I have determined differential roles for the VIP and VPAC2 neurons in circadian timekeeping.

xii, 109 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number. / There are two fundamental environmental rhythms that organisms in nature encounter: (1) the daily rhythm of light and dark that is due to the rotation of the earth about its axis and (2) the yearly seasonal rhythm due to the angle of the earth's rotation relative to the plane of its orbit around the sun. All eukaryotes have an endogenous circadian (daily) clock that allows for the timing of biological events within the context of the daily light:dark cycle. A wide diversity of plants and animals in temperate regions use photoperiodic (daylength) cues to time life history events, such as reproduction and diapause (insect dormancy) within the context of the yearly seasonal cycles. This dissertation focuses on the relationship between the circadian clock, photoperiodic time measurement and diapause. Chapter I serves as an introduction to biological timing and briefly summarizes the chapters that follow Chapter II outlines why Drosophila melanogaster , the workhorse of modern insect genetics, is not an appropriate system for the study of photoperiodism. Chapter III defines the Nanda-Hamner response, the circadian phenotype used in this dissertation, and proposes that the NH response is due to a rhythmic level of circadian disorganization in response to environmental cycle length. Chapters IV and V deal primarily with the long-held proposition that the circadian clock forms the causal basis of photoperiodic time measurement. I show that variation in the circadian clock does not covary with photoperiodic phenotypes among natural populations of Wyeomyia smithii , and thus these two processes are evolutionarily independent. Chapter VI describes the first forward genetic screen for candidate genes involved in photoperiodism and diapause termination in any animal. Chapter VII is a discussion of the complexity involved in studies of the genetics of photoperiodism and diapause and how historical inertia of scientific hypothesis acts to confound, rather than clarify, the relationship between genotypes and phenotypes. Chapter VIII is a concluding discussion of the implications of the work presented. This dissertation includes both previously published and co-authored material. / Committee in charge: William Cresko, Chairperson, Biology; William Bradshaw, Advisor, Biology; Patrick Phillips, Member, Biology; Eric Johnson, Member, Biology; Stephen Frost, Outside Member, Anthropology

Diabetes has afflicted 8.3%, approximately 25.8 million, of the United States population and is the seventh leading cause of death [1]. Type I diabetes (T1D) accounts for 5 to 10% of all diagnosed cases of diabetes in the United States [2]. If present trends continue, the rate of T1D incidence among children under the age of 14 will increase by 3% globally [3]. T1D is an autoimmune disorder in which the β-cells of the pancreatic islets are destroyed, leading to high blood sugar. Hyperglycemia and loss of immunological tolerance to self-antigens are common associations of T1D [4]. Periodontal disease impacts as much as 47% of the U.S. population and is a significant cause for tooth loss in adults [5]. Chronic infections from bacterial populations that colonize the tooth root surface result in the activation of immunological mediators and various metabolic byproducts, such as cytokines, chemokines, and tissue-destructive enzymes [6, 7]. Studies have demonstrated that the increased systemic inflammation associated with periodontal disease appears to contribute to several systemic diseases, particularly diabetes [8, 9], with a strong, bi-directional, relationship between diabetes and periodontal disease in which glycemic control is a major determinant. Improved biomarkers for T1D prediction are needed. Cytokines serve an important part in the onset of T1D and strongly determine the ultimate fate of β cell destruction [10]. Such cytokines include interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α). Th1 cytokines such as IL-1β, IFN-γ, and TNF-α have been demonstrated to induce pancreatic β-cell apoptosis. Matrix metalloproteinases (MMPs) have been demonstrated to participate in the pathogenesis of periodontitis. Hence, the measurement of these inflammatory cytokines and MMPs may serve as a marker for the onset or progression of T1D and glycemic control. There have been no previous studies describing the distribution of salivary biomarkers of inflammation in T1D. Saliva represents a suitable bioreservoir for cytokines and can be collected noninvasively with very little to no stress upon the donor allowing for multiple collections if needed and it is easy to collect, store, and transport [11], however there are circadian patterns that must be accounted for. Therefore, we measured the levels of cytokines and MMPs in the saliva of T1D patients, characterized diurnal patterns of salivary cytokines in healthy subjects, and explored sources of inflammation to increase our understanding of salivary biomarkers of inflammation as a prediction of the progression of T1D and gum health and glycemic control. This work demonstrated that specific salivary inflammatory markers - MMP-8, MMP-9, and TNF-α - in T1D subjects are associated with decreased glycemic control. Diurnal patterns of salivary proteins must be accounted for upon collection due to the unique rhythms of cytokine expression within each individual. Upon glucose stimulation, pro-inflammatory (Th2) cytokines, such as IFN-γ and IL-13, tend to decrease, whereas anti-inflammatory (Th1) cytokines, such as IL-10, tend to increase. Hyperglycemic conditions may promote an anti-inflammatory profile of human submandibular gland cells.

Orientador: Milva Maria Figueiredo De Martino / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-04T03:29:08Z (GMT). No. of bitstreams: 1 Simoes_AnaLedaBertoncini_M.pdf: 1152293 bytes, checksum: 939294f259cff182dfd66288e6a3ac44 (MD5) Previous issue date: 2005 / Resumo: Esta pesquisa teve como objetivo verificar a variabilidade circadiana das temperaturas timpânica, oral e axilar; correlacionar as medidas da temperatura timpânica considerando o ângulo de posicionamento e comparar as medidas entre si, em pacientes adultos hospitalizados. Participaram, 15 pacientes do sexo masculino sem sinais de processos infecciosos, com idade entre 22 a 75 anos com diversos diagnósticos clínico e cirúrgico, internados nas enfermarias de Cardiologia, Gastroclínica e Enfermaria Geral de Adultos (EGA). Foram medidas as temperaturas ao longo do período de vigília, iniciando às 6 horas da manhã e a última às 22 horas, com um total de nove medidas. Verificou-se também a temperatura ambiente nas enfermarias durante o período das 5h30, às 14 horas e às 20 horas. Os resultados mostraram que houve diferença significativa entre as médias dos termômetros; as médias dos horários medidos; às médias entre as temperaturas dos termômetros no período noturno e entre as médias nos períodos matutino e vespertino (p-value=0,0001). Não houve diferença significativa entre os horários medidos no período noturno (p-value=0,8) e entre as médias das temperaturas nos períodos matutino e vespertino (p-value=0,4), quando utilizada a técnica paramétrica de análise de variância e o teste de Tukey para comparações múltiplas. O nível de significância adotado foi ? = 0,05. O termômetro timpânico registrou a variabilidade circadiana dos pacientes e seus valores de temperatura foram maiores em relação aos outros locais de medida / Resumo: Esta pesquisa teve como objetivo verificar a variabilidade circadiana das temperaturas timpânica, oral e axilar; correlacionar as medidas da temperatura timpânica considerando o ângulo de posicionamento e comparar as medidas entre si, em pacientes adultos hospitalizados. Participaram, 15 pacientes do sexo masculino sem sinais de processos infecciosos, com idade entre 22 a 75 anos com diversos diagnósticos clínico e cirúrgico, internados nas enfermarias de Cardiologia, Gastroclínica e Enfermaria Geral de Adultos (EGA). Foram medidas as temperaturas ao longo do período de vigília, iniciando às 6 horas da manhã e a última às 22 horas, com um total de nove medidas. Verificou-se também a temperatura ambiente nas enfermarias durante o período das 5h30, às 14 horas e às 20 horas. Os resultados mostraram que houve diferença significativa entre as médias dos termômetros; as médias dos horários medidos; às médias entre as temperaturas dos termômetros no período noturno e entre as médias nos períodos matutino e vespertino (p-value=0,0001). Não houve diferença significativa entre os horários medidos no período noturno (p-value=0,8) e entre as médias das temperaturas nos períodos matutino e vespertino (p-value=0,4), quando utilizada a técnica paramétrica de análise de variância e o teste de Tukey para comparações múltiplas. O nível de significância adotado foi ? = 0,05. O termômetro timpânico registrou a variabilidade circadiana dos pacientes e seus valores de temperatura foram maiores em relação aos outros locais de medida / Abstract: The aim of this research was to verify the daily variation of the tympanic, oral and axillary temperatures, and correlate measurements of the Tympanic temperature considering the positioning angle and to compare the set of measurements in adult volunteer patients during treatment in the Clinics Hospital of Universidade Estadual de Campinas, São Paulo. The results refer to fifteen male in patients, 22 to 75 years old with no signal of infectious processes, having different clinical and cirurgic diagnostics in the Cardiology, Gastroclinics, and Adult General Nursery. The temperatures were measured nine times between 6 am and 10 pm. The ambient nurserys temperature was also monitored, at 5:30 am, 2 pm, and 8 pm. The results show that there was a significant difference between: the mean measured temperatures in different positions; the mean values of the different scheduled times; the mean values of the morning and afternoon periods (p-value=0,0001). When using the parametric technique of analysis of variance and the Tukey¿s test of multiple comparation, there was no significant difference between the measured values (p-value=0,8). The significance level adopted was ? = 0,05. The tympanic thermometer has registered the daily variation of the patients¿ temperature and its values were bigger than the measured by the other places of measurement / Abstract: The aim of this research was to verify the daily variation of the tympanic, oral and axillary temperatures, and correlate measurements of the Tympanic temperature considering the positioning angle and to compare the set of measurements in adult volunteer patients during treatment in the Clinics Hospital of Universidade Estadual de Campinas, São Paulo. The results refer to fifteen male in patients, 22 to 75 years old with no signal of infectious processes, having different clinical and cirurgic diagnostics in the Cardiology, Gastroclinics, and Adult General Nursery. The temperatures were measured nine times between 6 am and 10 pm. The ambient nurserys temperature was also monitored, at 5:30 am, 2 pm, and 8 pm. The results show that there was a significant difference between: the mean measured temperatures in different positions; the mean values of the different scheduled times; the mean values of the morning and afternoon periods (p-value=0,0001). When using the parametric technique of analysis of variance and the Tukey¿s test of multiple comparation, there was no significant difference between the measured values (p-value=0,8). The significance level adopted was ? = 0,05. The tympanic thermometer has registered the daily variation of the patients¿ temperature and its values were bigger than the measured by the other places of measurement / Mestrado / Enfermagem e Trabalho / Mestre em Enfermagem

Mole-rats from the family Bathyergidae are endemic to Africa, this family exhibits a continuum of sociality, comprising both solitary and social species. Sociality is related to the degree of aridity and the distribution of the underground food resource. All the members of the bathyergid family are strictly subterranean, and occur in a niche which is devoid of light cues and thermally buffered from ambient and surface extremes. Since vision is redundant in a lightless environment, mole-rats have subsequently undergone ocular regression over evolutionary time. As a consequence of the minute eyes, the visual system of mole rats is severely regressed and, in addition, the proportional retinal innervation to different structures is modified. The classical visual system is reduced while the circadian system is expanded. Retinal projection studies on the giant Zambian mole-rat, Cryptomys mechowi and an albino highveld mole-rat, Cryptomys hottentotus pretoriae, confirmed sparse contralateral retinal projections to structures of the visual system, while the circadian system received relatively dense bilateral innervation. The innervation pattern of an albino Damaraland mole-rat, Cryptomys damarensis differed from the other animals. Investigations of Fos expression in neurons over circadian time suggested that the phase response curve of the solitary mole rat, Georychus capensis, resembles that of aboveground mammals whereas the social Cryptomys hottentotus pretoriae, does not display differential sensitivity to light in the subjective day and night. The influence of increasing light intensities showed that higher light intensities elicit a more pronounced Fos expression in SCN of all the species investigated. In addition, longer light pulses also increases the Fos induction in the SCN. A preliminary investigation into the effect of temperature on the Fos induction in the SCN of three mole-rat species, demonstrated that a higher Fos response could be expected with higher ambient temperatures. However the sample size was very small, and could have influenced the outcome of the experiment. Behavioural locomotor activity rhythms of the solitary species, Georychus capensis, and the social species Cryptomys hottentotus pretoriae and Cryptomys damarensis, confirmed that activity patterns correlate with trends displayed in Fos expression. The solitary species exhibited much more defined rhythmicity than the social species and a higher percentage of the animals displayed distinct endogenous rhythms. African mole rats provide an interesting model to study not only the features of the circadian system in a group of animals with a naturally regressed visual system, but also the influence of sociality on the degree of regression. / Dissertation (MSc (Zoology))--University of Pretoria, 2005. / Zoology and Entomology / unrestricted

The past two decades have highlighted the utility in using the fruit fly Drosophila as a model organism for unravelling the molecular and functional complexities of two important fields of research: the systems that guide retinal determination (RD) and circadian rhythms (the daily body clock or oscillator). RD and clock factors are of great interest as they are: (1) highly conserved in vertebrates; (2) also essential for other physiological systems; (3) implicated in several congenital disorders and other diseases. The RD factors operate within a network in which several of their interactions have been described. Two such factors, eyes absent (eya) and sine oculis (so), are known to function as a unit to direct transcriptional regulation during photoreceptor (PR) differentiation. The regulation of eya and so by a transcriptional repressor at the heart of the clock mechanism, vrille (vri), is here investigated. Two distinct observations advocated exploration of a link between vri and eya/ so is of interest. (1) vri is a core component of the clock and interacts with RD but the RD function is unknown. (2) Recent evidence suggests that an RD factor directly upstream of eya and so, twin-of-eyeless (toy), interacts with the oscillator mechanism through direct and indirect pathways. It is possible that the indirect influences of toy on the oscillator are mediated via eya and/ or so. Interactions between eya, so and vri during RD and within oscillator cells are investigated here.Eye development function was studied using immunohistochemistry and transgenic manipulation. VRI is not expressed within the developed PRs; rather, expression of VRI is down-regulated prior to differentiation. In addition, conversely to the hypothesised role, VRI is co-expressed with EYA in some regions. Together with data from transgenic manipulation of VRI regional expression, I propose that VRI is predominantly part of a developmental pathway but can attenuate eya and so expression.The VRI binding site has been described previously and several sites were identified within eya/ so loci, some of which were tested in an in vitro binding assay. Two such sites were located adjacent to a known enhancer of so. I generated two transgenic fly lines containing: 1) an extension of the original enhancer to contain the VRI sites; and 2) a similar construct with the VRI sites ablated. Comparison of the original enhancer to those from the current study confirmed that the VRI sites attenuate expression and that intervening regions must contain binding sites for other transcription factors.In adult brains over a circadian light-dark cycle, EYA protein was expressed in three of the central brain clock neurones. Furthermore, expression of eya and so transcripts in adult heads, PRs and the brain, changed over the light/ dark cycle independently of the clock - indicating that their expression is modulated over the light-dark cycle but not by the oscillator mechanism. These data suggest interactions between eye development factors eya/ so and oscillator components, or, the light/ dark cycle exist. These interactions may be important for tissue-specific circadian physiology as well as the overall oscillator mechanism and offer an intriguing route for future investigation.