New research at Rutgers University may help shed light on how and why nervous system changes occur and what causes some people to suffer from life-threatening anxiety disorders while others are better able to cope.

Maureen Barr, a professor in the Department of Genetics, and a team of researchers, found that the architectural structure of the six sensory brain cells in the roundworm, responsible for receiving information, undergo major changes and become much more elaborate when the worm is put into a high stress environment.

Scientists have known for some time that changes in the tree-like dendrite structures that connect neurons in the human brain and enable our thought processes to work properly can occur under extreme stress, alter brain cell development and result in anxiety disorders like depression and Post Traumatic Stress Disorder affecting millions of Americans each year.

What scientists don’t understand for sure, Barr says, is the cause behind these molecular changes in the brain.

“This type of research provides us necessary clues that ultimately could lead to the development of drugs to help those suffering with severe anxiety disorders,” Barr says.

In the study published today in Current Biology,scientists at Rutgers have identified six sensory nerve cells in the tiny, transparent roundworm, known as the C. elegans and an enzyme called KPC-1/furin which triggers a chemical reaction in humans that is needed for essential life functions like blood-clotting. 

While the enzyme also appears to play a role in the growth of tumors and the activation of several types of virus and diseases in humans, in the roundworm the enzyme enables its simple neurons to morph into new elaborately branched shapes when placed under adverse conditions.

Normally, this one-millimeter long worm develops from an embryo through four larval stages before molting into a reproductive adult. Put it under stressful conditions of overcrowding, starvation and high temperature and the worm transforms into an alternative larval stage known as the dauer that becomes so stress-resistant it can survive almost anything – including the Space Shuttle Columbia disaster in 2003 of which they were the only living things to survive.  

“These worms that normally have a short life cycle turn into super worms when they go into the dauer stage and can live for months, although they are no longer able to reproduce,” Barr says.

What is so interesting to Barr is that when a perceived threat is over, these tiny creatures and their IL2 neurons transform back to a normal lifespan and reproductive state like nothing had ever happened. Under a microscope, the complicated looking tree-like connectors that receive information are pruned back and the worm appears as it did before the trauma occurred.

This type of neural reaction differs in humans who can suffer from extreme anxiety months or even years after the traumatic event even though they are no longer in a threatening situation.   

The ultimate goal, Barr says, is to determine how and why the nervous system responds to stress. By identifying molecular pathways that regulate neuronal remodeling, scientists may apply this knowledge to develop future therapeutics.

Novel research identifies gene targets of stress hormones in the brain

Chronic stress is a well-known cause for mental health disorders. New research has moved a step forward in understanding how glucocorticoid hormones (‘stress hormones’) act upon the brain and what their function is. The findings could lead to more effective strategies in the prevention and treatment of mental health disorders.

(Image caption: A magnified image of developing young human neurons. The mineralocorticoid receptor, coloured red, was found in the cell nucleus of these neurons. Credit: University of Bristol)

The study, led by academics at the University of Bristol and published in Nature Communications,has discovered a link between corticosteroid receptors – the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) - and ciliary and neuroplasticity genes in the hippocampus, a region of the brain involved in stress coping and learning and memory.

The aim of the research was to find out what genes MR and GR interact with across the entire hippocampus genome during normal circadian variation and after exposure to acute stress. The research team also wanted to discover whether any interaction would result in changes in the expression and functional properties of these genes.

The study combined advanced next-generation sequencing, bioinformatics and pathway analysis technologies to enable a greater understanding into glucocorticoid hormone action, via MRs and GRs, on gene activity in the hippocampus.

The researchers found a previously unknown link between the MR and cilia function. Cilia are small hair-like structures that protrude from cell bodies. Effective cilia function is vitally important for brain development and ongoing brain plasticity, but how their structure and function is regulated in neurons is largely unknown.

The discovery of the novel role of 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 help resolve cilia-related (developmental) disorders in the future.

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

Although further research on the role glucocorticoid hormones play in the regulation of these genes is needed, the findings fill the gap between the long-known involvement of glucocorticoids in mental health disorders and the existence of vulnerability genes.

Hans Reul, Professor of Neuroscience in Bristol Medical School: Translational Health Sciences (THS), said: “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 aetiology of severe mental disorders like depression, anxiety and PTSD.”

Next steps for the research 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.

The study, supported by the BBSRC and a Wellcome Trust Neural Dynamics PhD studentship, was carried out by the Neuro-Epigenetics Research Group led by Professor Hans Reul and Dr Karen Mifsud, in collaboration with Bristol’s Stem Cell Biology Group - Dr Oscar Cordero Llana and Ms Andriana Gialeli - and sequencing specialists and bioinformaticians at the University of Oxford.

me: i think im doing alright, all things considered

my edgelord^TM brain: okay but have you considered how good it would feel for your flesh to burn and sting right now?

me: ooooookayy maybe i should reconsider…