Human brain and circuit board, illustration
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Chronic stress is a well-known cause for mental health disorders, and new research led by researchers at the University of Bristol has uncovered a link between corticosteroid receptors and ciliary and neuroplasticity genes in the hippocampus, a region of the brain involved in stress coping and learning and memory. The findings represent a step forward in understanding how glucocorticoid hormones (GCs)—or “stress hormones”—act upon the brain and what their function is, and could help in the future development of effective strategies for preventing and treating mental health disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD).

The scientists, headed by Hans Reul, PhD, professor of neuroscience at Bristol Medical School: Translational Health Sciences (THS), reported on their findings in Nature Communications. The paper is titled “Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors.”

GCs are of critical importance for central nervous system functioning, both during everyday activities and after a stressful challenge, the researchers explained. GCs play a pivotal role in stress resilience and behavioral adaptation, and impaired GC secretion and function has been associated with stress-related mental disorders, such as major depression and PTSD.

GC secretion from the adrenal glands varies over the circadian cycle, and exposure to stress adds an extra, temporary surge of GC secretion on top of that circadian variation. GCs bind to two types of receptor in the brain, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), which show “striking differences” in their localization and function, the team noted. Expression of MR is predominantly in neurons within specific limbic structures such as the hippocampus and lateral septum, whereas GR is widely distributed throughout the brain, including the hippocampus. MRs and GRs co-localize in hippocampal neurons. “It is thought that genomic actions in the hippocampus underlie the distinct roles of MR and GR in the control of circadian and stress-related physiology, cognition, and behavior,” the investigators further noted. “… however, the molecular underpinnings of these receptor-mediated actions are still largely unresolved.”

The aim of the newly reported research was thus to find out which genes MR and GR interact with across the entire hippocampus genome, both during normal circadian variation and after exposure to acute stress. “Comprehensive knowledge about genome-wide MR and GR interactions within the hippocampus under physiological conditions is currently lacking,” the investigators pointed out. “Specifically, which genes are regulated by MR and/or GR after stress or across the circadian cycle is still unknown.”

Reul and colleagues also wanted to discover whether any interaction would result in changes in the expression and functional properties of these genes. To carry out their studies the team combined advanced next-generation sequencing, bioinformatics, and pathway analysis technologies to enable a greater understanding of glucocorticoid hormone action, via MRs and GRs, on gene activity in the hippocampus. “We conducted genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus to elucidate MR- and GR-regulated genes under circadian variation or acute stress,” they explained.

The results of detailed pathway analyses clearly indicated functional differences between constant MR-associated genes and stress/circadian-responsive MR/GR-associated genes. In particular, the studies identified a previously unknown link between the MR and cilia function. “Cilia are hair-like protrusions from the cell body, thought to be involved in neuronal development and communication, but their function is still largely unknown,” the authors acknowledged. Effective cilia function is vitally important for brain development and ongoing brain plasticity, but how their structure and function are regulated in neurons isn’t understood. The newly reported results now highlight what the team called “unique roles” for MR in the hippocampus regarding neuronal differentiation and ciliary structure and function. “We find that MR, not GR, is the predominant receptor binding to >50 ciliary genes; and that MR function is linked to neuronal differentiation and ciliogenesis in human fetal neuronal progenitor cells.”

A magnified image of developing young human neurons. The mineralocorticoid receptor, colored red, was found in the cell nucleus of these neurons. [University of Bristol]
The discovery of the novel role for MR in cilia structure and function in relation to neuronal development has increased knowledge of the role of these cell structures in the brain and could, in the future, help to resolve cilia-related (developmental) disorders.

The team also found that MR and GR interact with many genes that are involved in neuroplasticity processes, such as neuron-to-neuron communication, and learning and memory processes. Some of these genes have been linked to the development of mental health disorders such as major depression, anxiety, PTSD, and schizophrenia spectrum disorders.

“Pathway analysis uncovered that MR and GR regulate a substantial number of genes involved in synaptic/neuro-plasticity, cell morphology and development, behavior, and neuropsychiatric disorders,” the scientists stated. Consequently, glucocorticoid hormone dysfunction, as observed in chronic stress, could have a harmful effect on mental health through their action on these vulnerability genes, providing a potential new mechanism to explain the long-known involvement of glucocorticoids in the etiology of mental health disorders.

Although further research on the role played by glucocorticoid hormones in the regulation of these genes is needed, the findings help to fill the gap between the long-known involvement of glucocorticoids in mental health disorders and the existence of vulnerability genes. Reul commented, “… this research is a substantial step forward in our efforts to understand how these powerful glucocorticoid hormones act upon the brain and what their function is. We hope that our findings will trigger new targeted research into the role these hormones play in the etiology of severe mental disorders like depression, anxiety, and PTSD.”

The authors concluded, “Collectively, our work underlines the multifarious complexity of GC action in the brain and provides the molecular basis for the study of the functional role of these hormones under physiological and pathological conditions … GCs are known to promote resilience, adaptability, and cognitive performance to cope with challenges from the environment … The present work shows that these hormone actions are mediated by hippocampal MRs and GRs acting at the genomic level on multiple molecular and cellular aspects of neuronal plasticity, in response to an acute stressful challenge as well as anticipatory at the start of the active phase.”

Next steps for the research will include studying how glucocorticoid hormone action via MR and GR on the hippocampus genome changes under chronic stress conditions and, thanks to a new BBSRC grant, glucocorticoid action via MR and GR upon the female brain genome. Very little is known about this research area in females as most studies on stress and glucocorticoid hormones have been conducted in males.

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