Neuropeptides found to encode danger in the brain

The process of translating pain into a ‘threat memory’ occurs so quickly that scientists originally thought it must be mediated by fast-acting neurotransmitters. Now, a research team led by the Salk Institute for Biological Studies has revealed that the so-called fear circuit actually relies on slower-acting molecules called neuropeptides as its primary messengers, and more than one neuropeptide is involved in the process. Their findings, published in the journal Cell, could lead to the development of more effective painkillers or new treatments for fear-related conditions like anxiety and PTSD.

To process and react to things in our environment, information must travel throughout our body and brain. These signals are sent and received by neurons, which form organised circuits that guide information where it needs to go. Neurons communicate with each other by sending and receiving molecules like neurotransmitters and neuropeptides.

Neuropeptides are generally accepted as neuromodulators that help and modulate the action of the main neurotransmitters. However, pioneers like 1977 Nobel Prize winner Roger Guillemin proposed that neuropeptides can act as main transmitters themselves. This concept had not been rigorously tested due to a lack of tools for visualising and manipulating their release in behaving animals, so the Salk team created two genetically encoded tools that allowed them to observe and manipulate neuropeptide release in the brains of live mice.

To specifically target neuropeptides, Associate Professor Sung Han and his team took advantage of one of their unique characteristics — while typical neurotransmitters are packaged in small spheres called synaptic vesicles, neuropeptides are packaged in large dense core vesicles. By engineering biochemical tools to target these large vesicles, they created neuropeptide sensor and silencer tools. The sensor tags large dense core vesicles with proteins that glow when they are released from the nerve ending, allowing the researchers to watch neuropeptide release in live time. The silencer specifically degrades neuropeptides within large dense core vesicles, revealing what happens in the brain when neuropeptides are absent.

“We have created a novel way to trace neuropeptide travel and function in the brains of living animals,” said postdoctoral researcher Dong-Il Kim, first author on the study. “These tools will help further our understanding of the brain’s neuropeptide circuits and enable neuroscientists to explore questions that were previously difficult to address.”

Using their newly developed neuropeptide sensor and silencer, together with existing sensor and silencer tools for glutamate (the brain’s most abundant neurotransmitter), the researchers looked at how neuropeptides and glutamate behaved in live mice as they experienced a mild stimulus — just enough to stimulate the fear circuit. They found that neuropeptides, but not glutamate, were released during the stimulus. What’s more, silencing neuropeptide release reduced fear behaviours in the mice, but silencing glutamate had no effect.

To Han’s surprise, this brainstem fear circuit relied on neuropeptides as its primary messenger molecules rather than glutamate. Furthermore, the team’s findings support their ongoing investigation into PACAP — a neuropeptide that modulates panic disorder.

“These new tools and discoveries are an important step toward better neurological drug development,” Han said. “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.”

Equipped with their new neuropeptide toolbox, the team will soon begin to explore other brain circuits and processes. Future insights into neuropeptide signalling in other areas of the brain, as well as the newfound understanding that targeting multiple neuropeptides at once is necessary, should inspire the development of more effective drugs to treat diverse neurological disorders.

“We believe these new tools will significantly advance the field of neuropeptide research, and our discovery of their role in fear processing is really just the beginning,” Han said.

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