Novel gene therapy can reduce depression, fear, and anxiety
[Apr. 22, 2023: JD Shavit, The Brighter Side of News]
Researchers have found that a well-known gene, Tob, plays an important role in reducing depression, fear, and anxiety. (CREDIT: Creative Commons)
Researchers from the Okinawa Institute of Science and Technology (OIST) have discovered a new role for the Tob gene, which has long been known for its involvement in cancer and regulation of the cell cycle and immune response.
In a multidisciplinary study combining molecular biology and neuroscience, the team found that the gene also plays an important role in reducing depression, fear, and anxiety. Lead author Dr. Mohieldin Youssef, a former PhD student in OIST’s Cell Signal Unit, explained that the presence of the Tob gene helps with stress resilience and that its removal leads to an increase in depression, fear, and anxiety. The findings were published in the journal Translational Psychiatry.
First characterized in Prof. Tadashi Yamamoto’s former lab in Japan in 1996, the Tob gene is named after the Japanese verb “tobu,” which means to fly or jump, due to its protein levels jumping in activity when a cell is exposed to a stimulus. The gene is classified as an immediate-early gene because of its fast response.
While Tob has been associated with many different phenomena, this research is the first to clarify its function in the brain against stress, according to Prof. Yamamoto.
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The team drew their conclusion that the Tob gene is linked to anxiety, fear, and depression from several experiments. They first exposed mice to stress and found that Tob protein levels increased, as expected. They then used mice born without a Tob gene and observed an increase in depression, fear, and anxiety. For instance, when a mouse with the Tob gene was placed in a bucket of water, they would swim and try to escape, but a mouse without the Tob gene would simply float, indicating a lack of will to fight a difficult situation, which is one way that researchers determine depression.
The mice without the Tob gene also appeared not to learn, as they still showed increased levels of fear even after several days when placed day-after-day in a place that evokes fear memory. The researchers then teamed up with OIST’s former PhD student Dr. Hiroaki Hamada from the Neural Computational Unit to conduct an MRI study.
They found that the connectivity between the hippocampus and pre-frontal cortex, two key places regulating the brain’s stress resilience, was altered when the Tob gene was removed. From there, the researchers decided to examine the specific role the gene plays within the hippocampus. They took mice without the Tob gene and injected this gene into the hippocampus while leaving it nonexistent in other parts of the body. The level of fear and depression returned to normal, but the mice still had increased anxiety.
An MRI of the hippocampus and the pre-frontal cortex when the Tob gene was removed. This MRI allowed the researchers to determine that the connectivity between the hippocampus and the pre-frontal cortex had been altered. The image is from the press release "Jumping gene found to be strongly linked to depression, fear, and anxiety." (CREDIT: OIST)
The researchers then created a mouse that had no Tob gene in the cells in the hippocampus but had it in the cells in the rest of the body. In this case, they found that the mice had normal levels of anxiety but increased fear and depression.
“We’ve concluded that the Tob gene within the hippocampus suppresses fear and depression,” explained Dr. Youssef. “But the suppression of anxiety must be regulated by another part of the brain.”
Summary showing the role of TOB in hippocampus-mediated stress response. Tob deletion induces fear and depression-like behaviors. This can be explained by the altered functional connectivity between the hippocampus and the pre-frontal cortex. The neurons in the hippocampus showed increased excitation and decreased inhibition. There were also impacts on other genes and proteins. (CREDIT: OIST)
Researchers from OIST’s former Brain Mechanisms for Behavior Unit also measured the function of the neurons within the hippocampus of mice without the Tob gene. They found that excitation was increased while inhibition was decreased, suggesting that the overall balance was impacted, which would affect the behavior of the mice.
Finally, the team conducted molecular analyses after exposing the mice to stress and found that expression did not immediately change with stress, but 15 minutes after exposing the mice to stress, changes occurred. Other genes and proteins were impacted if the Tob gene was deleted, suggesting that the Tob gene likely has multiple direct and indirect impacts.
TOB protein expression levels increase in response to stress. Western blotting of TOB expression levels in hippocampal lysates without stress and after 30 min of restraint stress at different times: 15 min, 1 h, 3 h, 5 h after stress exposure (n = 4). D Western blotting of TOB expression levels in hippocampal lysates without stress and after inescapable electric shock for different durations: 15 min, 1 h, 3 h, 5 h post-exposure to stress (n = 3). (CREDIT: OIST)
The findings of this study are indeed significant, as depression, fear, and anxiety are prevalent mental health conditions that can greatly impact an individual's quality of life. According to the World Health Organization (WHO), depression is the leading cause of disability worldwide, affecting more than 264 million people, while anxiety disorders affect 284 million people globally.
Dr. Youssef and his team's work sheds light on the underlying mechanisms behind stress resilience and the role of the Tob gene in regulating mood and behavior. By understanding how this gene impacts the brain and its response to stress, researchers may be able to develop new treatments for mental health conditions.
Deletion of Tob alters brain functional connectivity. After surgery to introduce a head-fixation bar on the skull, mice were allowed to recovery. After recovery periods, mice underwent habituation training 2 h for 7 days prior to fMRI sessions. (CREDIT: OIST)
The research has already garnered attention from the scientific community and the public alike. The team's work has also been recognized by the OIST, which issued a press release highlighting the importance of the study's findings. The release notes that the research has opened up new avenues for understanding the role of the Tob gene in regulating stress and mood, and could lead to new treatments for mental health conditions.
Overall, the multidisciplinary study conducted by Dr. Youssef and his team at the OIST is a significant step forward in our understanding of the underlying mechanisms behind stress resilience and the role of the Tob gene in regulating mood and behavior. The team's findings could have important implications for the development of new treatments for mental health conditions, and their work is sure to inspire further research in this area.
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