How the brain collects fear signals and transforms them into fear

Summary: CGRP neurons found in subregions of the thalamus and cerebellum convey multisensory threat information to the amygdala. These neural circuits are critical for forming negative memories, new research suggests.

A source: Salk Institute

Salk scientists have discovered a molecular pathway that translates frightening sights, sounds and smells into a single message: Don’t be afraid.

A molecule called CGRP combines fear-sensing signals to neurons in two different regions of the brain into a single signal, labels it as negative, and transmits the signal to the amygdala, which translates the signal into fear.

A study published in Cell Reports August 16, 2022 could 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 signaling system,” said senior author Sun Han, an assistant professor in Salk’s Clayton Foundation Laboratory of Peptide Biology.

“We were excited to find that CGRP neurons are activated by negative sensory signals from all five senses—sight, sound, taste, smell, and touch. Identifying new pathways of fear will provide insights into the treatment of diseases associated with fear.”

Most external threats involve multisensory cues such as the heat, smoke, and smell of fire. Previous studies have shown that different pathways independently convey fear of sound, sight, and touch to multiple regions of the brain. A single pathway connecting all these signals would be useful for life, but no one has yet found such a pathway.

Previous studies have also shown that the amygdala, which initiates behavioral responses and forms fear memories for environmental and emotional stimuli, receives strong input from regions of the brain filled with the neuropeptide CGRP (calcitonin gene-related peptide), an aversive brain chemical.

“Based on these two pools of research, we propose that CGRP neurons, particularly located in subregions of the thalamus and brain, send multisensory threat information to the amygdala,” said first author Shijia Liu, a graduate student in the Han lab. .

“These circuits may generate appropriate behavioral responses and help us to remember threatening cues.”

The team conducted several experiments to test their hypotheses. They used single-cell calcium imaging of CGRP neuron activity to present multisensory threat signals to mice, allowing the researchers to pinpoint which sets of neurons contained which sensory modality.

Subregions of the amygdala, the emotional center of the brain, receive threat signals from different brain regions, including the brainstem (red) and the thalamus (green). Credit: Salk Institute

They used different colored fluorescent proteins to determine the path taken by signals after they leave the thalamus and brain stem. And they administered behavioral tests to measure memory and fear.

Taken together, their findings suggest that two distinct populations of CGRP neurons—one in the thalamus and one in the brainstem—project to nonoverlapping regions of the amygdala, forming two distinct circuits. Both populations interact with local brain networks that encode fearful sights, sounds, smells, tastes, and touches.

Finally, they suggested that both circuits are necessary for the formation of aversive memories, in other words, “keep away.”

“When mice were used in this study, the same brain regions overexpressed CGRP in humans,” said Hahn, who holds the Pioneer Foundation Development Chair. “This suggests that the circuits described here may also be involved in psychiatric disorders related to threat perception.”

The authors hope to study how CGRP signaling in these circuits mediates disorders that include multisensory stimulus processing abnormalities such as migraine, PTSD, and autism spectrum disorders.

“We haven’t tested it yet, but migraines may activate these CGRP neurons in the thalamus and brainstem,” said first author Sukjae Joshua Kang, a postdoctoral fellow in the Khan lab.

“CGRP-blocking drugs have been used to treat migraines, so I’m hoping our research will pave the way for using a similar drug to reduce fear memories in PTSD or sensory hypersensitivity in autism.”

Fear and neuroscience research news about it

Author: Press service
A source: Salk Institute
The connection: Press service – Salk Institute
Photo: Photo courtesy of the Salk Institute

See also

It shows that it started above some gray clouds

Original research: Open access.
Sukjae J. Kang et al. Cell Reports


The amygdala is a central signaling system gating multisensory innate threat signals

Important moments

  • CGRPSPFp and CGRPPB neurons mediate multisensory innate threat perception
  • These neurons send negative information to different subregions of the amygdala
  • CGRPSPFp→LA and CGRPPBel→CeA Schemas are very important for creating aversive memories

A result

Accepting risks is essential to survival. Previous findings suggest that parallel pathways independently transmit innate fear signals from different sensory modalities to multiple brain regions, such as the midbrain and hypothalamus, for immediate avoidance.

However, little is known about whether and how multisensory innate threat signals are integrated from each sensory modality to the amygdala, a critical brain region for threat perception and learning.

Here, we report that calcitonin gene-related peptide (CGRP)-expressing neurons in the parvocellular subparafascicular nucleus in the thalamus and the parabrachial nucleus in the lateral forebrain transmit negative valence laterally and laterally in response to multisensory threat signals from different sensory modalities. central amygdala respectively.

Both CGRP populations and their amygdala projections are required for multisensory threat perception and memory impairment.

Identifying common pathways of innate fear may provide insights into the development of therapeutic candidates for diseases associated with innate fear.

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