Biological clocks are genetically codified oscillators that allow the organisms to keep track of the environment. Among the biological clocks is the circadian system, which is a time control structure responsible for the regulation of many physiological, metabolic and behavioral functions in periods close to 24 hours. Within the physiological functions related to the circadian rhythms, is the production of melatonin by the pineal gland. This hormone is synthesized and secreted mainly during the dark phase of the light/dark cycle and its production shows a circadian variation. This circadian secretion pattern creates a daily as well as a seasonal message to melatonin-sensitive structures. Melatonin up- and downregulates the expression of many genes, usually in a circadian manner, possibly using epigenetic mechanisms. Recent evidences in the literature suggest that melatonin is an important agent in the context of neurogenesis, which is the process of generation of new neural cells that occurs along the central nervous system development and in adults. Two specialized regions of the adult central nervous system are known to be neurogenic niches: the subventricular zone of the lateral ventricules (SVZ) and the subgranular zone in the dentate gyrus of the hippocampus (SGZ). Neurogenesis in the adult can be modulated by both internal (within the regions) and external stimuli (physiological, pathological or pharmacological). Epigenetic changes take place as part of the balance control between cellular proliferation and differentiation that features adult neurogenesis. The miRNAs are among the epigenetic factors that participate in controlling gene expression by neural stem cells. Taking in account all of this, our hypothesis consists in the idea that melatonin in the cerebrospinal fluid of adult mice could "imprint" the neural stem cells in the SVZ through epigenetic mechanisms. This imprinting would influence the proliferative capacity of these cells depending on the hour of the day that the animals have been euthanized to obtain the cells. Thus, the goal of this project is to study whether melatonin concentration present in the cerebrospinal fluid of the animal in the time of euthanasia influences the proliferation profile of neural stem cells from SVZ when cultured in vitro as neurospheres. Additionally, it is intended to verify if there is a difference in the expression of target genes and miRNAs between cells obtained from mice euthanized during dark or light phases. The present study intends to contribute with the comprehension of physiological controls of neural stem cell proliferation in adult mammals.
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