Discovery of a natural anti-stress pathway could help anxiety

by | May 24, 2023

A pathway in the brain that forms its natural stress response could be used to make new treatments for anxiety.
A spiralling tunnel

Up to a quarter of people globally experience anxiety and related disorders at some stage of their life, and current treatments do not help all patients achieve remission. Treatments include medications that depress the central nervous system or increase levels of a chemical messenger in the brain called serotonin, which is associated with mood. However, these and other medications can have unwanted side effects and tend to treat symptoms, not necessarily the underlying cause of anxiety.

The problem is we know little about what is going on within neurons during stress-induced anxiety. According to Valentina Mosienko, a neuroscientist from the University of Bristol, there are several reasons for this. “Anxiety disorders are complex and are a result of changes in the expression of multiple genes in combination with the significant influence of various environmental factors including major psychological traumas,” she explained.

If we better understand brain changes that cause anxiety, new and better treatments targeting these alterations can be developed.

Unravelling a natural pathway in the brain

To address this, Mosienko, and colleagues, including Robert Pawlak, Chair in Functional Cell Biology at the University of Exeter, focused on examining a specific type of RNA molecules called microRNAs in mice brains. These are small but influential molecules that can turn multiple genes on or off.

“MicroRNAs are uniquely placed to drive the development and progression of complex psychiatric conditions, including anxiety, as they can orchestrate the expression of several genes,” said Mosienko. With so little known about the role of microRNAs in regulating stress response, the team had their work cut out for them. But by pinpointing the specific microRNAs activated by acute stress, the scientists hoped to decipher key pathways controlling the process leading to anxiety.

But where in the brain should these investigations be focused? There is a group of brain structures known as the stress circuit that works together to detect and process stress stimuli. Within this circuit is the amygdala, a brain region at the centre of emotions, including fear, stress, and anxiety.

It is here that information from the environment is processed, and stress signals are sent to other brain regions, causing the behavioural changes commonly found in anxiety. The researchers, therefore, focused on this amygdala region to investigate microRNAs.

Learning from stress

Most likely evolved to improve our chance of survival, our brains have some capacity to adapt to stressful conditions when a direct threat is perceived. However, severe and prolonged stress can cause more permanent adaptations, leading to anxiety.

Mariusz Mucha, lead author of the study, and Mosienko described anxiety as, “[…] a specific type of emotional response characterized by feelings of fear, worry, and unease, often more focused on an anticipated threat rather than an immediate one or without any threat whatsoever.”

Their study in mice shows that the brain’s response to stress is to increase a small RNA molecule called miR483-5p in synapses, which neurons use to communicate. Synapses receiving messages are formed in the part of the neuron called dendritic spines, which take on a mushroom-like shape when mature.

The researchers found the increase in miR483-5p repressed the stress-associated gene, Pgap2, resulting in more mature mushroom-shaped dendritic spines.

“Such morphological changes drive the ability to learn that not every stressful situation is an actual threat and associate the experience as unpleasant but not directly dangerous,” Mucha explained. “These memories last for the rest of life and allow us to avoid developing anxiety or anxiety-related mood disorders when facing the same stressful situation in the future.”

A molecular brake

Described by the researchers as a “molecular brake,” could treatments targeted at amplifying miR483-5p in the stress circuit put the brakes on anxiety?

Although the study was done in animals, the team is confident their findings will translate into humans because of similar molecules, pathways, and brain structures. Looking forward, Mosienko says, “Next, working with pharmacologists and pharmaceutical companies will allow us to find a molecule enhancing this pathway and that can be developed into an anti-anxiety drug.”

“The discovery of this novel amygdala pathway will pave the way towards novel, more potent, and much-needed treatments for anxiety disorders and, in the longer term, support more people to better manage their anxiety symptoms and improve their quality of life,” she continued.

Anxiety is a complex disorder requiring more studies in both animals and humans to unravel the many remaining unknowns. However, this breakthrough could be a crucial first step in the quest to fully understand the intricacies of this disorder that affects so many of us.

Reference: Mariusz Mucha, Valentina Mosienko, et al., miR-483-5p offsets functional and behavioural effects of stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala, Nature communications (2023) DOI: 10.1038/s41467-023-37688-2

Feature image: Lanju Fotografie on Unsplash

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