More than 30 years ago, scientists discovered that neurological illnesses such as mad cow and Creutzfeldt-Jakob diseases are caused by misfolded proteins called prions. But in recent years, researchers demonstrated in mice that some prions are beneficial and serve important biological functions in the brain and body. New Columbia research describes how one such prion-like protein, encoded by a gene called TIA1, helps the brain keep fearful memories in check. Without this gene, female mice exhibit the tell-tale signs of post-traumatic stress disorder, or PTSD.
The results of this study, published in Cell Reports, point to TIA1 as a new target in the fight against PTSD, which is about twice as common in women as in men.
"When neurons undergo stress, such as in response to a viral infection, the TIA1 protein sequesters non-essential biomolecules inside the cell," said the paper's first author. "This allows the cell to focus all its efforts on fighting the stress."
TIA1 is present in many brain regions but is particularly active in the ventral hippocampus, an area known to regulate memories associated with stress and fear. The authors wondered if disruptions to TIA1 function could cause disruptions in fear memory -- which plays a key role in PTSD.
To find out, the researchers changed the amount of TIA1 in the ventral hippocampus of both male and female mice. The scientists then trained the mice to associate an innocuous smell, that of ethanol, with a stressful experience. When placed in other ethanol-scented environments, the animals exhibited avoidance behavior: they tended to move away from the stressful scent.
But when the researchers removed TIA1, they saw a change in behavior -- a change that was restricted to female mice. Removing TIA1 appeared to have no effect on the males, but the females' avoidance behavior skyrocketed; their fearful memories were heightened significantly.
The researchers argue that this marked sex difference may be an essential key to uncovering why the prevalence of PTSD is so much higher in women, as compared to men. It also emphasizes the importance of including female mice in scientific research, a practice that has long been discouraged by the scientific community.
"Not only that, but the gene that encodes TIA1 in mice also exists in the human genome," said the first author.. "To search for links between TIA1 activity levels and stress responses in humans, we are currently analyzing DNA from individuals in Sweden."
"We hope our work, combined with the work of others, will lead to the identification of a large number of genes, each of which contributes a certain amount of PTSD risk," said the senior author. "Advances in computational and theoretical modeling could soon allow us look at a person's particular genetic composition and identify his or her risk for developing a psychiatric disorder, such as PTSD -- and then offer the best way to treat it at the molecular level."
A prion-like protein keeps fear memory at bay in female mice
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