The gene Tob, which was first characterized in 1996 in the former laboratory of Prof. Tadashi Yamamoto in Japan, is known for its role in cancer. Previous research has also shown that it plays a role in regulating the cell cycle and the body’s immune response. Now, in a multidisciplinary 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, anxiety and anxiety. Their work was published by the magazine Translational Psychiatry.
“This research is about understanding stress resilience,” explains lead author Dr. Mohieldin Youssef, former PhD student in OIST’s Cell Signal Unit, which is headed by Prof. Yamamoto. “The presence of the gene aids in stress tolerance and if it is removed there is an increase in depression, anxiety and anxiety.”
Tob is named after the Japanese verb “tobu”, which means to fly or jump. This is because when the cell is exposed to a stimulus, the protein levels jump into activity. dr. Youssef said this has led to the gene being classified as a direct-early gene because it responds so quickly.
“The Tob gene is related to many different phenomena, but working on the brain system is particularly challenging,” says Prof. Yamamoto. “Although it was previously suspected, this study is the first work to clarify that Tob has a function in the brain against stress.”
Their conclusion that this gene is related to anxiety, fear and depression came from several experiments. First, the researchers exposed mice to stress and, as expected, saw Tob protein levels increase. They then used mice born without a Tob gene and found an increase in depression, anxiety and fear. For example, if a mouse with the Tob gene was placed in a bucket of water, they would swim and try to escape. However, a mouse without the Tob gene just floated. This lack of will to fight a difficult situation is one way researchers determine that an animal is depressed.
In addition, the mice without the Tob gene did not seem to learn. dr. Youssef explained that when mice are placed day after day in a place that triggers fear, they normally learn that it’s not so bad and are not so scared anymore. But those without the Tob gene still showed increased levels of anxiety perceived as frostbite even after several days.
The researchers then teamed up with OIST’s former PhD student Dr. Hiroaki Hamada of the Neural Computational Unit. Through an MRI, they found that the connectivity between two key sites that regulate the brain’s stress resistance was altered when the Tob gene was deleted — the hippocampus and the prefrontal cortex. From there, the researchers decided to look at the specific role the gene plays within the hippocampus. They took mice without the Tob gene and injected this gene into the hippocampus, when it didn’t exist in other parts of the body. The level of anxiety 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 a Tob gene in the cells in the hippocampus, but did in the cells in the rest of the body. In this case, they found that the mice had normal levels of anxiety, but increased anxiety and depression.
“We concluded that the Tob gene in the hippocampus suppresses anxiety and depression,” explains Dr. Youssef out. “But the suppression of fear must be regulated by another part of the brain.”
Next, researchers at OIST’s former Brain Mechanisms for Behavior Unit measured the function of the neurons in the hippocampus of the mice lacking the Tob gene. They found that arousal had increased, while inhibition had decreased, suggesting that the overall balance was affected, which would influence the mice’s behavior.
Finally, the researchers performed molecular analyzes after exposing the mice to stress. Interestingly, they found that expression did not immediately change with stress. But 15 minutes after the mice were exposed to stress, there were changes. Other genes and proteins were affected if the Tob gene was deleted. This suggests that the Tob gene likely has multiple direct and indirect effects.
“Uncovering this role of the Tob gene in anxiety, depression and anxiety could have huge implications for the development of therapies for psychiatric stress,” said Dr. youssef.