New Tools Uncover Neuropeptides' Crucial Role in Fear Processing

Researchers at the Salk Institute have uncovered the pivotal role of neuropeptides in the brain's fear circuit. This discovery, published in Cell, challenges the long-held belief that fast-acting neurotransmitters were the primary messengers in pain-to-fear signal transmission.

The team, led by Associate Professor Sung Han, developed innovative tools to observe and manipulate neuropeptide release in live mice. These tools, including a neuropeptide sensor and silencer, allowed them to visualize the release of neuropeptides from large dense core vesicles in real-time and selectively silence their activity.

Contrary to expectations, the study revealed that neuropeptides, not glutamate (the brain's most abundant neurotransmitter), were the main messengers in the brainstem fear circuit. When mice experienced a mild stimulus, neuropeptides were released, while glutamate remained inactive. Furthermore, silencing neuropeptide release reduced fear behaviors in mice, while silencing glutamate had no effect.

"These new tools and discoveries are an important step toward better neurological drug development. We found that multiple neuropeptides are packaged together in a single vesicle and released all at once by a painful stimulus to function in this fear circuit which made us think, ‘This might be why some drugs that target only one neuropeptide are failing in clinical trials.’ With this new information, we can provide insights to develop new drugs that target multiple neuropeptide receptors at once, which may serve as better painkillers or help treat fear-related disorders like PTSD.”

The research also sheds light on why some drugs targeting single neuropeptides have failed in clinical trials. Han suggests that developing drugs that target multiple neuropeptide receptors could lead to more effective painkillers and treatments for fear-related conditions.