New insights into the influence of stress hormones on the brain

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Chronic stress puts a strain on the human body and mind, which can manifest itself in mental illnesses that can affect the quality of life. A thorough understanding of the biological mechanisms underlying 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 called. In the brain, glucocorticoid hormones bind to specific receptors, including the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). This binding effect triggers a cascade of molecular events that include changes in gene expression in specific regions of the brain.

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

The researchers discovered a novel connection between MR and cilia, organelles that protrude from the cell surface and act as “antennas” for the extracellular fluid that surrounds them. While the role of cilia in the brain needs further elucidation, it is known that they play a role in brain development and neuroplasticity through the transduction and regulation of various signaling pathways.

Research conducted by the University of Bristol team shows for the first time that cortisol-mediated activation of MR affects ciliary genes and affects cilia expression and function. These results expand our understanding of how stress affects the brain and pave the way for further research into the possible role of ciliary genes in mental disorders.

Technology networks spoke with Professor Hans Reul the end Bristol Medical School: Translational Health Sciences (DBS) to learn more about this research and its uses. Reul also explains the biological reaction of the human body to stressful stimuli and emphasizes why this work is “state-of-the-art”.

Molly Campbell (MC): Can you summarize the biological response of the human body to stress stimuli for our readers who may not be familiar?

Hans Reul (HR):
A stressful event (e.g. quarrel, accident, loss of a loved one or family member, dismissal, etc.) triggers alarm reactions (i.e. the stress reaction) in our body. The body initiates the stress response in order to acutely cope with the challenge and to adapt to it. There are fast reactions, such as the well-known fight or flight reaction caused by adrenaline, and slower reactions mediated by the glucocorticoid hormone cortisol (corticosterone in rodents). Together, these hormones change the metabolism, blood flow, immune function and many other body functions in order to support coping and adaptation to the stressful event. In addition, the glucocorticoid hormone cortisol plays an important role in our mental handling, ie in our brain, with the event. Making memories of the event is part of that process. This is important because it teaches us to deal with problems and to react better if a similar event were to occur. Cortisol plays a vital role in forming memories of the event; Memories like what happened, where did it happen, what time of day and how I felt, etc. The hormone does this by acting on neurons in the brain that play a role in learning and memory. The effect is believed to involve changes in the activity of genes within these neurons. So far we didn’t know what kind of genes would be involved. Our study provides an answer to this question for the first time.

MC: What is the connection between chronic stress and mental disorders?

Personnel Department:
It has long been known that chronic stress can lead to mental disorders such as major depression and anxiety. It has also been suspected for many years that it is the glucocorticoid hormone cortisol, because, to put it simply, chronic stress leads to hypersecretion of cortisol and many patients who suffer from major depression, bipolar disorder, PTSD, schizophrenia or anxiety , show impaired cortisol secretion and function. In addition, successful antidepressant treatment has been shown to normalize glucocorticoid hormone function in depressed patients.

MC: “It is believed that genomic actions in the hippocampus underlie the different roles of MR and GR in controlling circadian and stress-related physiology, cognition and behavior.” Can you please expand that?

Personnel Department:
Glucocorticoid hormones, such as cortisol in humans and corticosterone in rodents, work by binding to two receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Both receptors are located in a limbic brain region called the hippocampus, which is important for coping with stress as well as for learning and memory processes. As mentioned earlier, these hormones play an important role in the physiological and mental / behavioral responses to stress. The hormones also show a circadian secretion pattern; In humans, cortisol levels are higher in the morning when we start the day than in the evening when our rest / sleep phase begins. With regard to their “genomic effects”, I have to explain that MR and GR are predominantly intracellular receptors that can function as so-called transcription factors. That is, after MR and GR have bound the hormone cortisol, they can bind directly to special recognition sites within or near genes and change the transcriptional activity of these genes, ie how much RNA is transcribed by these genes. Changes in gene activity lead to changes in the function of those neurons that are involved in the mental / cognitive / behavioral response to the stressful event.

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

Personnel Department:
One of the great discoveries in our work is the connection between MR and ciliary function. Cilia are specialized cell organelles that look like protrusions from the cell body. In general, they play an important role in intracellular communication. Neurons also have cilia. Not so much is known about their role in the brain. Cilia have been shown to be important for adult neurogenesis in the hippocampus and certain hippocampal-associated behaviors. They also seem to be able to sense changes in the flow of the extracellular fluid that includes neurons. Our work shows that MR interacts with many ciliary genes that are involved in the structure and function of the cilia. This means that cortisol can change the expression and function of cilia on neurons via MR. Our work on human fetal neural progenitor cells underscores the importance of MR for cilia expression on neurons. We show that if we block MR function at the beginning of neuronal differentiation, the cells will not express cilia and the differentiation process will be stopped. Therefore, the MR ciliary connection is important for ciliogenesis and neuronal differentiation. These are important findings as not much is known about the function of the cilia in the brain. Mutations are known in ciliary genes that lead to severe developmental problems and even cognitive deficits. Ciliary genes could be involved in mental health (disorders) but we basically don’t know yet.

MC: Can you please discuss your choice of technologies for the study?

Personnel Department:
The two main technologies used are chromatin immunoprecipitation (ChIP) and RNA analysis. These technologies were combined with next generation sequencing for genome-wide analyzes. ChIP was used to study the interaction of MR and GR with their recognition sites within genes.

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

MC: Are there any limitations that you would like to highlight?

Personnel Department:
The work in our study is state of the art. Even so, science is never finished. In fact, more work needs to be done. One step should be the transferability of our results to the human situation.

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

Personnel Department:
This is basic neuroscientific research and cannot immediately be applied to clinical questions. However, given the large number of people suffering from stress-related mental disorders, there is a great deal of interest from society in this research. Our research provides important clues to the many scientists working on stress-related mental disorders as to the genes that may underlie the etiology of these severe disorders.

There are many lines of research that could be followed next. In the press release we mention chronic stress, but aging, adolescence and embryonic / postnatal development are also very relevant conditions to be aware of as these are phases of life that are sensitive to glucocorticoid hormones. As mentioned before, it is really important that we received a scholarship to study the effects of glucocorticoid hormones in the female brain. Relatively little is known about this in women, which is incredible, given that more women than men suffer from mental disorders. Finally, we would like to delve deeper into the molecular mechanisms that regulate MR and GR interaction with the genome.

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

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


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