Remodelling of corticotroph excitability in chronic stress: an integrated physiological and modelling analysis

We all experience stress whether it is because we are taking an exam or experience a frightening situation. In fact, a little bit of stress is good for us and allows us to cope with the demands of modern life. However, if we are chronically stressed this can lead to major health problems including obesity, diabetes, heart problems and inability to concentrate, learn new skills or cope with everyday life.

When we are stressed the body releases powerful glucocorticoid hormones into the blood stream that control many aspects of body function. This release of glucocorticoids is intricately regulated by the control of the electrical activity of corticotroph cells, located in the pea-sized anterior pituitary gland, at the base of the brain. The electrical activity of corticotrophs is stimulated by hormones released from the brain during stress, resulting in increased release of the stress hormone ACTH into the blood to control glucocorticoid synthesis and release from the adrenal gland. Normally, the glucocorticoids themselves act to switch off the electrical activity of the corticotroph cell to prevent ACTH release and thus ultimately reducing levels of glucocorticoid released into the body. However, when we are chronically stressed the corticotroph cells become overexcited and release more ACTH resulting in elevated glucocorticoid levels. Furthemore, the glucocorticoids no longer efficiently switch off the activity of the corticotrophs.

We have recently determined that in chronic stress the expression of many different proteins (ion pores) that control the electrical excitability of corticotrophs are up or down regulated. Using a mathematical model, we can make predictions of how this excitability may be changed and thus allow us to define new therapeutic targets to limit the effects of chronic stress. In this project we will exploit our mathematical model and combine this with experimental analysis of corticotroph electrical excitability and ACTH release in mice and in isolated cells.

Taken together we will unravel the mechanisms by which chronic stress controls anterior pituitary corticotroph function and define mechanisms and targets for potential therapeutic strategies to limit the deleterious effects of chronic stress.

Chronic stress (CS) is a major risk factor for development of a wide range of human disorders including diabetes, obesity, cardiovascular function as well as neurological and behavioural deficits. CS is typically associated with hypersensitivity of the hypothalamic-pituitary-adrenal (HPA) axis with escape from glucocorticoid negative feedback. The anterior pituitary corticotroph has been proposed as a major locus for CS-induced changes in HPA axis function, however the mechanisms are not defined.

We have recently identified that chronic stress promotes extensive remodelling of the corticotroph ion channel landscape, including channels critical to the control of 'basal' and hypothalamic CRH- and AVP-evoked ACTH secretion. Importantly, these data suggest that CS controls corticotroph hypersensitivity primarily by altering calcium-dependent signalling responses to CRH and/or AVP rather than through effects on ACTH content or availability for release. To address this, we will take an integrated hybrid experimental and mathematical modelling approach to define both in vivo and ex vivo: altered regulation of ACTH secretion by secretagogues and modification of glucocorticoid feedback following CS; the underlying mechanisms leading to altered corticotroph ion channel expression; and the reversibility of ion channel mediated corticotroph dysregualtion following either cessation of CS or pharmacological manipulation of intracellular signalling pathways.

Taken together we will unravel the molecular mechanisms by which chronic stress controls HPA axis function at the level of the anterior pituitary corticotroph and define mechanisms and targets for potential therapeutic strategies to limit the deleterious effects of sustained stress for validation in future translational studies.

This project will address how exposure to chronic stress changes the way in which our bodies respond to subsequent stress. In particular, we will be focussing on how the properties of cells in the pituitary gland that release stress hormones are altered by chronic stress. Understanding these mechanisms will not only provide important insight into how we respond to stress but also potentially identify new therapies to alleviate the debilitating consequences of chronic stress.

As such, in the short term (3-5 years) the primary beneficiaries of this project will be researchers (academic, industry and clinicians) in multiple fields spanning from endocrine regulation and control of the stress axis through to ion channel function and mathematical biology. Additional short-term societal/economic impact will be delivered though the training of highly-skilled researchers with a key set of transferable skills who will contribute directly to U.K. wealth generation. In addition, this will allow further development of major collaborations between both leading academic labs (e.g with Prof Richard Bertram in the USA) in the field and organisations facilitating engagement with translational, commercial and healthcare sectors (including for example Scottish University Life Sciences Alliance (SULSA), Nexxus and Scottish Developmental International (SDI)). In the longer term, the molecular underpinnings of regulation of the stress axis should reveal novel diagnostic and/or therapeutic targets for chronic stress and impact the healthcare sector and, of course, patients and their families.

Other beneficiaries of this research will be the various charities that provide an important support network for patients and their families. Stress represents one of the leading causes of absence from work (~10 million days lost per annum) as well as a major risk factor for a wide range of human disorders such as obesity, diabetes and cardiovascular disorders with an estimated cost to the UK economy of ~£6billion. Wider implications of the work in control of chronic stress will be of interest to broader policy makers for example in relation to food security, animal welfare/husbandry and disease diagnostic/therapeutics as well as for personnel management and human resources. A realistic time-scale for this type of impact is 10-15 years.

The work will also be of benefit to the broader public, including school children. Stress is something that the public readily identify with and thus from a longer-term perspective the work has the opportunity to improve life-long health. Importantly, it is an excellent opportunity to engage the public in the broader appreciation of the importance of fundamental science in understanding control of body function and developing an interest in science to ensure they are both informed and actively participate in science and debates impacting society in the future.