It is said that fear can be smelled, while the signals that generate fear are often multi-sensory. Fire, for example, has heat, smoke, and a smell to get rid of. A soaring eagle casts a shadow and creates a faint sound as it flips. It would be beneficial for survival if animals had a way to feed all that sensory information from sight, smell, touch, taste, and hearing into a neural circuit that stimulates a part of the brain called the amygdala to initiate a fear response. However, the existence of such a neural pathway has not yet been proven. A new study has now provided strong evidence for two non-overlapping circuits that work together to instill fear in our brains.
The research team behind the study began with suspicions that neurons using a molecule called calcitonin gene-related peptide (CGRP) played a significant role in this process, alongside the brain's "fear center" - the amygdala. By testing their hypothesis on genetically modified mice, they found two distinct groups of CGRP neurons in the brainstem and the thalamus connected to the amygdala of the animal. Human neurons also express CGRP, so this circuit may be involved in conditions like migraines, post-traumatic stress disorder, and autism spectrum disorder.
The researchers equipped the mice with a small calcium imaging device called a miniscope, which allows scientists to track the activity of CGRP neurons while the mouse roams freely and responds to its environment. The mice were then faced with threat stimuli, including a small shock to their foot, a burst of sound simulating thunder, an approaching shadow mimicking a bird overhead, a piece of cotton soaked in trimethylthiazolin, a component of fox feces that elicits fear in rodents, and a bitter quinine solution.
Scientists recorded the activity of 160 CGRP neurons, half from each type: CGRPSPFp and CGRPPBel. They found that most CGRP neurons increased their activity when the mouse encountered threatening sounds, tastes, smells, sensations, and visual cues. The neurons did not respond as strongly to safe stimuli. Song Han, a neuroscientist at the Salk Institute for Biological Studies in California, stated, "The brain pathway we discovered acts like a central alarm system. We were excited to find that CGRP neurons are activated by negative sensory signals from all five senses - sight, sound, taste, smell, and touch."
The researchers wanted to confirm that these CGRP neurons were necessary for perceiving multi-sensory threats. In other words, other neurons were not eliciting the same fear response. In the mice, they silenced the CGRP neurons and conducted the experiment again to see if the animals continued to display the same pattern of fear behavior in response to frightening stimuli. The researchers found that the mice exposed to the silencing of these neurons were less likely to respond to electric foot shocks or loud sounds. The researchers wrote in their paper, "These results indicate that CGRPSPFp and CGRPPBel neurons are required to mediate behavioral responses to different groups of multi-sensory threats."
The team also demonstrated that these CGRP neurons were essential for forming memories of threats using what is known as a Pavlovian learning experience. The researchers concluded that by compiling all these threat signals in one area of the brain, this may assist animals in decision-making. If the same CGRP neural circuit is found in humans, this research could help provide treatments for medical conditions.
