How the brain gathers threat cues and turns them into fear

The chemical route that transforms frightening sights, sounds, and odors into the single message "Be terrified" has been discovered by Salk scientists. Neurons in two different regions of the brain can combine dangerous sensory cues into a single signal using the chemical CGRP, classify it as negative, and send it to the amygdala, which interprets it as fear.

The study, which will be published in Cell Reports on August 16, 2022, may result in new treatments for hypersensitive illnesses like autism, migraines, and fibromyalgia as well as fear-related disorders like post-traumatic stress disorder (PTSD).

According to senior author Sung Han, an assistant professor in Salk's Clayton Foundation Laboratories for Peptide Biology, "the brain route we uncovered functions as a central alert system." "We were thrilled to discover that negative sensory inputs from all five senses—sight, sound, taste, smell, and touch—activate the CGRP neurons. Understanding how to manage illnesses caused by fear can be gained via identifying new danger pathways."

Multisensory cues, like the heat, smoke, and scent of a wildfire, are what most external hazards involve. Previous studies demonstrated that distinct routes separately transmit threat cues from sound, sight, and touch to numerous brain regions. It would be advantageous to have a single pathway that incorporates all of these stimuli, but nobody had ever discovered one.

Additionally, prior studies demonstrated that the amygdala, which triggers behavioral reactions and records memories of fear in response to emotional and environmental triggers, receives a lot of input from areas of the brain that are abundant in the neuropeptide CGRP, a chemical linked to aversion (calcitonin gene-related peptide).

According to co-first author Shijia Liu, a graduate student in the Han lab, "based on these two streams of research, we postulated that CGRP neurons, found particularly in subregions of the thalamus and the brainstem, transport multimodal threat information to the amygdala." The formation of aversive memories of threat stimuli may also be assisted by these circuits, which may also elicit appropriate behavioral responses.

To test their theories, the researchers ran many tests. They exposed mice to multimodal threat cues while recording CGRP neuron activity using single-cell calcium imaging, allowing the researchers to determine which sensory modality implicated which sets of neurons. They used fluorescent proteins of various colors to map the route that signals followed after leaving the thalamus and brainstem. They also tested them behaviorally to assess their fear and memory.

Overall, their research demonstrates that two different populations of CGRP neurons, one in the thalamus and one in the brainstem, each project to regions of the amygdala that do not overlap, so generating two independent circuits. By interacting with regional brain networks, both groups register dangerous sights, sounds, smells, tastes, and touches. Finally, scientists found that both circuits are required for the development of unpleasant memories—those that instruct you to stay away.

Han, who holds the Pioneer Fund Developmental Chair, notes that although mice were employed in this work, CGRP is abundantly expressed in the same brain regions in humans. This suggests that the circuits discussed here may also be involved in psychiatric illnesses linked to threat perception.

The scientists want to investigate how multimodal processing diseases including PTSD, autism spectrum disorder, and migraines are mediated by aberrant CGRP signaling in these circuits.

According to co-first author Sukjae Joshua Kang, a postdoctoral fellow in the Han lab, migraines may also activate these CGRP neurons in the thalamus and brainstem. "CGRP-blocking medications have been used to treat migraines, so I'm hoping that our study may serve as a springboard for using these medications to treat sensory hypersensitivity in autism and PTSD as well as threat memories in PTSD."

Other writers included Bryan A. Copits of Washington University in St. Louis, Benjamin Z. Roberts of UC San Diego, Kuo-Fen Lee, Mao Ye, Dong-Il Kim, Gerald M. Pao, and Michael R. Bruchas of the University of Washington.

Salk Institute