Role of corticosteroid receptor DNA binding in stress-induced hippocampal gene transcription in relation to glucocorticoid and behavioural responses

点击翻译按钮获取中文摘要

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. For many years it is known that 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 has been instrumental to the development of 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 thought to be important to change the function of nerve cells in order to respond and adapt properly to the challenge. Presently, however, it is unclear how these receptors bind to the genes. It has been assumed for decades that MR and GR binding to genes is proportional to the receptor's occupancy level by hormone; our pre-work indicate this is indeed the case for GRs but surprisingly not for MRs. Under baseline (Bs; non-stress) conditions GR occupancy by GCs is low as well as GR binding to genes whereas after stress GR occupancy is high and its gene binding is too. In contrast, despite a high level of MR occupancy by GCs under Bs conditions its DNA binding is low and only increases after exposure to a stressful challenge. This is an entirely new finding which could mean that the existing assumptions about the role of MRs and GRs in the brain need to be revised. We aim to investigate under which conditions (different types of stress, specific hormone stimulation) MRs and GRs bind to genes in the hippocampus (a part of the brain that is particularly involved in the regulation of GC secretion and behavioural responses after stress) and the consequences of this binding for the expression of these genes and for glucocorticoid and behavioural responses to stress. We have also planned to study whether for the fine-tuning of MR and GR binding additional proteins ('steroid receptor co-regulators') is required. In addition to acute stress models (e.g. forced swim stress, restraint stress), we will use a model of repeated variable stress as well. In this model it has been shown that hippocampal MRs and GRs have declined and GC secretion and anxiety and learning behaviour are disturbed. This model will increase our insight into how changes in MR and GR binding to genes contribute to the changes in expression of these genes as well as hormonal and behavioural changes. This work is of fundamental importance to increase our understanding into how stress affects brain function and will help to develop new ways to reduce the burden of stress-related disorders in humans and animals.