STRESS recovery
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Discovery Brain Sciences
Abstract
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. Many people are able to cope with chronic stress, whilst others are more susceptible, possibly because of their genetic background or other life experiences. Why some are more affected by long-term stress are unclear and this project will address this question and possibly identify strategies and drugs that may allow these people to become more resilient.
When we are stressed the body releases powerful glucocorticoid hormones from an organ just above the kidneys, the adrenal gland, into the blood stream and these control many aspects of body function that are important for responding to stress. This release of glucocorticoids is intricately controlled by the brain, which regulates the electrical activity of corticotrophs, cells that are located in the pea-sized anterior pituitary gland, at the base of the brain. Stimulation of corticotroph cells by hormones released from the brain during stress results in release of the stress hormone ACTH that is released 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 over excited and release more ACTH resulting in elevated glucocorticoid levels. It had been largely assumed that once the period of chronic stress was over the behaviour of the corticotrophs simply returned to the normal "pre-stress" level.
However, our remarkable recent findings reveal that corticotrophs undergo a persistent change in both their properties as well as the portfolio of genes they express. These persistent changes last for weeks after the stress is over suggesting that that the behaviour of the cells is altered and that stress regulation through their interaction with the brain and adrenal glands may then be different. This may help explain the variable ways people respond to new stressful situations after a period of chronic stress and the reason why some are resilient, while others susceptible, to the development of stress-related disorders.
An important technical development means that for the first time we are now able to measure how corticotrophs behave in real-time in the living animal. We will combine this with powerful techniques that allow us to measure corticotroph activity and make predictions about how corticotrophs and their hormone output are regulated, so that we can understand how this may be modified by chronic stress. 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.
When we are stressed the body releases powerful glucocorticoid hormones from an organ just above the kidneys, the adrenal gland, into the blood stream and these control many aspects of body function that are important for responding to stress. This release of glucocorticoids is intricately controlled by the brain, which regulates the electrical activity of corticotrophs, cells that are located in the pea-sized anterior pituitary gland, at the base of the brain. Stimulation of corticotroph cells by hormones released from the brain during stress results in release of the stress hormone ACTH that is released 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 over excited and release more ACTH resulting in elevated glucocorticoid levels. It had been largely assumed that once the period of chronic stress was over the behaviour of the corticotrophs simply returned to the normal "pre-stress" level.
However, our remarkable recent findings reveal that corticotrophs undergo a persistent change in both their properties as well as the portfolio of genes they express. These persistent changes last for weeks after the stress is over suggesting that that the behaviour of the cells is altered and that stress regulation through their interaction with the brain and adrenal glands may then be different. This may help explain the variable ways people respond to new stressful situations after a period of chronic stress and the reason why some are resilient, while others susceptible, to the development of stress-related disorders.
An important technical development means that for the first time we are now able to measure how corticotrophs behave in real-time in the living animal. We will combine this with powerful techniques that allow us to measure corticotroph activity and make predictions about how corticotrophs and their hormone output are regulated, so that we can understand how this may be modified by chronic stress. 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.
Technical Summary
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. Despite the impact of CS on health, its long-term effect on hypothalamic-pituitary-adrenal (HPA) axis function and how this relates to the resilience or susceptibility to the development of disorders is poorly understood. The anterior pituitary corticotroph has been proposed as a major locus for CS-induced changes in HPA axis function, however mechanisms are not defined.
Remarkably, we have recently identified that cessation of an episode of CS dramatically invokes a persistent change to corticotroph physiology with unpredictable consequences for ACTH output and HPA activity. RNAseq analysis revealed a surprising paucity of changes in corticotroph gene transcription during CS but a profound downregulation of gene transcription persisting up to 4 weeks post CS. Importantly, this shows that CS leads to more dramatic alteration of the HPA axis at the level of the pituitary than previously recognised.
To address whether these persistent changes in corticotroph function alter HPA axis regulation and response to further stress, we will determine the consequences of the long-term alteration of corticotroph function following CS. We will integrate functional studies in vitro and in vivo and interrogate molecular pathways defined by our RNA-Seq and modelling approaches. Importantly, our ability for the first time to measure corticotroph physiology in real-time in vivo will allow longitudinal monitoring of axis function before, during and after CS in the same animals, and define whether intervention in vivo can alter or reset the changes caused by CS.
Taken together we aim to unravel the molecular mechanisms by which alterations at the level of the pituitary corticotrophs underlie susceptibility to dysfunction and resilience following CS and potential targets for therapy
Remarkably, we have recently identified that cessation of an episode of CS dramatically invokes a persistent change to corticotroph physiology with unpredictable consequences for ACTH output and HPA activity. RNAseq analysis revealed a surprising paucity of changes in corticotroph gene transcription during CS but a profound downregulation of gene transcription persisting up to 4 weeks post CS. Importantly, this shows that CS leads to more dramatic alteration of the HPA axis at the level of the pituitary than previously recognised.
To address whether these persistent changes in corticotroph function alter HPA axis regulation and response to further stress, we will determine the consequences of the long-term alteration of corticotroph function following CS. We will integrate functional studies in vitro and in vivo and interrogate molecular pathways defined by our RNA-Seq and modelling approaches. Importantly, our ability for the first time to measure corticotroph physiology in real-time in vivo will allow longitudinal monitoring of axis function before, during and after CS in the same animals, and define whether intervention in vivo can alter or reset the changes caused by CS.
Taken together we aim to unravel the molecular mechanisms by which alterations at the level of the pituitary corticotrophs underlie susceptibility to dysfunction and resilience following CS and potential targets for therapy
Publications
Chamberlain LH
(2021)
Regulatory effects of protein S-acylation on insulin secretion and insulin action.
in Open biology
Duncan P
(2023)
Sex differences in pituitary corticotroph excitability
in Frontiers in Physiology
Duncan PJ
(2022)
Chronic stress facilitates bursting electrical activity in pituitary corticotrophs.
in The Journal of physiology
Le Tissier PR
(2022)
A New Perspective on Regulation of Pituitary Plasticity: The Network of SOX2-Positive Cells May Coordinate Responses to Challenge.
in Endocrinology
Le Tissier PR
(2021)
Renewing an old interest: Pituitary folliculostellate cells.
in Journal of neuroendocrinology
MacMillan S
(2022)
LKB1 is the gatekeeper of carotid body chemosensing and the hypoxic ventilatory response.
in Communications biology
Shipston MJ
(2022)
Glucocorticoid action in the anterior pituitary gland: Insights from corticotroph physiology.
in Current opinion in endocrine and metabolic research
Walker JJ
(2022)
Fast dynamics in the HPA axis: Insight from mathematical and experimental studies.
in Current opinion in endocrine and metabolic research
Description | Mark Hollywood |
Organisation | Dundalk Institute of Technology |
Country | Ireland |
Sector | Academic/University |
PI Contribution | Analysis of LINGO1-BK interactions and function |
Collaborator Contribution | Electrophysiological analysis of LINGO1-BK interactions and function |
Impact | LINGO1 is a regulatory subunit of large conductance, Ca2+-activated potassium channels Dudem S, et al. Proc Natl Acad Sci U S A 2020. PMID 31932443 |
Start Year | 2017 |
Description | Patrice Mollard |
Organisation | National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS) |
Department | Bordeaux |
Country | France |
Sector | Public |
PI Contribution | In vivoand in vitro analysis of corticotrophin function |
Collaborator Contribution | In vivo analysis of corticotrophin physiology and imaging |
Impact | None to date |
Start Year | 2019 |
Description | Richard Bertram: Modelling & simulations |
Organisation | University of Florida |
Country | United States |
Sector | Academic/University |
PI Contribution | Primary data for development of mathematical models |
Collaborator Contribution | Development of mathematical models |
Impact | Primary research publications including seminars and workshops at international symposia |
Start Year | 2014 |
Description | Going Global TNS Singapore |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Going Global TNE symposium with international reach and media coverage |
Year(s) Of Engagement Activity | 2022 |
Description | Invited research seminar |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Research symposium on pituitary biology |
Year(s) Of Engagement Activity | 2022 |
Description | Participation in research workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | approx 100 people attended international pituitary workshop in Crete, which led to new collaborative interactions |
Year(s) Of Engagement Activity | 2023 |
Description | Pituitary biology workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Collaborative workshop with UK investigators that have led to new projects and research directions |
Year(s) Of Engagement Activity | 2024 |
Description | Research symposium |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Research workshop highlighting new questions and approaches in stress and pituitary biology |
Year(s) Of Engagement Activity | 2022,2023 |
Description | School student visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | Multiple open days/visits for prospective students including widening access |
Year(s) Of Engagement Activity | 2022,2023 |