New Finding on How Stress Hormones Influence the Brain

Chronic stress exerts its toll on the human body and mind, which can manifest as mental health conditions that may adversely affect quality of life. A thorough understanding of the biological mechanisms underpinning stress responses in the brain is therefore crucial.    

The experience of stress in the body is mediated by a number of different molecules, including the glucocorticoid hormones, or "stress" hormones, as they are sometimes referred to. In the brain, glucocorticoid hormones bind to specific receptors, including the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). This binding action triggers a cascade of molecular events that includes changes to gene expression in specific regions of the brain.

A new study by researchers at the University of Bristol has utilized next-generation sequencing, bioinformatic tools and pathway analysis to further explore the effect of MR- and GR-mediated gene activity in the hippocampus, a brain structure implicated in learning, memory and stress reactivity.

The researchers discovered a novel link between MR and cilia, organelles that protrude from cell surfaces and act as "antennas" to the extracellular fluid surrounding them. While the role of cilia in the brain requires further elucidation, they are known to play a role in brain development and neuroplasticity via the transduction and regulation of different signaling pathways.

The research carried out by the University of Bristol team reveals – for the first time – that cortisol-mediated activation of the MR influences ciliary genes, impacting the expression and function of the cilia. These findings enhance our knowledge of how stress impacts the brain and paves the way for further research into the potential role of ciliary genes in mental health disorders.

Technology Networks spoke with Professor Hans Reul from Bristol Medical School: Translational Health Sciences (THS) to learn more about this research and its potential applications. Reul also explains the human body's biological response to stressful stimuli and emphasizes why this work is "state-of-the-art".

Molly Campbell (MC): For our readers that may be unfamiliar, please can you summarize the human body's biological response to stressful stimuli?

Hans Reul (HR): A stressful event (for instance a dispute, an accident, loss of beloved friend or family member, being fired, etc.) elicits alarm reactions (i.e., the stress response) in our body. The body initiates the stress response in order to acutely cope with the challenge and adapt to it. There are fast responses, like the well-known fight or flight response evoked by adrenaline, and slower responses, mediated by the glucocorticoid hormone cortisol (corticosterone in rodents). Together, these hormones change metabolism, blood circulation, immune function and many other body functions to support coping with and adaptation to the stressful event. Furthermore, the glucocorticoid hormone cortisol plays an important role in how we deal mentally, i.e., in our brain, with the event. Making memories of the event is part of this process. This is important because in this way we learn how to deal with problems and respond better if a similar event would occur. Cortisol plays a critical role in the formation of memories of the event; memories like what happened, where did it happen, what time of the day and how did I feel, etc. The hormone does this by acting on neurons in the brain that play a role in learning and memory. The action is thought to involve changes in the activity of genes within these neurons. Until now, we did not know which kind of genes would be involved. Our study now, for the first time, provides an answer to this question.

MC: What link exists between chronic stress and mental health disorders?

HR: It has been known for a long time that chronic stress can lead to mental health disorders like major depression and anxiety. Also, for many years, it is thought that this involves the glucocorticoid hormone cortisol because, to put it simply, chronic stress leads to hypersecretion of cortisol and many patients suffering from major depressive disorder, bipolar disorder, PTSD, schizophrenia or anxiety show disturbed cortisol secretion and function. Furthermore, successful antidepressant drug treatment has been shown to normalize glucocorticoid hormone function in depressed patients.

MC: "It is thought that genomic actions in the hippocampus underly the distinct roles of MR and GR in the control of circadian and stress-related physiology, cognition and behavior". Please can you expand on this?

HR: Glucocorticoid hormones, like cortisol in people and corticosterone in rodents, act by binding to two receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Both receptors can be found in a limbic brain region called the hippocampus which is important for stress coping and learning and memory processes. As explained before, these hormones play an important in the physiological and mental/behavioural responses after stress. The hormones also show a circadian secretory pattern; in people, cortisol levels are higher in the morning when we start the day than in the evening when our rest/sleep period starts. With regard to their "genomic actions", I need to explain that MR and GR are predominantly intracellular receptors that can act as so-called transcription factors. This means that, after MR and GR have bound the hormone cortisol, they can bind directly to special recognition sites within genes or within the vicinity of genes and change the transcriptional activity of these genes, i.e., how much RNA is transcribed from these genes. Changes in the gene activity will lead to changes in the function of such neurons involved in the mental/cognitive/behavioural response to the stressful event.

MC: You discovered a link between the MR and cilia function. Can you describe what cilia are, their role in the brain and what this link was?

HR: One of the big discoveries in our paper is the link between MR and cilia function. Cilia are specialized cell organelles which look like protrusions from the cell body. In general, they play an important role in intracellular communication. Neurons have cilia as well. There is not so much known yet about their role in the brain. Cilia have been shown to be important for adult neurogenesis in the hippocampus and certain hippocampus-associated behaviours. They also seem to be able sense changes in the flow of the extracellular fluid which encompasses neurons. Our works shows that MR interacts with many ciliary genes involved in cilia structure and function. This means that cortisol, via MR, can change the expression and function of cilia on neurons. Our work on the human foetal neural progenitor cells underlines the importance of MR for cilia expression on neurons. We show that when we block MR function at the start of neuronal differentiation, the cells do not express cilia and the differentiation process is stopped. So, the MR-cilia link is important for ciliogenesis and neuronal differentiation. These are important findings as not much is known about cilia function in the brain. There are mutations know in ciliary genes which lead to severe developmental problems including cognitive deficits. Ciliary genes could be involved in mental health (disorders), but we basically don’t know yet.

MC: Can you please summarize the key findings of your study?

HR: There are several key findings to highlight. I think these are the most important ones:

The discovery of the existence of a link between MR and cilia, as highlighted in the answer to your previous question. This was a fascinating and really unexpected finding! The link between MR and cilia seems to be really important for neuronal differentiation and development. Therefore, our results support a role of MR and cilia in brain development as well as adult neurogenesis. We hope this finding will trigger new research in these areas of neuroscience.

Another main finding was that MR and GR interact with so-called neuroplasticity genes. Neuroplasticity is a term describing the "changeability" of the brain: our brain of now is different from the one a couple of seconds ago. In our brain, we make new connections ("synapses") between our neurons and disrupt existing ones all the time and, in particular, after an event happens in our lives. After a stressful event, we need to cope with what has happened and, in part, this involves forming memories of the event so we can learn, for instance, to avoid certain situations or respond differently if a similar event would occur. Glucocorticoid hormones, which are abundantly secreted after stress, are well known to support this coping process including the formation of event-related memories. What we did not know is: how do these hormones do this? How are these hormones acting on neurons as part of this adaptive process? Our study discovered that glucocorticoid hormones via MR and GR interact with and stimulate the expression of many genes which are known to be involved in neuroplasticity. These genes, for instance, encode proteins known to play vital roles in the communication between neurons. It was just unknown, until now, that these genes are regulated by MR and GR, thus, providing a novel mechanism how glucocorticoid hormones support adaptation to stress at the molecular level. Our findings will, therefore, facilitate new research efforts into how we deal with stress. This is extremely important given the numbers of people suffering from stress-related mental health disorders like depression, anxiety and PTSD.

This brings me to another key finding our study. We found that glucocorticoid hormones via MR and GR regulate many genes which are known to be "vulnerability" genes for mental health disorders like depression, anxiety and PTSD. The term vulnerability is largely based on studies in which small variations (singly nucleotide polymorphisms – SNPs; pronounced as "snips") in gene sequences were found to be associated with an increased chance of developing a mental health disorder. Given that glucocorticoid hormone dysfunction, as in chronic stress, is known to be a contributory factor in these disorders, our novel findings open the opportunity to study if aberrant regulation of these vulnerability genes by glucocorticoids could be an underpinning mechanism for developing such a disorder. Such research may lead to the identification of new drug targets for the treatment of severe mental health disorders like major depression, anxiety and PTSD. 

MC: Please can you discuss your choice of technologies for the study?

HR: The two main technologies used are chromatin immuno-precipitation (ChIP) and RNA analysis. For the genome-wide analyses these technologies were combined with next-generation sequencing. ChIP was used to investigate the interaction of MR and GR with their recognition sites within genes.

We also used neurospheres formed by human foetal neural progenitor cells to investigate the role of MR in ciliogenesis and neuronal differentiation.

MC: Are there any limitations that you wish to highlight?

HR: The work in our study is state of the art. Nevertheless, science is never finished. Indeed, more work needs to be done. One step should be the translatability of our results to the human situation.

MC: What are the key applications of this work, and what are your next research steps?

HR: This is basic neuroscience research and cannot be immediately applied to clinical questions. However, there is a major interest from society in this research given the many people suffering from mental health disorders related to stress. Our research provides the many scientists working on stress-related mental health disorders important leads regarding the genes that may underpin the aetiology of these severe disorders.

There are many research lines that could be pursued next. In the press release, we mention chronic stress, but aging, adolescence and embryonic/postnatal development are also very relevant conditions to look at as they involve phases of life sensitive to glucocorticoid hormones. As mentioned, it is really important that we have received a grant to study glucocorticoid hormone action in the female brain. There is relatively little known about this in females which is incredible as more women than men suffer from mental health disorders. Finally, we would like to delve deeper into the molecular mechanisms regulating MR and GR interaction with the genome.

Hans Reul was speaking to Molly Campbell, Science Writer for Technology Networks.

Reference: Mifsud KR, Kennedy CLM, Salatino S, et al. Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors. Nat Comms. 2021;12(1):4737. doi: 10.1038/s41467-021-24967-z.