Summary: The TOB gene plays an important role in reducing depression, anxiety and fear in mouse models. The results could have positive implications for the development of new treatments for disorders associated with psychiatric stress.
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 resistance,” 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 it has been suspected before, this research is the first work that clarifies that Tob has a function in the brain against 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 after 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 after 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 must 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 after exposing the mice to stress. Interestingly, they found that the expression did not change immediately with stress. But, 15 minutes after 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 could have broad implications for the development of therapies for psychiatric stress,” Dr. Youssef said.
About this genetics and mental health research news
Author: Tomomi Okubo
Contact: Tomomi Okubo – OIST
Image: Image is in public domain
Original research: Free access.
“TOB is an effector of the hippocampus-mediated acute stress response” by Mohieldin M. M. Youssef et al. Translational psychiatry
TOB is an effector of the hippocampus-mediated acute stress response
Stress affects behavior and involves critical dynamic changes at multiple levels ranging from molecular pathways to neural circuitry and behavior. Abnormalities at any of these levels lead to decreased stress resilience and pathological behavior.
However, the temporal modulation of the molecular pathways underlying the stress response remains poorly understood.
The ErbB2.1 transducer, known as TOB, is involved in different physiological functions, including cellular stress and immediate response to stimulation. In this study, we investigated the role of TOB in the psychological stress machinery at the molecular, neural, and behavioral levels. Interestingly, TOB protein levels increased after mice were exposed to acute stress.
At the neural circuit level, functional magnetic resonance imaging (fMRI) suggested that intra-hippocampal and hippocampal-prefrontal connectivity was dysregulated in tob Knock out (tob-KO) mouse.
Electrophysiological recordings in hippocampal slices showed an increase in post-synaptic AMPAR-mediated neurotransmission, accompanied by a decrease in GABA neurotransmission and subsequently an altered excitatory/inhibitory balance after tob erasure. At the behavioral level, tobKO mice exhibit abnormal contextual, hippocampus-dependent fear conditioning and extinction, and depression-like behaviors.
In contrast, the increased anxiety observed in tob-KO mice are independent of the hippocampus. At the molecular level, we observed changes in factors involved in the stress response, such as a decrease in stress-induced LCN2 expression and ERK phosphorylation, as well as an increase in MKP expression. -1. This study presents TOB as an important modulator in the hippocampal stress signaling machinery.
In summary, we reveal a molecular pathway and neural circuit mechanism by which tob suppression contributes to the expression of pathological stress-related behavior.
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