The postnatal development of the mouse is characterized by a period of hypo responsiveness of the hypothalamic pituitary adrenal (HPA) axis to mild stressors. Maternal deprivation (MD) during this... Show moreThe postnatal development of the mouse is characterized by a period of hypo responsiveness of the hypothalamic pituitary adrenal (HPA) axis to mild stressors. Maternal deprivation (MD) during this period can disrupt the quiescence of the HPA-axis. The present study examined the influence of strain (outbred CD1 vs. inbred C57BL/6J mice) on some central and peripheral components of the HPA-axis in neonatal mice (5-day-old) in the presence of their mother or after 24 h MD (on postnatal day 4) under basal or mild stressful conditions. In the presence of the dam, adrenal corticosterone (CORT) secretion was low in both mouse strains. Compared to CD1 mice, C57BL/6J had lower CORT levels associated with higher ACTH levels and ACTH/CORT ratio (i.e., lower adrenal sensitivity to ACTH), and higher glucocorticoid receptor (GR) mRNA expression in the paraventricular nucleus. Although MD disinhibited the HPA-axis in both strains as reflected by increased basal CORT and ACTH, we found a strain-dependent pattern. MD increased CORT more in C57BL/6J compared to CD1 mice together with a lower ACTH/CORT ratio (i.e., higher adrenal sensitivity to ACTH), while GR mRNA was no longer different in the two strains. However, this increased adrenal sensitivity in maternally deprived C57BL/6J mice was not reflected in their CORT response to a subsequent novelty stressor, possibly due to an MD-induced ceiling effect in their steroidogenic capacity. In conclusion, the immediate outcome of MD depends on the genetic background of the mother infant dyad, suggesting that maybe also the outcome in later-life cannot be generalized. Show less
Currently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of... Show moreCurrently, the raising awareness of the role of glucocorticoids in the onset of numerous (neuro)-pathologies constitutes the increasing necessity of understanding the mechanisms of action of glucocorticoids in bodily processes and brain functioning. Glucocorticoids mediate their effects by binding to intracellular receptors which act as transcription factors. A remarkable and yet unexplained phenomenon described more than two decades ago, is the cell-specific effects glucocorticoids bring about on gene expression in brain. For example, while glucocorticoids suppress corticotrophin-releasing hormone (CRH) synthesis in the hypothalamus, production of CRH in the central nucleus of the amygdala (CeA) is stimulated by increased hormone levels. Inasmuch as the neuroanatomical distribution of the corticosteroid receptors does not satisfactorily explain these effects, it is of interest to decipher the role of recently discovered coregu lator proteins that modulate the direction and the magnitude of steroid receptor-driven transcription. Therefore, in the current thesis the expression and function of central coregulators was studied: the coactivators SRC1a and SRC1e along with the corepressors N-CoR and SMRT were found to be expressed in brain and involved in regulation of CRH gene expression. Finally, a method that allows detection of coregulator recruitment by steroid receptors in brain tissue was developed. 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
