Could a gene switch off anxiety?

Anxiety-producing gene

Several studies have shown that anxiety has increased in prevalence since, say, in the 1950s. However, it is unclear exactly why this is so. Now, researchers have found that at least some anxiety might have a genetic basis. The researchers found that the suppression of a particular gene in the brain of mice could reduce symptoms of anxiety. 

Interesting Engineering (IE) spoke to one of the lead authors of the study behind this finding, Dr. Valentina Mosienko, a Research Fellow and Lecturer in Neuroscience at the University of Bristol, about the research.

Speaking of the motivation behind the study, Mosienko said, "The current study was driven by the desire to help so many people living with anxiety and who poorly respond to the currently used anti-anxiety treatments."

"We know that anxiety is common — 1 in 4 people are diagnosed with an anxiety disorder at least once in their lifetime. Yet, more than half of patients do not achieve remission following the treatment with the currently used anti-anxiety medication."

To understand the significance of this work, let's first take a look at the biology of anxiety.

Biological basis of anxiety

Anxiety is a complex and intricate reaction in the brain involving the interplay of various neural circuits.

Anxiety typically originates in the limbic system, the part of the brain responsible for behavioral and emotional processing. When a person feels anxious, there is increased activity in the limbic system, which includes the hippocampus, amygdala, hypothalamus, and thalamus.

So, how exactly does this happen?

When the amygdala perceives a threat, it triggers a cascade of responses throughout the brain and body. The hypothalamus activates the stress response, leading to increased heart rate, blood pressure, and rapid breathing.

These physical manifestations of anxiety are designed to prepare us to respond — flight or fight — but in a modern context, where neither option is practical, they can be debilitating.

Other brain regions heighten vigilance and alertness. The hippocampus draws on past experiences to contextualize the threat, while the prefrontal cortex orchestrates a behavioral response.

Typically, the prefrontal cortex, responsible for executive functioning, regulates the emotional response of the amygdala. However, when the amygdala is activated, it releases signals that interfering with cognitive functions, including decision-making, and preventing the prefrontal cortex from shifting focus.

"Amygdala, together with other brain areas, is known to recognize the threat and act appropriately to the situation, forming the so-called brain anxiety circuit. Each area within this circuit consists of an extremely high number of neurons. Neurons can pass messages to one another through synapses, a space between two neuronal cells formed by a protrusion of their cell membranes," explained Mosienko.

In anxiety, specific populations of neurons in the prefrontal cortex are suppressed, disrupting the decision-making process and leading to a 'short circuit' in cognitive function. This disruption is due to the imbalance of certain neurotransmitters.

Neurotransmitters are chemical messengers that allow neurons in the brain to communicate with one another. Too much or too little of certain neurotransmitters can cause anxiety to flare up.

Neurotransmitters like GABA (gamma-aminobutyric acid) play a crucial role in anxiety regulation by inhibiting neuronal activity. Insufficient GABA levels have been linked to increased anxiety symptoms due to impaired emotional regulation.

Serotonin, responsible for mood regulation, is also associated with various anxiety disorders. Similarly, disregulation of norepinephrine, a stress-related neurotransmitter, can lead to heightened anxiety and hyperarousal.

While acute stress responses can be helpful in dangerous situations, chronic stress and anxiety can have a profound impact on the brain's structure and function.

Over time, the repeated activation of the stress response system can lead to alterations in neural circuitry and neurotransmitter activity. Impairment of the prefrontal cortex in chronic anxiety also leads to heightened emotional responses.

Genetics and environment 

Anxiety disorders have long been recognized as having a complex etiology, with both genetic and environmental factors playing significant roles. 

Previous studies have shown that anxiety disorders like GAD are heritable, with a moderate genetic risk of around 30%. However, despite recent research towards identifying the link between genetics and anxiety, the progress has been slow. 

According to a study led by Lauren M. McGrath from Massachusetts General Hospital, the reason for this slow progress can be attributed to factors such as small sample sizes, heterogeneity, complicated comorbidity profiles, and blurred lines between normative and pathological anxiety.

In addition to genetics, environmental factors have also been shown to affect anxiety. Stressors such as exposure to natural disasters, childhood sexual abuse, and combat or war can produce long-term symptoms of anxiety.

Most researchers argue that we should not dismiss the interplay between genetic and environmental factors on anxiety. 

In one study, led by Yan Clément from the Université Reims Champagne-Ardenne in France, the authors write, "Anxiety is a complex phenomenon, underlined not only by genetic or environmental factors but also by multiple interactions between genes and also between genetic and environmental factors."

Carlotta Notaro via GIPHY

The result of these interactions can produce anxiety-related behaviors. For example, in both humans and monkeys, mutations in the gene responsible for the serotonin transporter have been shown to lead to heightened anxiety in adulthood when coupled with a stressful environment during development. 

Further, twin studies also indicate that individuals with a smaller hippocampus may have an increased vulnerability to PTSD. 

Due to the limited research, the work by Mosienko and her team is potentially pivotal, as it may eventually offer an opportunity to 'switch off' the anxiety-triggering gene. Although, this is likely far off in the future.

"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."

"In addition, the brain anxiety circuit constitutes multiple regions. Hence, it is challenging to pin down a specific molecular pathway within a certain brain area driving anxiety," said Mosienko, explaining the slow progress of research in this area.

Switching off anxiety

Mosienko and her team wanted to understand how a specific molecule impacts stress levels in mice. They focused on microRNAs (miRNA), small compounds that play a role in gene regulation, including of genes which affect anxiety. 

Their aim was simple, see how miRNA affects anxiety symptoms in mice. For this, the team used a genetically modified miRNA called miR-483-5p and observed its effect on a gene called Pgap2 (the downstream target).

The team found that increased levels of miR-483-5p and the suppression of the Pgap2 gene relieved anxiety and stress symptoms. In other words, it switched off symptoms of anxiety and stress.

How does that work?

Neurons have little structures called dendritic spines. These spines can take different shapes and connect with other neurons to form synapses.

The team found that when miR483-5p increases and Pgap2 decreases, it leads to changes in the shape of the dendritic spines. This change helps us to learn from stressful situations and understand that not every stress represents a real danger to life or limb.

Instead, we learn to associate the experience as unpleasant but not directly harmful. These memories stay with us for a lifetime and help us avoid developing anxiety or mood disorders when we face similar stressful situations again.

Explaining the role of miRNAs in regulating complex neuropsychiatric conditions like anxiety, Mosienko said, "MiRNAs are uniquely placed to drive the development and progression of complex psychiatric conditions including anxiety as they can orchestrate the expression of several genes."

She is also confident that their finding will translate to humans, pointing out, "The current research is a preclinical study using an animal model where we looked at the amygdala. However, this research is directly translated to humans since the amygdala and discovered molecular pathways are also found in the human brain."

However, the research is still in the very early stages and requires collaboration with pharmacologists and pharmaceutical companies to reach a stage where anti-anxiety medication can be developed. 

Anxiety in the modern world

We've noted that genetics and environmental factors affect anxiety. But what about the world has changed in the last 50 years or so that has made it so prevalent?

The digital age, with its constant connectivity and information overload, has created a breeding ground for anxiety. Social media has changed the way we communicate and connect with people. 

Constantly needing reassurance that your life or job measures up, fear of missing out (FOMO), and cyberbullying have all contributed to heightened anxiety, especially among younger people. 

A study led by Renee D. Goodwin from Columbia University found that anxiety increased significantly from 2008 to 2018 among adult Americans, with the most notable rise observed in participants aged 18-25 years, with anxiety doubling from 7.97% to 14.66%.

In another study, led by Brian A. Primack from the University of Pittsburgh, scientists found that using anywhere between 7 and 11 social media platforms was linked to higher odds of increased depression and anxiety symptoms compared to using zero to two platforms.

Digitization has also eroded work-life balance, as the boundaries between professional and personal life blur in the era of remote work and constant connectivity. The pressure to achieve ever-higher productivity, constant monitoring, and managing personal responsibilities with less free time can also significantly impact mental well-being and increase anxiety levels.

A study led by Sang-Woo Kim, from Soonchunhyang University Hospital in South Korea, found that job-related factors such as high task complexity, tight deadlines, and insufficient decision-making authority were positively associated with work-related anxiety among Korean wage workers.

Urbanization and overcrowding, another hallmark of modern living, has also led to increased stressors. The fast-paced lifestyle and the struggle to keep up with urban demands can exacerbate anxiety levels in city dwellers.

The environmental factors associated with modernization have had a profound impact on anxiety levels in humans, introducing new challenges that humans are not equipped for and which were not prevalent even 50 years ago — all contributing to the widespread prevalence of anxiety in today's society.

Conclusion

Several variables are affecting anxiety in humans, from genetics to environment to modern challenges. However, there are still many things we don't know.

Are there any genetic markers to help diagnose anxiety? Can we develop other therapies that can turn off or suppress anxiety-inducing genes, as suggested by Mosienko and her team's research?

Unfortunately, we don't have the answers. But, Mosienko’s research is a step in the right direction, particularly for people who respond poorly to current anti-anxiety treatments, such as selective serotonin reuptake inhibitors (SSRIs) or benzodiazepines.

In suggesting that anxiety can be switched off or at least suppressed, the research may one day offer new treatments for anxiety.