First characterised in Prof. Tadashi Yamamoto’s former lab in Japan in 1996, the gene Tob is well-known for the role it plays in cancer. Previous research has also indicated that it has a hand in regulating the cell cycle and the body’s immune response. Now, in a multidisciplinary study that mixes molecular biology with neuroscience, researchers from the Okinawa Institute of Science and Technology (OIST) have found that this gene also plays a very important role in reducing depression, fear, and anxiety. Their work was published by the journal Translational Psychiatry.

“This research is about understanding stress-resilience,” explained lead writer, Dr. Mohieldin Youssef, former PhD student in OIST’s Cell Signal Unit, which is led by Prof. Yamamoto. “The presence of the gene helps with stress-resilience and if it’s removed, there’s a rise in depression, fear, and anxiety.”

Tob is known as for the Japanese verb “tobu”, which implies to fly or to leap. It is because when the cell is exposed to a stimulus, its protein levels jump in activity. Dr. Youssef said that this has resulted within the gene being classed as an immediate-early gene, because it has such a quick response.

The Tob gene is expounded to many alternative phenomena but working on the brain system is especially difficult. Even though it was previously suspected, this research is the primary work that clarifies that Tob has a function within the brain against stress.”

Prof. Tadashi Yamamoto

Their conclusion that this gene is linked to anxiety, fear, and depression was drawn from several different experiments. First, the researchers exposed mice to emphasize and, as expected, saw the Tob protein levels increase. They then used mice which had been born with no Tob gene and located a rise in depression, fear, and anxiety. For instance, when a mouse with the Tob gene was placed in a bucket of water, they’d swim and check out to flee. Nevertheless, a mouse without the Tob gene simply floated. This lack of will to fight a difficult situation is a method that researchers determine that an animal is depressed.

What’s more, the mice without the Tob gene didn’t appear to learn. Dr. Youssef explained that when mice are put day-after-day in a spot which evokes fear memory, they normally learn that it is not so bad and stop being as frightened. But those without the Tob gene still showed increased levels of fear observed as freezing, even after several days.

The researchers then teamed up with OIST’s former PhD student Dr. Hiroaki Hamada from the Neural Computational Unit. Through an MRI, they found that the connectivity between two key places regulating brain’s stress resilience was altered when the Tob gene was removed-;the hippocampus and the pre-frontal cortex. From there, the researchers decided to have a look at the precise role that the gene plays inside 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 extent of fear and depression returned to normal, however the mice still had increased anxiety. The researchers then did the opposite-;they created a mouse that had no Tob gene within the cells within the hippocampus but had it within the cells in the remainder of the body. On this case, they found that the mice had normal levels of hysteria but increased fear and depression.

“We have concluded that the Tob gene inside the hippocampus suppresses fear and depression,” explained Dr. Youssef. “However the suppression of hysteria have to be regulated by one other a part of the brain.”

Next, researchers from OIST’s former Brain Mechanisms for Behavior Unit measured the function of the neurons inside the hippocampus of the mice without the Tob gene. They found that excitation was increased, while inhibition was decreased, suggesting that the general balance was impacted, which might impact the behavior of the mice.

Finally, the researchers conducted molecular analyses after exposing the mice to emphasize. Interestingly, they found that expression didn’t immediate change with stress. But, quarter-hour after exposing the mice to emphasize, there have been changes. Other genes and proteins were impacted if the Tob gene was deleted. This means that the Tob gene likely has multiple direct and indirect impacts.

“Uncovering this role of the Tob gene in fear, depression, and anxiety could have vast implications for developing therapeutics for psychiatric stress,” said Dr. Youssef.

Source:

Okinawa Institute of Science and Technology (OIST) Graduate University

Journal reference:

Youssef, M.M.M., et al. (2022) TOB is an effector of the hippocampus-mediated acute stress response. Translational Psychiatry. doi.org/10.1038/s41398-022-02078-7.