Circadian Rhythms (CR) are driven by a biological clock called as suprachiasmaticnucleus (SCN), located in a brain region called the hypothalamus. These rhythms are very much necessary in maintaining the sleep and wake cycle at appropriate times in a day. As a starting step towards non-invasive investigation of CR, aim is to study changes in the physiological processes of two Regions of Interest (ROI), the hypothalamus and the visual cortex. This was studied using a functional Magnetic Resonance Imaging (fMRI) technique to investigate for any changes or differences in the Blood Oxygen Level Dependent (BOLD)signals extracted from the ROI during a visual stimulation. We acquired and processed fMRI data to extract BOLD signals from ROI and the extracted signals are again further used to study the correlation with the experimental ON-OFF design paradigm. The extracted BOLD signals varied a lot between the two specified brain regions within the same subject and between three types of fMRI data. These variations were found in terms of number of activated voxels and also Signal to Noise ratio(SNR) level present in the signals. The number of activated voxels and SNR werehigh in visual cortex whereas low number of activated voxels and low SNR were found in hypothalamus. The correlation between BOLD responses from primaryvisual cortex were shown as positive with the experimental stimulation whereas BOLD responses extracted from hypothalamus have shown a negative correlation in time with the experimental stimulation. As a start up of the project, these BOLD responses can provide references for a future use in research studies, especially to further study about change in phase of the BOLD signal extracted exactly from the SCN. These phase responses can then be used to study physiological processing in subjects affected by sleep disorders.

Le système circadien muti-oscillant est constitué de l'horloge suprachiasmatique (SCN), l'horloge principale dans l'hypothalamus antérieur, et de nombreuses horloges périphériques. L'horloge SCN synchronise les horloges périphériques situées dans chaque organe. L'horloge SCN est une horloge circadienne auto-entretenue qui maintient les rythmes quotidiens comportementaux, physiologiques et neuroendocriniens. Les donneurs de temps (zeitgebers), tels que lumière et nourriture, sont des synchroniseurs puissants, respectivement pour le SCN et les horloges périphériques. La thèse visait à mieux comprendre les interactions entre les horloges circadiennes et le comportement alimentaire chez les espèces nocturnes. Nous avons montré dans la première et la seconde partie que l'alimentation ultradienne affecte les horloges centrales et périphériques chez la souris et le rat. Dans la première étude, nous avons conclu que l'alimentation ultradienne chez la souris a un impact majeur sur la sortie de l'horloge SCN et sur l'horloge périphérique dans le foie, tandis que dans la seconde étude, l'alimentation ultradienne chez le rat n'a eu pas d'impact sur l'horloge SCN, mais il a modifié les horloges périphériques et le métabolisme des lipides. Dans la troisième partie, nous avons montré des effets différentiels du régime alimentaire et de la restriction alimentaire temporelle sur les horloges périphériques du tissu adipeux brun et du muscle squelettique. Dans la quatrième partie, nous avons démontré un rôle du gène d'horloge Rev-erbα dans le comportement alimentaire et le métabolisme énergétique en comparant des souris porteuses d’une délétion de Rev-erbα, soit globale, soit limitée au système nerveux central. L’ensemble de ces études révèle l'interdépendance des horloges circadiennes et du comportement alimentaire, ainsi que leurs effets sur le métabolisme énergétique. / The muti-oscillatory circadian system consists of the suprachiasmatic clock (SCN) the master clock, located above the optic chiasm of the anterior hypothalamus, and many peripheral clocks. The SCN clock synchronizes the other peripheral oscillators located in each organ. The SCN clock is a self-sustaining circadian oscillator maintaining the daily behavioural, physiological, and neuroendocrine rhythms. The zeitgebers such as light and food are potent synchronizers for the SCN and other peripheral clocks. The thesis was aimed to understand different aspects of the interactions between circadian clocks and feeding behaviour in nocturnal species. We showed in the first and second parts that the ultradian feeding affects the central and peripheral clocks in mice and rats. In the first part, we concluded that the ultradian feeding in mice has major impacts on the SCN clock output and the peripheral clock in the liver, while in the second part ultradian feeding in rats does not have impact on the SCN clock but it affects peripheral clocks and lipid metabolism. In the third part, we showed the differential effects of diet and time restricted feeding in brown adipose tissue and skeletal muscle peripheral clocks. In the fourth part, we showed the role of clock gene Rev-erbα on feeding behaviour and energy metabolism by comparing between global and brain specific knock-out mice. The present studies reveal the interdependency of the circadian clocks and feeding behaviour, and their effects on whole-body metabolism.

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Background: Circadian rhythm disturbance is commonly observed in Alzheimer's disease (AD). In mammals, these rhythms are orchestrated by the superchiasmatic nucleus (SCN). Our previous study in the Tg2576 AD mouse model suggests that inflammatory responses, most likely manifested by low GABA production, may be one of the underlying perpetrators for the changes in circadian rhythmicity and sleep disturbance in AD. However, the mechanistic connections between SCN dysfunction, GABA modulation, and inflammation in AD is not fully understood. Objective: To reveal influences of amyloid pathology in Tg2576 mouse brain on metabolism in SCN and to identify key metabolic sensors that couple SCN dysfunction with GABA modulation and inflammation. Methods: High resolution magic angle spinning (HR-MAS) NMR in conjunction with multivariate analysis was applied for metabolic profiling in SCN of control and Tg2576 female mice. Immunohistochemical analysis was used to detect neurons, astrocytes, expression of GABA transporter 1 (GAT1) and Bmal1. Results: Metabolic profiling revealed significant metabolic deficits in SCN of Tg2576 mice. Reductions in glucose, glutamate, GABA, and glutamine provide hints toward an impaired GABAergic glucose oxidation and neurotransmitter cycling in SCN of AD mice. In addition, decreased redox co-factor NADPH and glutathione support a redox disbalance. Immunohistochemical examinations showed low expression of the core clock protein, Bmal1, especially in activated astrocytes. Moreover, decreased expression of GAT1 in astrocytes indicates low GABA recycling in this cell type. Conclusion: Our results suggest that redox disbalance and compromised GABA signaling are important denominators and connectors between neuroinflammation and clock dysfunction in AD.

Thesis (M.S.)--Uniformed Services University of the Health Sciences, 2005. / Running title: Seasonal affective disorder and melanopsin. Typescript (photocopy).

Circadian system of mammals is generated in suprachiasmatic nuclei of hypothalamus. This system is synchronized with light conditions through phase shifts that occur after light exposition during the subjective night. Recent studies have shown that activation of endocannabinoid receptors attenuates the light-induced phase shifts and influences the ability of circadian system to light entrainment. The aim of this work is to examine this influence on behavioral level and on light-reactive cellular processes within the suprachiasmatic nuclei. Our results show that the activation of endocannabinoid system via CB1 receptor agonist modulates the light-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and the expression of c-Fos protein in neurons of suprachiasmatic nuclei in the rat's brain; these cellular processes correlate with the attenuation of light entrainment. Keywords: circadian system, suprachiasmatic nuclei, light entrainment, endocannabinoid system, CB1 receptors, extracellular signal-regulated kinase 1/2, ERK1/2, c-Fos

Made available in DSpace on 2014-12-17T15:36:53Z (GMT). No. of bitstreams: 1 RuthnaldoRML.pdf: 3880208 bytes, checksum: 7da0684594a4d62a80785416490983fa (MD5) Previous issue date: 2008-04-30 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / In rodents, the suprachiasmatic nucleus (SCN) and the intergeniculate leaflet (IGL) are the main components of the circadian system. The SCN is considerate the site of an endogenous biological clock because can to generate rhythm and to synchronize to the environmental cues (zeitgebers) and IGL has been related as one of the main areas that modulate the action of SCN. Both receive projections of ganglion cells of retina and this projection to SCN is called retinohypothalamic tract (RHT). Moreover, the IGL is connected with SCN through of geniculohypothalamic tract (GHT). In primates (include humans) was not still demonstrated the presence of a homologous structure to the IGL. It is believed that the pregeniculate nucleus (PGN) can be the answer, but nothing it was still proven. Trying to answer that question, the objective of our study is to do a comparative analysis among PGN and IGL through of techniques immunohystochemicals, neural tracers and FOS expression after dark pulses. For this, we used as experimental model a primate of the new world, the common marmoset (Callithrix jacchus). Ours results may contribute to the elucidation of this lacuna in the circadian system once that the IGL is responsible for the transmission of nonphotic information to SCN and participate in the integration between photic and nonphotic stimulus to adjust the function of the SCN. In this way to find a same structure in primates represent an important achieve in the understanding of the biological rhythms in those animals / O sistema de temporiza??o circadiana (STC) ? respons?vel pela gera??o e modula??o dos ritmos circadianos que s?o oscila??es end?genas manifestadas pelos seres vivos para a maioria das fun??es e comportamentos, com per?odo em torno de 24 horas. Estes ritmos s?o sincronizados principalmente ao ciclo claro-escuro di?rio. O STC ? constitu?do por um conjunto de estruturas neurais interligadas, incluindo na sua composi??o um marca-passo encarregado da gera??o do ritmo, vias sincronizadoras e de sa?da aos efetores comportamentais. O n?cleo supraquiasm?tico do hipot?lamo (NSQ) ? tido como principal marcapasso circadiano. A les?o desse conjunto de c?lulas deixa o animal arr?tmico para algumas fun??es circadianas. A principal via direta de sincroniza??o ? o tracto retinohipotal?mico (TRH), que leva informa??o f?tica ambiental da retina ao NSQ. Uma segunda via, tida como de sincroniza??o indireta para o NSQ, ? o tracto gen?culohipotal?mico (TGH), que se origina das c?lulas produtoras de neuropept?deo Y (NPY) do folheto intergeniculado (FIG) do complexo geniculado lateral do t?lamo de roedores. Essas c?lulas tamb?m recebem proje??o direta da retina. Em primatas essa estrutura ainda n?o foi identificada. No entanto, um conjunto de c?lulas medial ao n?cleo geniculado lateral dorsal (GLD) do t?lamo, denominado de n?cleo pr?geniculado (NPG), se apresenta como poss?vel estrutura hom?loga ao FIG dos roedores, j? que algumas c?lulas do NPG apresentam imunorreatividade ao anticorpo contra NPY em diversos primatas estudados. Sabe-se que o sistema FIG-TGH al?m de estar relacionado ? modula??o f?tica do NSQ, parece tamb?m estar fortemente envolvido na sincroniza??o n?o-f?tica desse sistema. Ainda, as c?lulas imunorreativas a NPY est?o claramente mais envolvidas na sincroniza??o n?o-f?tica, comprovado pela marca??o da atividade metab?lica envolvendo o gene c-fos (gene de express?o imediata). Considerando este aspecto funcional e a dificuldade de identificar com precis?o uma estrutura hom?loga ao FIG em primatas, realizamos a caracteriza??o neuroqu?mica, analisamos o padr?o da proje??o retiniana e a express?o da prote?na do gene c-fos ap?s pulso de escuro, para melhor definir o papel do NPG dentro do STC. Para isso, usamos como modelo experimental um primata do novo mundo, o Callitrhix jacchus, conhecido popularmente como sag?i. Nossos dados confirmaram a hip?tese inicial de que o NPG, ou parte dele, seria hom?logo ao FIG de roedores. Encontramos, em toda extens?o do NPG do sag?i, neur?nios imunorreativos a NPY e uma densa proje??o retiniana em uma regi?o localizada mais pr?xima ao GLD. Conclu?mos que esta ?rea situada mais internamente, em rela??o ao complexo geniculado lateral do t?lamo, corresponde ao FIG e a por??o mais externa ao n?cleo geniculado lateral ventral dos roedores