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published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

The biological clock are responsible for entraining of circadian rhytms in many physiological and behavioral functions, including the activity of immune system. In mammals, the biological clock are located in the suprachiasmatic nuclei of the hypothalamus and also on the periphery. The main oscillator in suprachiamatic nuclei synchronizes the phases of the peripheral oscillators in tissues and the other brain areas and it also drives synthesis of melatonin in the pineal gland. Its endogenous period Tau (τ) is being synchronized with external 24-hour day under normal conditions, mostly by the light-dark cycles during the day and night and also by non-photic stimuli. By the application of endotoxin, disruption of normal endogenous conditions in organism causes activation of the immune response, behavioral changes and phase shifts of the circadian rhythmicity. This work examines effect of acute application endotoxin lipopolysaccharid on the cellular signaling cascades in the cells of suprachiasmatic nuclei and pineal gland. Our data indicate, that levels of phosphorylated forms of kinases GSK3β, ERK1/2 and levels of phosphorylated forms transcription factors STAT3 are substantially modificated after administration of lipopolysaccharid in the suprachiasmatic nuclei and especially in the pineal gland of...

The main mammalian circadian pacemaker stored in suprachiasmatic nuclei of the hypothalamus (SCN) is adapted to changes in the external environement by synchronization of its endogenous period with periodic changes of light and dark during day and night. The information about light travels via glutamatergic retinohypothalamic tract to the ventrolateral part of the SCN. Activation of ionotropic glutamate receptors in this area provably mediates the transfer of information about light on the transcriptional mechanism of light-sensitive cells. The role of the NMDA type of ionotropic glutamate receptors is well studied in this field and it is known that some NMDA receptor subunits show a circadian rhythm and an increased expression after a light pulse. Signalization via AMPA type receptors is much less elucidated. The aim of this thesis was to determine which AMPA receptor subunits are expressed in the SCN of the rat and if these subunits show a daily rhythm of expression and a reactivity to light pulse, as well as to outline the possible roles of distinct AMPA receptor subunits in the SCN. Keywords: circadian rhythms, suprachiasmatic nuclei, glutamate receptors, AMPA

Os neurônios Kiss1 do núcleo anteroventral periventricular (AVPV/PeN) e núcleo arqueado (Arc) possuem o receptor de estrógeno alfa (ERα) e são essenciais no controle do ciclo ovulatório. Os neurônios Kiss1 do AVPV/PeN apresentam conexões com o núcleo supraquiasmático, através do qual a informação fótica poderia regular a ovulação. A vasopressina (VP) e o peptídeo intestinal vasoativo (VIP) são os principais peptídeos produzidos pelo NSQ, e estudos sugerem a participação deles na secreção de LH. Com isso, investigamos se fibras vasopressinérgicas estão em aposição com neurônios Kiss1 do AVPV/PeN e Arc; se os receptores de VP e VIP são expressos nestes núcleos; e se variações nos níveis circulantes de estradiol (E2) poderiam afetar a expressão destes receptores. Para isso, utilizamos camundongos divididos em: fêmeas em diestro; fêmeas que tiveram os ovários removidos (OVX); e fêmeas OVX que receberam reposição de E2 (OVX+E2). Observamos que neurônios Kiss1 do AVPV/PeN colocalizam com fibras vasopressinérgicas; e os níveis circulantes de estrógeno não afetou este contato e sim o número de neurônios Kiss1. No AVPV/PeN, as OVX tiveram aumento da expressão dos receptores VPAC1 e VPAC2; no Arc, a reposição com E2 induziu um aumento da expressão do Avpr1a. / The Kiss1 neurons in the periventricular anteroventral nucleus (AVPV/PeN) and arcuate nucleus (Arc) have the estrogen receptor alpha (ERα) and are essential in controlling the ovulatory cycle. The Kiss1 neurons of the AVPV/PeN have connections to the suprachiasmatic nucleus, through which the photic information could regulate ovulation. Vasopressin (VP) and vasoactive intestinal peptide (VIP) are the main peptides produced by the SCN, and studies suggest their participation in LH secretion. Thus, we investigated whether vasopressinergics fibers are in apposition with Kiss1 neurons in the AVPV/PeN and Arc; whether VP and VIP receptors are expressed in these nuclei; and if changes in circulating levels of estradiol (E2) could affect the expression of these receptors. We used mice divided into: females in estrus; females who had their ovaries removed (OVX); and OVX that receiving E2 replacement (OVX + E2). We observed that Kiss1 neurons of the AVPV/PeN in colocalization with vasopressinergics fibers; and circulating levels of estrogen did not affect this contact but the number of neurons Kiss1. In AVPV/PeN, the OVX had increased expression of VPAC1 and VPAC2 receptors; in the Arc, replacement with E2 induced an increased expression of Avpr1a.

Componente essencial do sistema de temporização circadiano, o núcleo supraquiasmático (NSQ) possui três aferências principais: o trato retinohipotalâmico (TRH), o trato geniculohipotalâmico (TGH) e as terminações serotonérgicas da rafe. Suas células possuem oscilação circadiana autônoma que resultam na expressão rítmica dos chamados genes do relógio. O presente estudo analisa as concentrações de 5-HT nos núcleos da rafe e NSQ de ratos em livre-curso e mostra que somente os núcleos obscuro e linear apresentam ritmos endógenos com ação determinante do ciclo claro-escuro na no ritmo diário; compara a organização intrínseca do NSQ de primatas e roedores, mostrando organização diferenciada dos terminais serotonérgicos e do TGH em relação aos do TRH sugerindo funções diferentes dessas aferências no NSQ de primatas. Além disso, o padrão de expressão dos genes do relógio no NSQ do primata ao longo do período de atividade mostrou que os genes BMAL1 e Per1 apresentam pico de expressão ao redor do ZT2 e o gene Per2 no ZT7. Os dados demonstram diferenças interespecíficas importantes nas características neuroquímicas e moleculares do NSQ. / Essential component of the circadian timing system, the suprachiasmatic nucleus (SCN) receives dense retinohypothalamic RHT, geniculohypothalamic tract GHT and serotonergic innervation arriving from the raphe nuclei. SCN has pacemaker cells that produce rhythmic expression of clock genes. This study investigates the levels of 5-HT in the raphe nuclei and SCN in free running rats and shows endogenous rhythms in the obscurus and linear raphe nuclei, which is regulated by the daily light: dark cycle rhythms. The comparative analysis of the intrinsic structure of the SCN of primates and rodents shows a different organizational pattern of serotonergic and GHT terminals and the RHT terminals, suggesting different actions of serotonin and neuropeptide Y in the control of circadian rhythmicity in primates. Moreover, the pattern of the clock genes SCN expression along the awaken period in the primates show that BMAL1 and Per1 RNAm peaks of expression occur around ZT2 and Per2 around ZT7. These data suggest that the neural organization of the circadian timing system in the studied primate differ from those of the most commonly studied rodents.