First characterized in Professor Tadashi Yamamoto’s former laboratory in Japan in 1996, the Tob gene is well known for its role in cancer. Previous research has also indicated that it has a role in cell cycle regulation and the body’s immune response. Now, in a multidisciplinary study that combines molecular biology with neuroscience, researchers from 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 has been published by the journal Translational psychiatry.
“This research aims to understand stress resilience,” explained lead author Dr Mohieldin Youssef, a former PhD student at OIST’s Cellular Signaling Unit, led by Professor Yamamoto. “The presence of the gene helps with resilience to stress and if it is removed there is an increase in depression, fear and anxiety. »
Tob takes its name from the Japanese verb “tobu”, which means to fly or jump. Indeed, when the cell is exposed to a stimulus, its protein levels increase in activity. Dr. Youssef said this resulted in the gene being classified as an immediate early gene because it has such a rapid response.
“The Tob gene is linked to many different phenomena, but working on the brain system is particularly difficult,” Professor Yamamoto said. “Although previously suspected, this research is the first work that clarifies that Tob has a function in the brain once morest stress. »
Their conclusion that this gene is linked to anxiety, fear and depression was drawn from several different experiments. First, the researchers exposed mice to stress and, as expected, saw Tob protein levels increase. They then used mice born without the Tob gene and found an increase in depression, fear and anxiety. For example, when a mouse with the Tob gene was placed in a bucket of water, it swam and tried to escape. However, a mouse without the Tob gene simply floated. This unwillingness to fight a difficult situation is one way researchers determine that an animal is depressed.
Moreover, mice without the Tob gene did not appear to learn. Dr. Youssef explained that when mice are placed day following day in a place that evokes the memory of fear, they normally learn that it’s not that bad and stop being so scared. But those without the Tob gene still showed increased levels of fear seen as a freeze, even following several days.
The researchers then teamed up with former OIST PhD student Dr. Hiroaki Hamada from the Neural Computational Unit. Using an MRI, they discovered that the connectivity between two key places regulating the brain’s resilience to stress was altered when the Tob gene was removed: the hippocampus and the prefrontal cortex. 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 that gene into the hippocampus, while leaving it non-existent 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 which had no Tob gene in the cells of the hippocampus but which had some in the cells of 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,” Dr. Youssef explained. “But the suppression of anxiety has to be regulated by another part of the brain. »
Next, researchers from the former Brain Mechanisms for Behavior Unit at OIST measured the function of neurons in 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 have an impact on the behavior of the mice.
Finally, the researchers performed molecular analyzes following exposing the mice to stress. Interestingly, they found that the expression did not change immediately with stress. But, 15 minutes following exposing the mice to the stress, there were changes. Other genes and proteins were impacted if the Tob gene was deleted. This suggests that the Tob gene likely has multiple direct and indirect impacts.
“Discovering this role of the Tob gene in fear, depression and anxiety might have broad implications for the development of therapies for psychiatric stress,” Dr. Youssef said.
