Increasing the activity of two enzymes better known for their role in oxidative stress metabolism turns normally relaxed mice into "Nervous Nellies," according to research conducted at the Salk Institute for Biological Studies and reported in the early online edition of Nature.
Locally overexpressing either glyoxalase 1 or glutathione reductase 1 in mouse brains significantly increased anxiety in usually relaxed mice and made already jittery mice even more anxiety-ridden. Inhibition of glyoxalase 1 had the opposite effect.
"Currently, very little is known about the genes that predispose to psychiatric disease," says first author Iiris Hovatta, who was a postdoctoral research in Salk's Laboratory of Genetics when the research was conducted. "All of the 17 genes that we identified are very good candidates for human anxiety disorders and most of them have never been associated with anxiety-related behavior before," she adds.
"This is a very exciting study where we can genetically interfere with the behavior outcome, emphasizing the genetic hard wiring of certain traits,'' says Inder Verma, professor in the Laboratory for Genetics at the Salk Institute.
Out of the 17 candidates, the researchers focused on the most promising ones, glyoxalase 1 and glutathione reductase 1, since both enzymes belonged to the same metabolic pathway. In addition, a study by Turkish scientists had found elevated levels of oxidative stress markers in patients with severe anxiety disorders. "It might be that oxidative stress metabolism and anxiety levels are linked, although we do not know the exact mechanism at the moment," says Hovatta.
Like other complex psychiatric traits, fear and anxiety are influenced by many genes. There is no such thing as a single "fear" gene that lets anxiety spiral out of control when the gene's regulation is disturbed, making it difficult to identify the genetic roots of anxiety disorders.
For their study, the scientists relied on inbred mouse strains that differ considerably in their natural anxiety levels. Just like in humans suffering from anxiety disorders, the sights and sounds of unfamiliar environments can trigger panic in mice with anxious dispositions, causing them to freeze in place. Unlike their more relaxed contemporaries, naturally nervous mice are not explorers and may seem wary of open spaces.
Instead of studying individual genes the researchers simultaneously assessed the activity patterns of about 10,000 genes in specific brain regions with the help of microarrays. This extensive scan allowed the researchers to pinpoint multiple genes whose expression levels differed in relaxed and anxiety-prone mice.
To increase the specificity of their microarray analysis, they looked in only specific brain areas that have been shown to play a role in anxiety and fear (the amygdala, bed nucleus of the stria terminalis, cingulate cortex, hippocampus, hypothalamus, central peri-aqueductal grey and pituitary gland).