The role of epigenetic processes in mediating the molecular and behavioural responses to stress in the dentate gyrus

Stress is part of everybody's daily life. We need to respond appropriately to stressful events and normally we learn from them to cope better the next time they are imposed on us. These learning and adaptation processes take place in the brain. These processes must work properly as improper functioning can cause illness such as depression and anxiety. However, we currently do not fully know how the healthy brain learns from stressful events. We have recently discovered that after stress certain molecular processes ('epigenetic modifications') occur in the nucleus of nerve cells which we think are crucial for the expression of certain genes necessary for the adaptation of these cells to a stressful event. Our proposal aims to identify those epigenetic modifications and the genes affected by these modifications. Collection of this information is crucial in order to gain insight into how nerve cells 'learn' from stressful events. Insight into these processes and the function of the genes involved will help to develop new drugs for the treatment of major depression and anxiety disorders that currently burden many people in our society.

Dealing with a psychologically stressful event requires, in addition to generation of the acute stress response, cognitive processing in order to learn from it and thus to be able to respond more appropriately in case of future recurrences. Insight into the molecular and cellular mechanisms underlying stress coping and stress processing in the brain is clearly vital for the development of strategies to improve the quality of life of humans and animals. We have found that, in the case of a learned behavioural response to stress in rats and mice, this process involves chromatin remodelling (driven by phosphorylation and subsequent acetylation of histone H3 (H3S10p-K14ac)) to induce transcriptional activation in dentate gyrus neurons in the limbic brain which is mediated through concurrent stimulation of glucocorticoid receptor (GR) and NMDA receptor (NMDA-R)/ERK/MSK signalling mechanisms. We hypothesise that in dentate neurons (1) the psychological stress-activated H3S10p-K14ac epigenetic marks are located in a specific set of gene promotors; (2) establishment of these marks is associated with site-specific lysine methylation and/or de-methylation within H3 tails and de-methylation of DNA of the involved gene promotors; and (3) this complex of epigenetic modifications is required for activation of gene transcription that is critical for the memory formation associated with the stressful event; To test these hypotheses we will use state-of-the-art lentiviral-driven RNA interference technology, chromatin immuno-precipitation (ChIP), gene promoter identification using gene tiling microarrays (ChIP-chip), and methylomic profiling using microarrays in combination with neuroanatomical, immunohistochemical and behavioural analyses.