Scientists Map the Scent of Fear in the Brain

The olfactory system (sense of smell) in mammals has many functions, from mating to fighting, but it is particularly important in their ability to detect danger and escape it. The smell of a predator’s urine triggers stress hormones in mice, preparing them to flee, but researchers at the Fred Hutchinson Cancer Research Center (FredHutch) wanted to know how these volatile predator odors are translated from the nose to the brains of mice to trigger this instinctive fear response.

They discovered a very specific, tiny area of the olfactory cortex is key. While humans don’t respond in the same instinctive way to predator odors, researchers see similarities in the human and mouse responses to fear and stress, as in disorders like PTSD, and hope the research could lead to development of therapeutics. Their results were published in the journal Nature. 

One of the lead researchers, neurobiologist Linda Buck, a Nobel Prize winner for her discovery of odorant receptors and organization of the olfactory system, tells mental_floss, “There are two arms of the instinctive fear response in mice: behavioral—so animals will freeze in place if they can’t escape—and hormonal. In [the hormonal] arm, the detection of predator odor stimulates an increase in stress hormones in the blood, which increase blood pressure, heart rate and blood glucose, to help prepare the body for escape.”

The researchers wanted to know how predator odors are detected and which receptors were involved in triggering an instinctive response. They began with the neurons that cause the rise in stress hormones: corticotropin-releasing hormone neurons, or CRH. 

First author on the study Kunio Kondoh, a postdoctoral research fellow at FredHutch, "spent several years developing new viruses we could use to infect CRH neurons and then chart neural pathways in reverse,” says Buck. In this technique, known as viral neuronal tracing, the virus infects neurons and hops from neuron to neuron across the cell synapses, leaving a visible trail in the infected neurons—and effectively charting a path to the source.

For the current study, by using viral neuronal tracing the researchers "found that volatile predator odors significantly activated neurons in only one tiny area of the olfactory cortex. We were really surprised, because the area was so small; it occupies less than 5 percent of the entire olfactory cortex, and nothing was reported or known about it before,” she says.

This area is called the amygdalo-piriform transition area, or AmPir, and it sits right beside the amygdala, a part of the brain involved in emotional regulation in animals and humans.

They next tested the responsiveness of the AmPir by directly stimulating the neurons. The result was an increase in blood levels of the CRH stress hormones, which confirmed that the AmPir can induce a stress response, says Buck.

They found they could dampen the stress response as well. “When we silenced the neurons, it dramatically reduced the ability of predator odors to cause an increase of blood levels of stress hormones," Buck says. "We were amazed. This indicates AmPir plays a major role in stress hormone response.”

CRH and other stress hormones play a role in human disorders like PTSD and depression, and Buck feels that this research may help them explore the biological basis for those disorders. “A lot of these basic functions: fear, appetite, sleep, are evolutionarily conserved in mammals, including humans, so I’ve always been interested in understanding the basic biology of the nervous system with an eye to uncovering information in genes and neural circuits that would be useful for the development of therapeutics that could be used in humans."