Bret S. Stetka, MD

Disclosures

June 10, 2014

In This Article

Genetic Contributions

Genetic influences also appear to be a major contributor to fear and anxiety. Of particular importance appears to be the gene encoding for brain-derived neurotrophic factor (BDNF), a neurotrophin responsible for neuronal growth, differentiation, and survival.

Casey's Cornell colleague Dr. Frances Lee has developed a new strain of mouse carrying a BDNF polymorphism in which methionine is substituted for valine. This BDNF Val66Met knock-in model results in decreased neurotrophin activity, biologically recapitulating the effects of the human polymorphism.[7] The mice mimic the "wallflower at the school dance," according to Casey: When tested in an open field task, they spent more time near the walls, an indication of anxiety-like behavior.[8]

Fatima Soliman, Casey and Lee's joint MD, PhD, student, performed a related study in the mice and humans with the BDNF Val66Met polymorphism,[9] looking at Pavlovian conditioning to fear cues and their ability to extinguish negative associations. The mice received a minor foot shock paired with a neutral audible tone, whereas the humans were played an intrusive sound -- Casey likened it to that "obnoxious alarm clock" -- paired with innocuous images of colored squares. Next, the conditioned stimuli were presented repeatedly without the noxious stimulus, and subjects were monitored for fear responses (in mice, freezing; in humans, sweating).

Wild-type mice were found to freeze at first, but not after numerous tone presentations; BDNF Val66Met mice exhibited freezing behavior that did not extinguish with subsequent trials. Similar findings were seen in humans with the polymorphism, present in roughly 30% of those of white persons.

A single polymorphism is unlikely to fully account for the complexities of human fear and associated neurodevelopmental aberrations, and with twice as many presentations, they eventually learned. However, in subjects carrying a substituted methionine in the BDNF gene, fear doesn't extinguish as readily in response to repeated nonthreatening cues; in those with a valine, it extinguishes more easily. Using neuroimaging, the authors showed that polymorphism carriers exhibited more amygdala and less PFC activity with subsequent cue presentations.

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