Epigenetic regulation of stress-induced glucocorticoid action in the dentate gyrus and its behavioural implications

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Stress affects the lives of both humans and animals in our society. Psychological stress, like marital problems and bullying, is very debilitating for mental health and wellbeing in humans. Our farmed and companion animals can also suffer from psychological stress such as overcrowding, long-distance transportation and abuse. Successful coping with such stressful events involves adaptive and cognitive processes in the brain that make the individual more resilient to similar stressors in the future. Some events, certainly when uncontrollable and repeated, can be highly traumatic leading to psychosomatic and behavioural disturbances and psychiatric diseases (anxiety and depression). To help people to cope with stress in their lives, to develop directives to reduce stress and to improve wellbeing of our companion and farmed animals, we need to obtain better insight into how the brain responds to psychologically stressful events. Currently, however, we do not fully understand how the healthy brain generates physiological and behavioural responses to stressful events and adapts in the long-term to such events. Stressful events result in the secretion of 'stress hormones' or glucocorticoid (GC) hormones from the adrenal glands into the blood stream. Work of the PI over the past 35+ years has contributed greatly to the concept that these hormones act in the brain to coordinate physiological and behavioural responses to stress through binding to two different GC hormone-binding 'receptors'. These receptors, called MRs and GRs, are protein molecules located in nerve cells. As a result of a stressful challenge, GC hormone is secreted and binds to these receptors resulting in translocation to the cell nucleus. The hormone-receptor complex can then bind to certain genes within the DNA and regulate the expression of those genes. These genes are important to change the function of nerve cells in order to respond and adapt properly to the challenge i.e. elicit an appropriate behavioural response. Presently, however, it is unclear which receptor-bound genes are important in the adaptive responses to stress. Furthermore, accessibility of the DNA for MRs and GRs may be regulated by so-called epigenetic mechanisms as these involve changes in the structure and function of proteins to which the DNA is attached. Such epigenetic mechanisms are however still unresolved. We recently discovered a specific epigenetic 'mark' ('H3K9ac-S10p') that may play a role in controlling the binding of MR and GR to genes leading to changes in the expression of these genes. Interestingly, in previous research we found that this epigenetic mark is strongly linked with the learning of an adaptive behavioural response after a stressful challenge (forced swimming). Combined assessment of these observations has led us to the idea that the presence of the H3K9ac-S10p mark can distinguish MR- and GR-bound genes that are specifically involved in learning the adaptive behavioural response after stress. After identifying these genes in hippocampal neurons, we wish to select a few of the genes and test if suppression of their activity would impair the expression of behavioural adaptation to forced swim stress. This work is of fundamental importance to increase our understanding into how the brain adapts to stressful events and will help to develop novel approaches to alleviate the burden of stress-related disorders in humans and animals.