How the brain gathers threat cues and turns them into fear

Salk scientists have uncovered a molecular pathway that distills threatening sights, sounds and  smells into a single message: Be afraid. A molecule called CGRP enables neurons in two separate areas of the brain to bundle threatening sensory cues into a unified signal, tag it as negative and convey it to the amygdala, which translates the signal into fear.

The research, published recently in Cell Reports, may lead to new therapies for fear-related disorders such as post-traumatic stress disorder or hypersensitivity disorders such as autism, migraines and fibromyalgia.

The team conducted several experiments to test their hypotheses. They recorded CGRP neuron activity using single-cell calcium imaging while presenting mice with multisensory threat cues, enabling the researchers to pinpoint which sensory modality involved which sets of neurons. They determined the path the signals took after leaving the thalamus and brainstem using different colored fluorescent proteins. And they conducted behavioral tests to gauge memory and fear.

Taken together, their findings show that two distinct populations of CGRP neurons-one in the thalamus, one in the brainstem-project to nonoverlapping areas of the amygdala, forming two distinct circuits. Both populations encode threatening sights, sounds, smells, tastes and touches by communicating with local brain networks. Finally, they discovered that both circuits are necessary for forming aversive memories-the kind that tell you, "Stay away."

Ref: Sung Han et. al, A central alarm system that gates multi-sensory innate threat cues to the amygdala,Cell Reports,16-Aug2022,10.1016/j.celrep.2022.111222