Medical discovery reduces fear, anxiety, and depression, study finds
Researchers have added a new dimension to Tob’s repertoire: a potential treatment for depression, fear, and anxiety. (CREDIT: Creative Commons)
In the nuanced landscape of molecular biology, few genes have captured the intrigue of the scientific community as the Tob gene has. Discovered in 1996 in Professor Tadashi Yamamoto’s lab in Japan, Tob’s influence stretches from cancer proliferation to the intricate dance of the cell cycle and the subtleties of immune responses.
Today, researchers at the Okinawa Institute of Science and Technology (OIST) have added a new dimension to Tob’s repertoire: a potential treatment for depression, fear, and anxiety.
“This research is about understanding stress-resilience,” Dr. Mohieldin Youssef, a pivotal figure in this groundbreaking study and a former PhD student in OIST’s Cell Signal Unit, elucidated. Prof. Yamamoto, leading the unit, has been at the helm of this discovery journey. “The presence of the gene helps with stress-resilience and if it’s removed, there’s an increase in depression, fear, and anxiety.”
An MRI of the hippocampus and the pre-frontal cortex when the Tob gene was removed. This MRI allowed the researchers to determine that the connectivity between the hippocampus and the pre-frontal cortex had been altered. The image is from the press release "Jumping gene found to be strongly linked to depression, fear, and anxiety." (CREDIT: OIST)
Tob, deriving its nomenclature from the Japanese verb “tobu,” to fly or jump, is an immediate-early gene, a classification speaking to its swift activation in the face of stimuli. The gene’s protein levels don’t just increase—they surge, reflecting its readiness to meet cellular demands.
“The Tob gene is related to many different phenomena, but working on the brain system is particularly challenging,” Prof. Yamamoto admits. Despite prior suspicions, it is this team’s effort that has crystallized Tob’s role in stress resistance within the brain’s complex circuitry.
To illustrate this connection, the OIST researchers embarked on a series of meticulous experiments. They began by exposing mice to stress, which predictably led to increased Tob protein levels. However, the real revelation came from studying mice genetically modified to lack the Tob gene.
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These mice displayed starkly increased signs of depression, fear, and anxiety. This behavioral change was dramatically observed during the ‘bucket of water’ test—while normal mice swam vigorously seeking escape, Tob-deficient mice remained listlessly afloat, emblematic of despair.
The lack of the Tob gene also seemed to stunt learning from repetitive exposure to stressors. Mice are typically capable of recognizing that recurrently encountered fear-provoking environments are not as threatening as initially perceived. However, Tob-deficient mice failed to exhibit this adaptive response, remaining consistently paralyzed by fear.
In a collaborative stride, OIST’s Dr. Hiroaki Hamada from the Neural Computational Unit brought neuroimaging expertise to the table. MRI analysis revealed that deleting the Tob gene disrupted the neural dialogue between the hippocampus and pre-frontal cortex—regions critical for managing stress resilience.
Tob deletion induces fear and depression-like behaviors. This can be explained by the altered functional connectivity between the hippocampus and the pre-frontal cortex. The neurons in the hippocampus showed increased excitation and decreased inhibition. There were also impacts on other genes and proteins. (CREDIT: OIST)
The researchers then narrowed their focus to the hippocampus, injecting the Tob gene into this region of Tob-deficient mice. The intervention normalized fear and depression but left anxiety untouched. Conversely, mice lacking the Tob gene specifically in the hippocampal cells—while retaining it elsewhere—experienced normal anxiety levels but heightened fear and depression.
“We’ve concluded that the Tob gene within the hippocampus suppresses fear and depression,” Dr. Youssef deduced, “But the suppression of anxiety must be regulated by another part of the brain.”
TOB protein expression levels increase in response to stress. Western blotting of TOB expression levels in hippocampal lysates without stress and after 30 min of restraint stress at different times: 15 min, 1 h, 3 h, 5 h after stress exposure (n = 4). D Western blotting of TOB expression levels in hippocampal lysates without stress and after inescapable electric shock for different durations: 15 min, 1 h, 3 h, 5 h post-exposure to stress (n = 3). (CREDIT: OIST)
Further exploration into the neuronal function within the hippocampus of these mice disclosed an imbalance between excitation and inhibition, offering a possible explanation for their altered behavior. Moreover, molecular analyses post-stress exposure indicated that the absence of the Tob gene not only has immediate effects but also triggers a cascade of genetic and protein alterations, underscoring Tob’s extensive influence.
The implications of these findings extend beyond theoretical genetics; they usher in hope for psychiatric stress-related interventions. The study, published by the prestigious journal Translational Psychiatry, included Western blot analyses that graphically represented the Tob protein's reaction to stress, providing a biochemical testament to the gene's responsive nature.
Deletion of Tob alters brain functional connectivity. (CREDIT: OIST)
“Uncovering this role of the Tob gene in fear, depression, and anxiety could have vast implications for developing therapeutics for psychiatric stress,” Dr. Youssef posits. The intricate relationship between our genetic makeup and psychological well-being has never been more palpable. With this research, a new path has been illuminated—one that may lead to novel strategies for bolstering mental health resilience, providing a beacon of hope for those grappling with the shadows of psychological stress.
Highlights
Researchers have found that a well-known gene, Tob, plays an important role in reducing depression, fear, and anxiety.
This conclusion was drawn after several different experiments involving mice in both cell biology and neuroscience.
They also found that the Tob gene within the hippocampus was important for reducing fear and depression, but not anxiety. That seemed to be controlled by another part of the brain.
What’s more, the mice without the Tob gene didn’t seem to learn that a place wasn’t so bad—they continued to show increased levels of fear observed as freezing, even after several days.
The researchers stated that uncovering this role of the Tob gene in depression, fear, and anxiety could have vast implications for developing therapeutics for psychiatric stress.
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