Breakthrough Discovery May Reduce Depression, Anxiety and Fear

Researchers have found that the well-known Tob gene plays an important role in reducing depression, fear and anxiety. (CREDIT: Creative Commons)

First characterized in the former laboratory of Professor Tadashi Yamamoto in Japan in 1996, the Tob gene is well known for its role in the development of cancer. Previous research has also shown that it is involved in regulating the cell cycle and the body’s immune response.

Now, in an interdisciplinary study combining molecular biology with neuroscience, researchers at the Okinawa Institute of Science and Technology (OIST) have found that this gene also plays an important role in reducing depression, fear and anxiety. Their work was published in the journal Translational Psychiatry.

“This study aims to understand stress resilience,” explained lead author Dr. Mohieldin Youssef, a former PhD student in the Cell Signaling Department of OIST, which is led by Professor Yamamoto. “Having the gene helps with stress tolerance, and if it’s removed, depression, fear and anxiety increase.”

Tob is named after the Japanese verb “tobu”, which means “to fly” or “jump”. This is because when a cell is exposed to a stimulus, its protein level rises dramatically. Dr. Youssef said this led to the gene being classified as an immediate early development gene because it has such a quick response.

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“The Tob gene is associated with many different phenomena, but working with the brain system is particularly difficult,” said Professor Yamamoto. “Although it has been speculated before, this study is the first work to clarify that Tob has anti-stress brain function.”

MRI of the hippocampus and prefrontal cortex with the removal of the Tob gene. This MRI allowed the researchers to determine that the connection between the hippocampus and the prefrontal cortex had been altered. Image taken from press release “Jumping gene found to be strongly associated with depression, fear and anxiety.” (CREDIT: OIST)

Their conclusion that this gene is associated with anxiety, fear and depression was based on several different experiments. First, the researchers stressed the mice, and as expected, Tob protein levels increased. They then used mice born without the Tob gene and found an increase in depression, fear and anxiety. For example, when mice with the Tob gene were placed in a bucket of water, they swam and tried to escape. However, the mouse without the Tob gene simply swam. This lack of will to fight a difficult situation is one of the ways researchers determine that an animal is depressed.

What’s more, mice without the Tob gene don’t seem to have learned anything. Dr. Youssef explained that when mice are placed day in and day out in a place that evokes fear memories, they usually learn that it’s not so bad and stop being afraid. But those without the Tob gene still showed increased levels of fear, seen as a freeze, even after a few days.

Deletion of Tob causes fear and depressive behavior. This can be explained by an altered functional connection between the hippocampus and the prefrontal cortex. Hippocampal neurons showed increased excitation and decreased inhibition. There were also effects on other genes and proteins. (CREDIT: OIST)

The researchers then teamed up with former OIST graduate student Dr. Hiroaki Hamada from the Department of Neural Computing. Using MRI, they found that the connection between two key sites that regulate brain stress tolerance was altered when the Tob gene, the hippocampus and prefrontal cortex, was removed.

From there, the researchers decided to look at the specific role the gene plays in the hippocampus. They took mice without the Tob gene and injected the gene into the hippocampus, leaving it missing in other parts of the body. The level of fear and depression returned to normal, but the mice still had increased anxiety.

The researchers then did the opposite: they created a mouse that did not have the Tob gene in hippocampal cells, but did have it in cells from the rest of the body. In this case, they found that the mice had normal levels of anxiety, but increased fear and depression.

“We concluded that the Tob gene in the hippocampus suppresses fear and depression,” explained Dr. Youssef. “But anxiety suppression has to be regulated by another part of the brain.”

Next, researchers from OIST’s former Brain Mechanisms of Behavior unit measured neuronal function in the hippocampus of mice lacking the Tob gene. They found that excitation increased and inhibition decreased, indicating an imbalance in the overall balance that affected the behavior of the mice.

Finally, the researchers performed a molecular analysis after the mice were exposed to stress. Interestingly, they found that facial expressions did not immediately change when stressed. But 15 minutes after the mice were exposed to stress, there was a change. Other genes and proteins were affected if the Tob gene was deleted. This suggests that the Tob gene probably has multiple direct and indirect effects.

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 impression 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 unavoidable shock of varying duration: 15 min, 1 h, 3 h, 5 h after stress exposure (n = 3). (CREDIT: OIST)

“Uncovering this role of the Tob gene in fear, depression, and anxiety could have huge implications for the development of mental stress therapies,” Dr. Youssef said.

Basic moments

• Researchers have found that the well-known Tob gene plays an important role in reducing depression, fear and anxiety.

• This conclusion was reached after several different experiments with mice in both cell biology and neuroscience.

• They also found that the Tob gene in the hippocampus is important in reducing fear and depression, but not anxiety. It seemed to be controlled by another part of the brain.

• What’s more, mice without the Tob gene didn’t seem to realize that the place wasn’t so bad after all – they continued to show increased levels of fear, seen as freezing, even after several days.

• The researchers said that uncovering this role of the Tob gene in depression, fear and anxiety could have huge implications for the development of mental stress therapies.

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Note. Materials provided above by the Okinawa Institute of Science and Technology. Content can be edited for style and length.

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