The Smell of Fear: Neurons Involved in Rodent Stress Response Identified

The odor of bobcat urine, if you ever get a chance to take a whiff, is unforgettable — like rotten meat combined with sweat, with something indescribably feral underlying it. To humans, it’s just nose-wrinklingly disgusting.

But to mice, it smells like one thing: danger.

Rodents react instinctually to this trace of their natural predator. Even lab-raised mice that have never been exposed to bobcats — or cats of any sort — have a fear response to this unmistakable scent.

For mice, this instinctual reaction can be lifesaving. The fear response triggers a surge of stress hormones which sends the mice into hyper-preparedness, helping them to respond and flee quickly from hungry predators. Although humans and mice have different stress triggers, this response is reminiscent of our physiological responses to fear and stress.

Now, a study published online Monday in the journal Nature has identified nerve cells and a region of the brain behind this innate fear response. With a technique that uses specially engineered viruses to uncover the nerve pathway involved, a research team led by Fred Hutchinson Cancer Research Center neurobiologist and Nobel Prize winner Dr. Linda Buck has pinpointed a tiny area of the mouse brain responsible for this scent-induced reaction.

It’s known as the “amygdalo-piriform transition area,” or AmPir for short. The researchers were surprised to find that the fear response was so concentrated in this one small region of the olfactory cortex, a part of the brain responsible for perceiving odors.

Although humans do not show instinctive fear to predator odors, studying how mice respond to predator cues can help us learn about our own innate emotions and responses, Buck said.

“The stress hormone response is very reminiscent of human responses to fear and stress. And of course there are disorders in that, like PTSD,” she said. “Understanding the neural circuitry underlying fear and stress of various sorts is very important, not just to understand the basic biology and functions of the brain but also for potentially finding evolutionarily conserved neural circuits and genes that play an important role in humans.”

A trail of breadcrumbs in the brain

Fear triggers both physiological changes (surges of the stress hormones in their blood) and behavior changes in mice. The animals freeze when smelling the predator odor so they won’t be detected.

“Increased stress hormone levels in the blood cause a faster heart rate, blood pressure and increased awareness — it changes many things so the mice can survive and prepare for a coming threat,” said Fred Hutch postdoctoral research fellow Dr. Kunio Kondoh, also an author on the Nature study.

Researchers know which neurons cause the stress hormone increases but not which cells drive the freezing behavior, so the researchers set out to trace how the “danger” signal from the mouse’s nose gets to those stress hormone-triggering cells.

Kondoh and Dr. Zhonghua Lu, also a postdoctoral research fellow working on Buck’s laboratory team and an author on the study, modified a research tool known as viral neuronal tracing. Their technique was built on the backbone of the pseudorabies virus, which can infect neurons and moves from neuron to neuron across cell synapses, the special cellular bridges that nerve cells use to send signals to their direct partners. This pseudorabies virus only travels in reverse in the brain, in the opposite direction of neuron signals — like a salmon swimming upstream.

The researchers modified the virus to light up its pathway, leaving a trail of fluorescent breadcrumbs as it traveled from the neurons in the mouse brain that induce stress hormones to the cells that send signals to those stress-response neurons. They saw multiple different areas of the brain where the viral tracer had blazed its backwards path.

To pinpoint which of those areas was involved in the specific fear response to predator odors, Kondoh exposed mice in the lab to smells — the aforementioned bobcat urine, purchased from a hunting supply store, or a chemical from fox feces — and looked for olfactory neurons activated in response to those noxious scents. The researchers then looked at the cross-section of the two experiments — those nerve cells that send signals to the stress-response cells of the brain and that also light up when mice smell traces of their predators — and found them to be concentrated in one area of the olfactory cortex, the AmPir.

The AmPir is a small region of the rodent brain and, like most parts of the brain involved in sensing and responding to odors, it’s fairly mysterious, Buck said.

“We had actually never even heard of the AmPir. It’s a very tiny area and nothing was known about it,” she said. “We don’t know whether it even exists in humans.”

Illustration of a brain and a green cloud.
With a technique using specially engineered neuron-infecting viruses, Fred Hutch researchers have pinpointed the tiny region of the mouse brain involved in fear. Credit: Jacqueline Morgado / Fred Hutch News Service.

What is known about the AmPir is that it sits right next to the amygdala, a part of the brain that in humans and other animals plays a role in some emotions — including fear.

Kondoh also found that stimulating the AmPir directly boosted stress hormone levels, and that blocking this brain region’s activity blocked the hormone surge when animals were exposed to predator odors. (Animals with an inactive AmPir still froze when they smelled predator odors, though, suggesting to the researchers that the stress hormone response and behavior changes may be controlled by different parts of the brain.)

The next steps

The next steps for the research team are to uncover the molecules involved in the neural circuits they found, Buck said. The researchers would like to identify genetic signatures in the neurons involved in fear responses. If they find unique molecular signatures for those neurons and if those signatures occur in humans too, such discoveries could lead to a better understanding of stress disorders, such as PTSD and depression, Buck said — and perhaps even point to novel targets for therapeutics.

There’s also evidence suggesting that other scents, like rose oil, can block the fear response to predator odors. Buck’s research team is currently working to uncover the neurons that could suppress stress hormones and the fear response in rodents.

“We’re just beginning to scratch the surface,” Buck said. “By pursuing these various connections, I think there is the potential to identify neural circuits that would be relevant to humans and to the treatment of human psychiatric disorders.”

About this neuroscience research

Source: Rachel Tompa – Fred Hutchinson Cancer Research Center
Image Credit: The image is credited to Jacqueline Morgado / Fred Hutch News Service.
Original Research: Abstract for “A specific area of olfactory cortex involved in stress hormone responses to predator odours” by Kunio Kondoh, Zhonghua Lu, Xiaolan Ye, David P. Olson, Bradford B. Lowell and Linda B. Buck in Nature. Published online March 21 2016 doi:10.1038/nature17156


A specific area of olfactory cortex involved in stress hormone responses to predator odours

Instinctive reactions to danger are critical to the perpetuation of species and are observed throughout the animal kingdom. The scent of predators induces an instinctive fear response in mice that includes behavioural changes, as well as a surge in blood stress hormones that mobilizes multiple body systems to escape impending danger1, 2. How the olfactory system routes predator signals detected in the nose to achieve these effects is unknown. Here we identify a specific area of the olfactory cortex in mice that induces stress hormone responses to volatile predator odours. Using monosynaptic and polysynaptic viral tracers, we found that multiple olfactory cortical areas transmit signals to hypothalamic corticotropin-releasing hormone (CRH) neurons, which control stress hormone levels. However, only one minor cortical area, the amygdalo-piriform transition area (AmPir), contained neurons upstream of CRH neurons that were activated by volatile predator odours. Chemogenetic stimulation of AmPir activated CRH neurons and induced an increase in blood stress hormones, mimicking an instinctive fear response. Moreover, chemogenetic silencing of AmPir markedly reduced the stress hormone response to predator odours without affecting a fear behaviour. These findings suggest that AmPir, a small area comprising <5% of the olfactory cortex, plays a key part in the hormonal component of the instinctive fear response to volatile predator scents.

“A specific area of olfactory cortex involved in stress hormone responses to predator odours” by Kunio Kondoh, Zhonghua Lu, Xiaolan Ye, David P. Olson, Bradford B. Lowell and Linda B. Buck in Nature. Published online March 21 2016 doi:10.1038/nature17156

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