Both humans and mice carrying a variant of a gene that plays a role in memory were slow to learn to forget a fear-based memory. The parallels in gene effects observed in mice and humans in this work means that investigation using the mouse model can provide insights into effects in humans; results may inform treatment approaches to anxiety disorders such as post-traumatic stress disorder.
Vulnerability to mental health disorders as well as tendencies toward certain behaviors are associated with variations in the numerous genes involved in shaping brain function. Brain-derived neurotrophic factor (BDNF) is a protein that supports the development of neurons and is involved in learning and memory. Previous research has suggested that a pinpoint variation in the gene for BDNF, found only in humans, is associated with some disorders of mental health, including anxiety-based disorders. (The variation—a single nucleotide polymorphism or SNP—is a substitution of a single link in the chemical chain that makes up genes. It results in a change in the protein’s activity.) The variant has been designated Val66Met.
In this study, scientists Fatima Soliman, Francis Lee, B.J. Casey and colleagues at Weill Cornell Medical College in New York City, and Stanford University in California, conducted parallel studies in humans and mice on the impact of the Val66Met variant on fear learning and extinction of fearful memories. The Val66Met substitution occurs naturally only in human populations. In this study, the scientists determined which of the human subjects in the study carried the variant vs. the more common form of the gene. They used genetic techniques to introduce the human Val66Met variant into mice.
Following a classic fear learning procedure, the investigators exposed mice and humans repeatedly to a neutral stimulus (for the mice a sound; for the humans, colored squares) simultaneously with an unpleasant one (for mice a foot shock; for humans, a loud noise). Eventually both mice and humans reacted to the neutral stimulus with an anxiety response, even if there was no accompanying unpleasant stimulus. Afterwards, mice and humans repeatedly exposed to the neutral stimulus alone eventually lost the fear association, a process known as fear extinction. In both humans and mice, however, carriers of the Val66Met variant took longer to lose the fear association than noncarriers.
The investigators also used functional brain imaging in the human subjects to monitor areas of the brain known to be involved in fear extinction. The results paralleled the behavioral responses; the area of the cortex that is engaged during fear extinction showed less activity during extinction in the carriers of the Val66Met variant. In contrast, an area of the brain involved in emotional responses—the amygdala—showed continued activity during extinction in Val66Met carriers relative to what was seen in subjects without the substitution. In these individuals, then, the activity of the amygdala—a reflection of emotional arousal—remained elevated, instead of subsiding as it would normally if the level of fear were decreasing.
The change in behavior observed in this study was not the result of a general increase in anxiety or level of fear arousal, but an effect on a specific brain circuit involved in the extinction of fear memory in both humans and mice. Treatment for anxiety-based disorders and phobias sometimes involves exposing patients—in a safe environment—to the objects or situations they fear. The ability to test for the presence of genetic variants, like the BDNF Val66Met substitution in patients, could provide useful information to therapists on what to expect in terms of responses to treatment in different individuals.
Evidence suggests that disorders of mental health are genetically complex, with many genes contributing to risk, each one having a small, sometimes difficult to measure, effect. Teasing out the effects of individual genes and gene variants on specific facets of behavior can help provide information on the contributions of these genes to personality and to risk of mental illness.