The thesis describes the application of several different magnetic resonance (MR) techniques to study the effects of the progression of disease in a transgenic mouse model of Alzheimer's. Using MR... Show moreThe thesis describes the application of several different magnetic resonance (MR) techniques to study the effects of the progression of disease in a transgenic mouse model of Alzheimer's. Using MR imaging, the amyloid plaque deposition was visualized and the plaque load quantified in the same mice as they aged. Concurrently the transverse relaxation time (T2) was measured in affected brain regions and shown to decrease over time as plaque-load increased. To study the neurochemical profile in the mouse brain brain both one- (1D) and two-dimensional (2D) MR spectroscopic techniques were employed. 1D MRS is widely used in similar research, but has limited spectral resolution. To overcome this limitation, a 2D MRS technique was implemented and optimized for use in mouse brain. This technique, L-COSY, allowed the detection of several metabolites which were not visible using standard 1D MRS techniques. This technique was subsequently used to study the effects of Alzheimer's on the neurochemical profile. Observed changes were correlated with plaque deposition. 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
