Fear and Unpleasant Memories Depend on Integrated Parallel Pathways

Our survival depends on our reactions to threats. It is well known that the amygdala is central in regulating fear. But little is known about how or even if cues from our five sense organs are processed before they reach the amygdala.

A study published in the journal Cell Reports has identified two distinct populations of neurons in the thalamus and the brainstem that are activated by threat cues from the senses. Both these populations express a protein called CGRP (Calcitonin Gene-Related Peptide). The study showed that these neuronal clusters form two parallel pathways that group threatening sensory cues into an integrated signal, label the unified signal “negative,” and convey it to two non-overlapping regions of the amygdala. This facilitates the formation of unpleasant memories that provoke fear.

The findings published in the article (“A central alarm system that gates multi-sensory innate threat cues to the amygdala”) may lead to new treatments for post-traumatic stress disorder (PTSD), hypersensitivity, autism, migraines, and fibromyalgia.

Senior author of the study Sung Han, PhD, an assistant professor in the Clayton Foundation Laboratories for Peptide Biology at the Salk Institute, said, “The brain pathway we discovered works like a central alarm system. We were excited to find that 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.”

The existence of an integrated pathway with a survival advantage, that the current study demonstrates, undermines the prevailing view that different pathways for each sense independently convey cues to scattered regions of the brain. Earlier studies also showed that the amygdala receives abundant incoming signals from regions of the brain expressing CGRP, a peptide associated with aversion.

Co-lead author Shijia Liu, a graduate student from Han’s lab said, “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. These circuits may generate appropriate behavioral responses and help form aversive memories of threat cues.”

The researchers conducted miniscope single-cell calcium imaging experiments in freely moving mice fitted with optical fibers, to record CGRP neuronal activity. This allowed them to identify neuronal paths associated with each sensory stimulus. They also used retrograde tracing using different fluorescent tags to determine the path the signals took upon leaving the thalamus and brainstem. In addition, the team conducted behavioral experiments to assess fear responses upon inhibiting or activating each pathway.

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

Postdoctoral fellow Sukjae Kang, PhD, said, “Migraines might also activate these CGRP neurons in the thalamus and brainstem. Drugs that block CGRP have been used to treat migraines, so I’m hoping, our study can be an anchor to use this kind of drug in relieving threat memories in PTSD, or sensory hypersensitivity in autism, too.”

In future experiments, Han’s team intends to understand the role of abnormalities in CGRP signaling in the two parallel circuits during migraine, PTSD, and autism.