Analiza zmian architekturalnych jądra komórkowego neuronów i astrocytów w eksperymentalnych modelach stresu i depresji : praca doktorska

Pels, Katarzyna Karolina

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Analiza zmian architekturalnych jądra komórkowego neuronów i astrocytów w eksperymentalnych modelach stresu i depresji : praca doktorska

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Tytuł: Analiza zmian architekturalnych jądra komórkowego neuronów i astrocytów w eksperymentalnych modelach stresu i depresji : praca doktorska

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The depression, according to World Health Organization is a leading cause of disability worldwide, affecting more than 270 million people. This is a multifactorial disease of still unknown pathogenesis. Unfortunately, contemporary therapies using antidepressants are not effective enough, and their therapeutic effect is usually significantly delayed. The latter fact suggests that antidepressants work by affecting long-term brain plasticity, probably associated with changes in gene activity orchestrated by reorganization of the chromatin architecture. One of the best-known pathogenic changes in depression are disturbances of the hypothalamic-pituitary-adrenal (HPA) axis regulating the release of cortisol. Cortisol, under physiological conditions, exerts a pleiotropic effect on various organs, including brain, and prepares us to "fight or flight" from danger. Nevertheless, severe stress causes disturbances in the HPA axis, which results in morphological and behavioral abnormalities. It is believed that such disruption is associated with abnormal glucocorticoid receptor (GR) function. GR regulates the activity of many genes, including the negative-feedback autoregulation of Nr3c1 gene encoding GR. Although structural changes involved in GR autoregulation on DNA level, were studies in proliferating cell, not much is known about its function in cells terminally differentiated, including neurons and astrocytes. Therefore, the presented dissertation is an attempt to investigate the architectural changes induced by GR activation in brains cells. Experiments presented in this thesis have indicated, a close relationship between activity changes of the Nr3c1 gene and its location within the cell nuclei of brain cells, under stress conditions, in three brain structures associated with the pathogenesis of depression. Application of STED super-resolution microscopy confirmed that changes in the location of the Nr3c1 gene result from its binding to active or inactive chromatin and ChIA-PET analysis clearly shown reorganization of the chromatin architecture caused by GR activation. The presented data show for a first time, that GR stimulation in brain cells leads to changes of the chromatin organization not only within this particular gene but also at the global level. And that those changes differ between neurons and astrocytes