The Tob gene, which was initially discovered by Prof. Tadashi Yamamoto’s old group in Japan in 1996, is well known for its connection to cancer. Previous studies have shown that it also plays a role in controlling the cell cycle and the immunological response of the body.
Now, scientists from the Okinawa Institute of Science and Technology (OIST) have discovered that this gene also has a significant role in lowering depression, fear, and anxiety in a multidisciplinary study that blends molecular biology with neuroscience. The Translational Psychiatry journal published their study.
This research is about understanding stress-resilience. The presence of the gene helps with stress-resilience and if it is removed, there is an increase in depression, fear, and anxiety.”
Dr Mohieldin Youssef, Study Lead Author and Former PhD Student, Cell Signal Unit, Okinawa Institute of Science and Technology
The Cell Signal Unit is led by Prof. Tadashi Yamamoto.
The Japanese verb “tobu,” which means to soar or jump, inspired the name “Tob.” This is due to the cell’s protein levels becoming more active when exposed to a stimulus. According to Dr. Youssef, since the gene responds so quickly, it has been classified as an immediate-early gene.
The Tob gene is related to many different phenomena but working on the brain system is particularly challenging. Although it was previously suspected, this research is the first work that clarifies that Tob has a function in the brain against stress.”
Tadashi Yamamoto, Professor, Okinawa Institute of Science and Technology
Multiple tests led them to the conclusion that this gene is associated with anxiety, fear, and depression. Initially, the scientists placed mice under stress, and as predicted, the levels of Tob protein rose.
When they employed mice born lacking the Tob gene, they discovered an increase in depression, fear, and anxiety. For instance, if a mouse carrying the Tob gene were dropped into a pail of water, the mouse would swim and attempt to get out.
A mouse lacking the Tob gene, however, simply floated. Researchers can tell an animal is depressed when they notice it has little desire to confront a challenging circumstance.
Additionally, the mice lacking the Tob gene appeared incapable of learning. Dr. Youssef added that when mice are left in an environment that triggers fear memories on a daily basis, they typically come to realize that it is not all that horrible and stop being scared.
But even after several days, those lacking the Tob gene continued to exhibit elevated levels of fear manifested as frozen.
The scientists then collaborated with Dr. Hiroaki Hamada from the Neural Computational Unit, a former Ph.D. student of OIST. An MRI revealed that when the Tob gene was removed, the connectivity between the hippocampus and the pre-frontal cortex—two critical regions controlling the brain’s resilience to stress—was changed.
The scientists then made the decision to focus on the gene’s precise function within the hippocampus. Injecting the Tob gene into the hippocampus of mice lacking the Tob gene while leaving it dormant in other bodily regions. The mice’s depression and fear levels returned to normal, but their anxiety levels remained elevated.
The scientists then performed the exact opposite, breeding a mouse that lacked the Tob gene in the hippocampus but had it in the rest of its body. They discovered that the mice in this instance exhibited normal levels of anxiety but higher degrees of fear and depression.
Dr. Youssef stated, “We have concluded that the Tob gene within the hippocampus suppresses fear and depression. But the suppression of anxiety must be regulated by another part of the brain.”
The performance of the neurons in the hippocampus of the mice lacking the Tob gene was then evaluated by researchers from OIST’s former Brain Mechanisms for Behavior Unit. They discovered that while inhibition was reduced, excitation was raised, indicating that the overall balance had changed, which would have an effect on the mice’s behavior.
Eventually, after subjecting the mice to stress, the researchers performed genetic studies. It is interesting that they discovered that stress did not immediately alter expression. However, there were alterations 15 minutes after the mice were stressed.
If the Tob gene was deleted, it had an effect on other genes and proteins. This shows that there are probably several direct and indirect consequences of the Tob gene.
Dr. Youssef concluded, “Uncovering this role of the Tob gene in fear, depression, and anxiety could have vast implications for developing therapeutics for psychiatric stress.”
Youssef, M. M. M., et al (2022) TOB is an effector of the hippocampus-mediated acute stress response. Translational Psychiatry. doi:10.1038/s41398-022-02078-7