Exposure to an acutely stressful event leads to activation of NMDA receptors, initiating a cascade of MAPK/ERK signalling, epigenetic modifications and lEG induction in sparse neurons of the dentate gyrus (DG); these changes have been shown to be vitally important for long-term memory formation. The glucocorticoid receptor also plays an important role in this cascade. The work presented in this thesis continues to explore this signalling pathway in the DG and CA regions of the hippocampus in the context of Morris water maze (MWM) learning. Phosphorylation of ERK1/2, phosphorylation of histone H3 at serine 10 and NMDAR-dependent induction of immediate early genes (lEGs) were found to occur in sparse neurons of the hippocampus following MWM training. Although these lEGs are known to be important for learning and memory, the epigenetic and gene induction changes were induced in both MWM-trained and swim control (sq rats to a remarkably similar extent. Nevertheless, a significantly higher Arc induction was found in the MWM group in the CA regions on the second day of training. Chromatin immuno-precipitation was used to investigate the epigenetic mark H3K9acSlOp, which was found to be associated with lEG promoters both under baseline conditions and after MWM or SC procedures; further study with an increased sample number will be required to confirm whether there is increased association after training. Finally, RNA-sequencing was used to identify late-response genes up-regulated in the DG three hours after MWM and SC procedures. Many genes were identified which are regulated by MWM or SC training; however, there were no genes differentially regulated between the MWM and SC groups. This thesis has advanced our knowledge of the molecular and gene expression changes occurring within neurons of different hippocampal sub-regions after learning under stressful conditions. In addition, it has cast light on the factors determining lEG responses in hippocampal neurons and has led to the identification of novel genes previously not known to be regulated after MWM learning.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:681551 |
| Date | January 2014 |
| Creators | Carter, Sylvia Dawn |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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