How the Brain Turns Threat Cues Into Fear, Reveals Molecular Pathway That May Lead to Treatments for PTSD, Autism, Migraines

Researchers have recently revealed a molecular pathway filtering terrifying sights, sounds, and smells into a single message that reads, "Be afraid."

CGRP, a molecule, enables neurons in two separate sites of the brain to bundle threatening sensory signals into a unified sign, tag it as negative, and have it conveyed to the amygdala, translating the signal into fear, a EurekAlert report specified.

The study may lead to new treatments for fear-associated disorders like post-traumatic stress disorder or PTSD or hypersensitivity disorders like autism, fibromyalgia, and migraines.

According to the study's senior author Sung Han, assistant professor in Salk's Clayton Foundation Laboratories from Peptide Biology, the brain pathway the researchers found functions like a central alarm system.

The assistant professor also said they are excited to discover that the CGRP neurons are stimulated by negative sensory cures from all five senses, including sight, smell, taste, sound, and touch. Determining the new threat pathways offers insights into treating fear-associated disorders.

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(Photo: Wikimedia Commons/Pancrat)
Amygdale, hippocampe et fornix sur une coupe anatomique, d'après Digital Anatomist Project (Univ of Washington), dessin à la tablette graphique et Artweaver.

Neuropeptide Calcitonin Gene-related Peptide

Most external threats involve multisensory cues, such as a wildfire's heat, smoke, and smell. 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 benefit survival, but no one had ever found such a pathway. 

Past studies also showed that the amygdala, which specifies behavioral responses and forms fear memories to emotional and environmental stimuli, is receiving heavy input from brain regions laden with chemicals linked to aversion, the neuropeptide calcitonin gene-related peptide or CGRP.

According to Shijia Liu, co-first author of the study published in Cell Reports and a graduate student in the Han Lab, based on the said two pools of studies, the researchers proposed that CGRP neurons, found specifically in subregions of the thalamus and the brainstem, are relaying multisensory threat information to the amygdala.

Such circuits may both produce proper behavioral responses and help form aversive memories of danger signals.

Amygdala

The team carried out various experiments to test their hypotheses. They recorded the activity of CGRP neurons using single-cell calcium imaging while presenting mice with multisensory threat cues, allowing the researchers to pinpoint which sensory modality engaged which neuron sets.

They identified the signals' path after leaving the brainstem and thalamus using different colored fluorescent proteins. More so, they carried out behavioral tests to measure memory and fear.

Taken together, the team's findings reveal that two unique populations of CGRP neurons, one in the thalamus, and one in the brainstem, project to nonoverlapping sites of the amygdala, forming two unique circuits.

Both populations encode threatening sights, smells, touches, and sounds by communicating with local brain networks.

Lastly, the researchers discovered that both circuits are essential for forming aversive memories, the kind Han said, "that tells you to stay away."

Potential for Certain Conditions

Sukjae Joshua Kang, the study's co-first author and a postdoctoral fellow in the Han lab, said they had not tested the work yet, although migraines might also activate such CGRP neurons in the thalamus and brainstem.

A Bioengineer.org report specified that the co-first author also explained that drugs blocking CGRP had been used to treat migraines and thus, "I'm hoping that their research can be an anchor to use this kind of drug in relieving threat memories in PTSD, or sensory hypersensitivity in autism, as well.

Related information about how the brain processes fear is shown on Mount Sinai Health System's YouTube video below:

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