How the brain turns threats into fear

US scientists, led by the Salk Institute for Biological Studies, have uncovered a molecular pathway that distils threatening sights, sounds and smells into a single message: be afraid. Their research, published in the journal Cell Reports, may lead to new therapies for fear-related disorders and/or hypersensitivity disorders.

Most external threats involve multisensory cues, such as the heat, smoke and smell of a wildfire. Previous research has shown that different pathways independently relay sound, sight and touch threat cues to multiple brain areas, but no one has ever found a single pathway that integrates all these cues. Previous research also shows that the amygdala, which initiates behavioural responses and forms fear memories to environmental and emotional stimuli, receives heavy input from brain regions that are laden with a chemical associated with aversion, the neuropeptide CGRP (calcitonin gene-related peptide).

“Based on these two pools of research, we proposed that CGRP neurons, found especially in subregions of the thalamus and the brainstem, relay multisensory threat information to the amygdala,” said graduate student Shijia Liu, co-first author on the new study. “These circuits may both generate appropriate behavioural responses and help form aversive memories of threat cues.”

The researchers conducted several experiments to test their hypothesis. 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 coloured fluorescent proteins, and they conducted behavioural 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 non-overlapping 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.”

Subregions of the amygdala, the brain’s emotion centre, receive threat cues from different brain areas, including the brainstem (red) and thalamus (green). Image credit: Salk Institute.

“The brain pathway we discovered works like a central alarm system,” said senior author Sung Han, assistant professor in Salk’s Clayton Foundation Laboratories for Peptide Biology. “We were excited to find that the CGRP neurons are activated by negative sensory cues from all five senses — sight, sound, taste, smell and touch.

“While mice were used in this study, the same brain regions also abundantly express CGRP in humans. This suggests that the circuits reported here may also be involved in threat perception-related psychiatric disorders.”

The authors hope to examine how CGRP signalling in these circuits mediates disorders involving multisensory stimuli processing abnormalities, such as migraines, PTSD and autism spectrum disorder.

“We haven’t tested it yet, but migraines might also activate these CGRP neurons in the thalamus and brainstem,” said postdoctoral fellow Sukjae Joshua Kang, co-first author on the study. “Drugs that block CGRP have been used to treat migraines, so I’m hoping that our study can be an anchor to use this kind of drug in relieving threat memories in PTSD, or sensory hypersensitivity in autism, too.”

Top image credit: iStock.com/PeopleImages

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