Scientists at Salk have found a molecular pathway that turns scary sights, sounds, and smells into a short message: Be afraid. A molecule called CGRP makes it possible for neurons in two different parts of the brain to combine threatening sensory cues into a single signal, label it as bad, and send it to the amygdala, which interprets the signal as fear.
The study, published in the journal Cell Reports today, could lead to new treatments for fear-related disorders like post-traumatic stress disorder (PTSD) and hypersensitivity disorders like autism, migraines, and fibromyalgia.
“The brain pathway we discovered works like a central alarm system,” explains senior author Sung Han. “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 threats from the outside involve more than one sense, like a wildfire’s heat, smoke, and smell. Previous studies demonstrated that distinct routes separately transmit threat cues from sound, sight, and touch to numerous brain regions. A single pathway that takes all of these cues into account would be good for survival, but no one has ever found one.
Previous studies demonstrated that the amygdala, which begins behavioral responses and builds fear memories in response to environmental and emotional cues, receives substantial input from brain regions rich in the neuropeptide CGRP (calcitonin gene-related peptide), which is associated with aversion.
“Based on these two pools of research,” According to co-first author Shijia Liu, “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 both generate appropriate behavioral responses and help form aversive memories of threat cues.”
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.
When all of their findings are put together, they show that two different groups of CGRP neurons, one in the thalamus and one in the brainstem, connect to different parts of the amygdala to make two separate circuits. By interacting with regional brain networks, both groups register dangerous sights, sounds, smells, tastes, and touches. In the end, they found that both circuits are needed to make “aversive” memories, which are the ones that tell 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 CGRP signaling in these circuits mediates illnesses characterized by aberrant multimodal stimuli processing, such as migraines, PTSD, and autism spectrum disorder.
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. “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.”
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