PASADENA, Calif. –In most old-fashioned black-and-white horror flicks, it always seems there's some hapless hero or heroine who gets caught up in a life-threatening situation. Instead of making the obvious choice--to run like hell--he/she freezes in place. That decision, alas, leads to their ultimate demise.
While their fate was determined by bad scriptwriting, scientists already know that in real life, environment and experience influence defensive behaviors. Less understood are the neural circuits that determine such decisions. Now, in an article in the May 1 issue of the Journal of Neuroscience, researchers at the California Institute of Technology have developed an experimental model using mice that can map and manipulate the neural circuits involved in such innate behaviors as fear.
Raymond Mongeau, Gabriel A. Miller, Elizabeth Chiang, and David J. Anderson, in work performed at Caltech, manipulated either a flight or freeze reaction in mice through the use of an ultrasonic auditory stimulus, and further, were able to alter the mouse's behavior by making simple changes in the animal's environment. They also found that flight and freezing are negatively correlated, suggesting that a kind of competition exists between these alternative defensive motor responses. Finally, they have begun to map the potential circuitry in the brain that controls this competition.
"Fear and anxiety are important emotions, especially in this day and age," says Anderson, a Caltech professor of biology and an investigator with the Howard Hughes Medical Institute. "We know a lot about how the brain processes fear that is learned, but much less is known about innate or unlearned fear. Our results open the way to better understanding how the brain processes innately fearful stimuli, and how and where anxiety affects the brain to influence behavior."
Using the ultrasonic cue, the researchers were able to predict and manipulate the animal's reaction to a fearful situation. They found that mice exposed to the ultrasonic stimulus in their home cage (a familiar environment) predominantly displayed a flight response. Those placed in a new cage (an unfamiliar environment), or treated with foot shocks the previous day, primarily displayed freezing and less flight.
Anderson noted that in previous fear "conditioning" experiments, where mice learn to fear a neutral tone associated with a footshock, the animals show only freezing behavior and never flight, even though in the wild, flight is a normal and important fear response to predators. This suggests that the ultrasonic stimulus used by Anderson and colleagues is tapping into brain circuits that mediate natural, or innate, fear responses that include flight as well as freezing.
What causes the shift from flight to freezing behavior? Probably high anxiety and stress, say the authors, caused by an unfamiliar environment or the foot shocks. The researchers suggest that freezing requires a higher threshold level of anticipatory fear (the heroine inside a dark, spooky house) before it can be elicited by the ultrasound.
Most brain researchers believe the brain uses a hierarchy of neural systems to determine which defensive behaviors, like flight or freezing, to use. These range from an evolutionary older neural system that generates "quick and dirty" defensive strategies, to more evolved systems that produce slower but more sophisticated reactions. These systems are known to interact, but the neural mechanisms that decide which response wins out are not understood.
One of the goals of their work was to map the brain regions that control the behaviors triggered by the fear stimulus, to observe whether any change in brain activity correlated with the different defensive behaviors. They achieved this, all the way down to the resolution of a single neuron, by mapping the expression pattern of the c-FOS gene, a so-called "immediate early gene" that is turned on when neurons are excited. The switching on of the c-FOS gene can therefore be used as an indication of neuronal activation.
A map of the c-FOS expression patterns during flight vs. freezing revealed that mice displaying freezing behavior had neural activity in different regions of the brain than those that fled. Some of these regions were previously known to inhibit each other, providing a possible explanation for the apparent competition between flight and freezing observed in the intact animal.
Anderson notes that more work needs to be done to pin down where and how anxiety modifies defensive behavior. "This system may also provide a useful model for understanding the neural substrates of human fear disorders, like panic and anxiety," says Anderson, "as well as provide a model for developing drugs to treat them."
Contact: Mark Wheeler (626) 395-8733 firstname.lastname@example.org
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