This molecule triggers fear: Researchers look into brain pathways

A team of researchers in the US have discovered a molecular pathway that processes threatening sights, sounds and smells into a fear response.

The molecule called CGRP (calcitonin gene-related peptide) allows neurons in two separate areas of the brain to group together threatening sensory cues into a singular signal, mark it as negative and communicate it to the amygdala, which turns the signal into fear.

The research published in Cell Reports on August 16, 2022 says it may pave the path for new therapies for fear-related disorders such as post-traumatic stress disorder (PTSD) or hypersensitivity disorders such as autism, migraines and fibromyalgia.

“The brain pathway we discovered works like a central alarm system,” says senior author Sung Han, assistant professor in Salk Institute’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. Identifying new threat pathways provides insights into treating fear-related disorders.”

According to a news release by the Salk Institute, “Most external threats involve multisensory cues such as the heat, smoke and smell of a wildfire”.

Research conducted earlier suggests that different pathways independently relay sound, sight, and touch threat cues to several brain areas. 

“However, the existence of such pathways has yet to be established”.

Another research on the topic also showed that the amygdala, “a well-known limbic structure crucial for initiating behavioural responses to environmental stimuli and forming associative memories” gets a lot of input from brain regions filled with a chemical associated with aversion, the neuropeptide CGRP.

“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,” says co-first author Shijia Liu, a graduate student in the Han lab.

“These circuits may both generate appropriate behavioural responses and help form aversive memories of threat cues.”

Hypotheses and findings

The researchers carried out multiple 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 behavioural tests to gauge memory and fear,” the Salk Institute news release explains.

Their findings indicate that the CGRP neurons, one set in the thalamus, and one set in the brain stem, form two distinct circuits as they connect to non-overlapping areas of the amygdala. 

Both sets were found to be needed for forming aversive memories, encoding threatening sights, sounds, smells, tastes and touches by communicating with local brain networks.

“While mice were used in this study, the same brain regions also abundantly express CGRP in humans,” says Han, holder of the Pioneer Fund Developmental Chair. 

“This suggests that the circuits reported here may also be involved in threat perception-related psychiatric disorders.”

In the future, the researchers would like to further explore CGRP’s effects on the circuits formed with brain regions and how they affect disorders that are related to multisensory stimuli processing abnormalities, including 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,” says co-first author Sukjae Joshua Kang, a postdoctoral fellow in the Han lab.

“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.”