Summary: CGRP neurons found in subregions of the thalamus and brainstem relay multisensory threat information to the amygdala. These neural circuits are essential for the formation of aversive memories, a new study reports.
Source: Salk Institute
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 in Cell Reports on August 16, 2022, may lead to 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’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.”
Most external threats involve multisensory cues, such as the heat, smoke and smell of a wildfire. Previous research showed that different pathways independently relay sound, sight, and touch threat cues to multiple brain areas. A single pathway that integrates all these cues would be beneficial to survival, but no one had ever found such a pathway.
Previous research also showed that the amygdala, which initiates behavioral 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,” says co-first author Shijia Liu, a graduate student in the Han lab.
“These circuits may both generate appropriate behavioral responses and help form aversive memories of threat cues.”
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.”
“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.”
The authors hope to examine how CGRP signaling 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,” 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.”
A central alarm system that gates multi-sensory innate threat cues to the amygdala
CGRPSPFp and CGRPPBel neurons mediate multi-sensory innate threat perception
These neurons send aversive information to different subregions of the amygdala
CGRPSPFp→LA and CGRPPBel→CeA circuits are crucial for aversive memory formation
Perception of threats is essential for survival. Previous findings suggest that parallel pathways independently relay innate threat signals from different sensory modalities to multiple brain areas, such as the midbrain and hypothalamus, for immediate avoidance.
Yet little is known about whether and how multi-sensory innate threat cues are integrated and conveyed from each sensory modality to the amygdala, a critical brain area for threat perception and learning.
Here, we report that neurons expressing calcitonin gene-related peptide (CGRP) in the parvocellular subparafascicular nucleus in the thalamus and external lateral parabrachial nucleus in the brainstem respond to multi-sensory threat cues from various sensory modalities and relay negative valence to the lateral and central amygdala, respectively.
Both CGRP populations and their amygdala projections are required for multi-sensory threat perception and aversive memory formation.
The identification of unified innate threat pathways may provide insights into developing therapeutic candidates for innate fear-related disorders.