Gluco- and mineralocorticoid receptor regulation of regional brain neurotrophism

Abstract: Gluco- and mineralocorticoid hormones exert powerful actions on brain function and are important in the mediation of the stress response and the survival of hippocampal neurons. The aim of this thesis was to study the influence of glucocorticoid (GR)/mineralocorticoid receptor (MR) actions on brain neurotrophism including analyses of immediate early genes (IEGs) and of feedback responses on GR and/or MR. In order to independently study the acute effects of gluco- and mineralocorticoid hormones via GR and/or MR activation on gene expression levels the experimental animals were adrenalectomized (ADX) and thus depleted of all endogenous adrenal steroid hormones. Changes in hormonal levels appear to have profound effects on the expression of the neurotrophic factors while their receptors are only moderately affected. It was found that activated GR and MR act in concert or alone to mediate glucocorticoid hormone effect in various regions of the hippocampus. For example, GR and MR regulate basic fibroblast growth factor (bFGF) in CA2, CA3 and dentate gyrus together, but GR seems to act on bFGF alone in CA1 and CA4, suggesting that adrenal steroid hormones participate in the control of neurotrophic factor signaling in a highly subregion- and also cellular-dependent manner. The present thesis also shows that a depletion of adrenal steroid hormones after ADX may alter bFGF gene expression in the rat hippocampus through post-transcriptional rather than transcriptional mechanisms. However, evidence was also found that GR and MR activation might indeed involve onset of bFGF transcription. In time course experiments for corticosterone action in ADX rats, differential responses in bFGF and brainderived neurotrophic factor (BDNF) expression were found: bFGF mRNA levels were upregulated while BDNF mRNA and protein levels were downregulated. Peak effects on mRNA levels were found at 4 h for both genes. Because of the complexity of the BDNF promoter region the negative regulation of this gene by corticosterone was further analyzed by in situ hybridization with a number of exon-specific riboprobes. It appears that only the promoter II and especially the promoter IV are targets of the corticosterone effect. The present thesis also shows that the effects of corticosterone on bFGF and BDNF expression are preceded by a downregulation of the Fos-family of inducible transcription factors. To study the function of c-fos, the transcriptionally most active member of the Fos-family, an antisense gene "knockdown" approach was developed. Using intrahippocampal administered c-fos antisense oligodeoxynucleotides, it was demonstrated that within the CAI region c-fos seems to counteract the corticosterone effects on bFGF and BDNF expression. It was also shown that besides die well-known negative feedback regulation of GR and MR gene expression by adrenal steroid hormones in the hippocampus, there exists a biphasic autoregulation of MR mRNA by aldosterone via activation of MR alone in the medial septal nucleus. These findings suggest a unique responsiveness to MR activation in this nucleus which may be of importance for the regulation of septohippocampal cholinergic, pathways and thus of limbic circuits. In summary, this thesis will help to define the role of brain GR and MR in neurotrophic responses, and thus in brain plasticity.