Pronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body__s major neuroendocrine axes, were already... Show morePronounced ultradian and circadian rhythms in the hormones of the hypothalamic-pituitary-adrenal (HPA) axis (i.e. glucocorticoids), one of the body__s major neuroendocrine axes, were already demonstrated several decades ago. Until now, the clinical relevance of the pulsatile nature of glucocorticoids was poorly understood or sometimes even regarded as not important. Its evolutionary conservation across many species however implies biological significance. Indeed, glucocorticoids have been proven to be crucial for a plethora of bodily functions, e.g. emotion, cognition and the central mechanism underlying the adaptation to stress. Furthermore, disturbances in the characteristic temporal pattern of glucocorticoid exposure have often been described in stress-related pathology. However, the significance of glucocorticoids secretory patterns for physiology, stress responsiveness and nuclear receptor signalling is still largely unexplored and is accordingly addressed in this thesis. A new concept in the endocrinology of glucocorticoids has evolved from the data presented here showing that pulsatile release of glucocorticoids is a major determinant in __resilience__ of glucocorticoid signalling in neuronal cells and stress responsiveness. Moreover, we show that particularly the glucocorticoid receptor is affected after disrupting glucocorticoid pulsatility and could thus provide an excellent target for therapy to normalise the downstream effects of disturbances in glucocorticoid rhythms in stress-related disease. Show less
Glucocorticoid hormones exert modulatory effects on neural function in a delayed genomic fashion. The two receptor types that can bind glucocorticoids, the mineralocorticoid receptor (MR) and the... Show moreGlucocorticoid hormones exert modulatory effects on neural function in a delayed genomic fashion. The two receptor types that can bind glucocorticoids, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), are ligand-inducible transcription factors. Therefore, changes in gene expression most likely underlie glucocorticoid-mediated genomic effects on neural function. In this thesis, the central aim was to gain more insight into the transcriptional changes that mediate the effects of acutely activated GRs on neural function. Two different biological substrates i.e. ex vivo hippocampal slices and neuronal catecholaminergic PC12 cells, were used to measure the transcriptional response after GR-activation. Using microarrays, an interesting time-dependent pattern of gene transcription was observed, shifting from exclusively downregulated genes 1 hour after GR-activation to both up and downregulated genes 3 hours afterwards. This pattern suggests that the fast genomic effects of glucocorticoids may be realized via transrepression, preceding a later wave of transactivation. Additionally, many new candidate genes were found that could potentially underlie (part of) the effects glucocorticoids mediate on hippocampal and catecholaminergic neuronal function. Hence, these candidate genes can be used to formulate new hypotheses on how glucocorticoids affect neural function and future research should therefore focus on testing these hypotheses. Show less
