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).

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

La lumière influence fortement la physiologie et le comportement en exerçant des effets non-visuels de deux types : i) indirects, via la resynchronisation de l’horloge centrale qui est située dans les noyaux suprachiasmatiques (NSC), ii) directs, indépendants du processus circadien, via des mécanismes encore mal compris. Nos travaux chez la souris ont montré que l’influence directe de la lumière constitue un mécanisme majeur de régulation du sommeil, de l’éveil et de l’humeur, au même titre que le processus circadien. Ces effets sont majoritairement médiés par la mélanopsine, un photopigment exprimé dans la rétine, et relayés au niveau cérébral par différentes structures comme les NSCs et le VLPO. Ainsi, le rôle des NSCs ne doit pas être interprété qu’au travers de leur fonction d’horloge. Ensuite, dans une perspective de recherche translationnelle de l’animal à l’homme, nous avons validé Arvicanthis ansorgei, comme modèle d’étude du sommeil afin de pouvoir interpréter nos résultats chez un rongeur diurne. Enfin, de nombreuses données suggérant que les effets directs de la lumière modulent l’activité du système dopaminergique, nous avons évalué l’intérêt de la luminothérapie dans des pathologies dopaminergiques (maladie de Parkinson, syndrome des jambes sans repos, troubles de l’humeur). Ces avancées ouvrent de nombreuses perspectives pour une meilleure utilisation de la lumière dans notre société ainsi qu’en pathologie. / Light influences physiology and behavior through both types of non-image-forming effects: i) indirect, synchronizing the circadian master clock located in the suprachiasmatic nucleus (SCN), ii) direct effects, independent from the circadian process though mechanisms poorly understood. Our studies in mice demonstrate that the direct influence of light constitutes a key mechanism of regulation for sleep, alertness and mood and is as important as the circadian process. The direct effects of light are mainly mediated through melanopsin, a retinal photopigment that projects to the different structures of the brain such as the SCN and the VLPO. The SCN, beyond their role as circadian clock are also a relay system for the direct effects of light. Further, we validated Arvicanthis ansorgei as a diurnal model for the study of sleep regulatory mechanisms. This is an important step in the translational approach from animal research to applications in humans. Various data suggest that the direct effects of light interact with the dopaminergic system. In the last part of this thesis, we evaluated the indication of bright light therapy in dopaminergic pathologies (Parkinson disease, restless legs syndrome, mood disorders). These advances open up new perspectives for possible applications of light therapy and may help improving societal lightening conditions.