HHMI scientists identify a region of the brain that is critical in translating danger signals detected by the nose into physiological responses.

When the twitching pink nose of a mouse detects danger, the animal has to act fast. Fortunately, a predator rapidly triggers the release of stress hormones in the mouse and prompts behaviors that reduce the risk of it becoming the predator’s latest snack. Howard Hughes Medical Institute (HHMI) scientists have now identified a brain area that is critical to this instinctive fear response, helping explain how the brain translates danger signals detected by the nose into a physiological response. The research offers clues to the larger puzzle of how animals, including humans, perceive and respond to fear.

The research, led by HHMI investigator Linda Buck at the Fred Hutchinson Cancer Research Center, was published online March 21, 2016, in the journal Nature.

Buck says that prior to her team's research, it was well known that certain odors produced by predators—components of fur or urine, for example—trigger a fear response in mice. In a lab, this causes the animals to freeze in place when they detect such smells; in the wild, they might do the same, or choose to flee instead. This behavioral response is accompanied by a surge of stress hormones in the bloodstream—an effect that also occurs in humans when they encounter frightening situations.

Buck and her team knew that specific neurons in the brain's hypothalamus control this hormonal fear response, so they began by looking for connections between those cells—corticotropin releasing hormone (CRH) neurons—and the part of the brain that processes information relayed from odorant-sensing neurons in the nose. The olfactory cortex, as it is called, is large and complex, containing 11 distinct anatomical regions whose specific functions are largely unknown.

Kunio Kondoh and Zhonghua Lu, postdoctoral researchers in Buck's lab, infected CRH neurons with viruses they had genetically engineered to allow the viruses to hop between connected neurons. This  approach allowed the scientists to effectively trace the neural circuit in reverse. In doing so, they learned that five different parts of the olfactory cortex signaled to the hormone-releasing cells.

But when they investigated how those neurons behaved when mice were exposed to bobcat urine or a danger-signaling fox odor, Kondoh and Lu found that only a small fraction of them fired, signaling to the CRH neurons. The active neurons were all clustered in the amygdalo-piriform transition area (AmPir), a part of the olfactory cortex that is so small that Buck says she had barely noticed it before.

Now that the AmPir region had their attention, Buck and her team tested whether artificially activating cells there would lead to a surge in stress hormones even in the absence of any predator-associated odor. Using designer receptors that they introduced into the cells to place them under chemical control, the scientists switched AmPir cells on in the brains of mice, then measured stress hormones in the animals' blood. They found that the hormones spiked just as they do when the animals detect the scent of a potential predator. The researchers also showed that when they blocked AmPir cells from signaling, the hormonal response to predator odors was dramatically reduced. “It's clear that the AmPir plays a major role in the hormonal fear response,” Buck says.

In contrast, the experiments also revealed that AmPir neurons are not responsible for the behavioral response to predator odors: Silencing those neurons did not prevent animals from freezing when they smelled predator odors. So while the AmPir neurons trigger hormone-induced changes that prepare the body to escape potential danger, such as an increased heart rate and a rise in blood sugar, a separate part of the brain appears to direct the behaviors themselves. “Somewhat surprisingly, different parts of the olfactory cortex may be involved in these two different arms of the fear response,” Buck says.

Buck and her team are now confident that this tiny part of the brain plays a critical role in animals' instinctive fear response to predator odors. Unraveling the neural circuitry that controls fear in mice may reveal important principles about parallel processes in humans, and could lead to a better understanding of fear and anxiety disorders. Ultimately, Buck says, she hopes her research might help identify better ways of treating these disorders.

“This is the first time that anyone has looked at neural circuits that involve these CRH neurons, which play an extremely important role in stress and fear responses in animals as well as in humans,” Buck says. She and her colleagues plan to continue investigating not only the CRH neurons' connections to the olfactory cortex, but also their wide-reaching connections to other parts of the brain. “It's very likely that these neural circuits are going to prove to be evolutionary conserved,” she says. 

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