summary: Researchers have discovered that the primary messengers in the brain’s fear circuits are neuropeptides rather than neurotransmitters, a discovery that could lead to the development of better painkillers and treatments for fear-related conditions.
Scientists have used innovative tools to observe neuropeptides released during fear responses in live mice. The study highlights the possibility of targeting multiple neuropeptides for more effective treatments.
Key Facts:
- Neuropeptides are key transmitters in the brain’s fear circuits.
- New tools now allow for the observation of neuropeptide release in live mice in real time.
- Targeting multiple neuropeptides may lead to improved treatment of PTSD and pain.
sauce: Salk Institute
The moment you accidentally touch the hot handle of a cast iron skillet, you experience a sense of pain and danger. Sensory signals travel from pain receptors in your fingers, up your spinal cord, and to your brain stem. Once there, a special set of neurons relays the pain signal to a higher brain region called the amygdala. There, the pain signal triggers an emotional fear response, helping to remind you to avoid the hot pan in the future.
This process of converting pain into a memory of a threat happens so quickly that scientists thought it must be mediated by fast-acting molecules called neurotransmitters. But when Salk researchers investigated the role of larger, slower-acting molecules called neuropeptides, they found these It was a key communicator in this fear circuit.
Neuropeptides are known to play an important role in brain communication, but the details have remained unclear because scientists lacked the right tools to study them in behaving animals.
To clarify the role of neuropeptides in this circuitry, the Salk team created two new tools that allow scientists to observe and manipulate the release of neuropeptides in the brains of living mice.
A new study published in 2014 found that cell A study published on July 22, 2024 revealed that danger circuits use neuropeptides, rather than neurotransmitters, as their primary messengers, and that multiple neuropeptides are involved in the process.
Their findings could lead to the development of more effective painkillers and new treatments for fear-related conditions such as anxiety and post-traumatic stress disorder.
“There is still much to learn about neuropeptides, but thankfully at Salk we have the legacy of Nobel Prize winner Roger Gilman’s work to highlight their importance and encourage our discoveries,” said lead author Song Han, associate professor and Pioneer Fund Development Chair at the Salk Institute.
“To this end, we have created two genetically encoded tools to monitor and inhibit the release of neuropeptides from nerve endings. We are confident that these new tools will significantly advance the field of neuropeptide research, and that discovering the role of neuropeptides in fear processing is just the beginning.”
To process and react to things in our environment, information needs to travel throughout our body and brain. These signals are sent and received by neurons, which form organized circuits that direct information to where it needs to be. Neurons communicate with each other by sending and receiving molecules such as neurotransmitters and neuropeptides.
Neuropeptides are generally accepted as neuromodulators that complement and modulate the actions of primary neurotransmitters, but early pioneers such as Roger Gilman proposed that neuropeptides themselves may act as primary transmitters.
This concept has not been rigorously tested due to a lack of tools to visualize and manipulate neuropeptide release in behaving animals.The Salk team set out to investigate neuropeptides with the goal of developing new tools to better understand their role in brain circuits.
To target neuropeptides, Han’s team exploited one of their unique properties: Neurotransmitters Synaptic vesiclesNeuropeptides are Large dense-core vesiclesBy designing biochemical tools to target these large vesicles, neuropeptides have been created. sensor and silencer tool.
of sensor They labeled the large dense-core vesicles with a protein that glows when released from the nerve terminal, allowing the researchers to observe the release of neuropeptides in real time. silencer In particular, we resolve neuropeptides within large dense-core vesicles to reveal what happens in the brain in their absence.
“We developed a new method to track the trafficking and function of neuropeptides in the brain of living animals,” says Kim Dong-il, first author of the study and a postdoctoral researcher in the Han lab.
“These tools will improve our understanding of the brain’s neuropeptide circuits and enable neuroscientists to explore questions that have been difficult to answer until now.”
The researchers combined their newly developed neuropeptide sensors and silencers with existing sensor and silencer tools for glutamate (the brain’s most abundant neurotransmitter) to examine how the neuropeptides and glutamate respond when live mice are subjected to a mild stimulus that is strong enough to activate the fear circuitry.
They found that neuropeptides, but not glutamate, were released during stimulation, and furthermore, inhibiting neuropeptide release reduced fear behavior in mice, but inhibiting glutamate release had no effect.
To Han’s surprise and delight, this brainstem fear circuit uses a neuropeptide, rather than glutamate, as its primary transmitter molecule. Moreover, this finding supports ongoing research into PACAP, a neuropeptide that regulates panic attacks.
“These new tools and discoveries are an important step towards improving the development of neuropharmacological drugs,” Han said. “We discovered that multiple neuropeptides are packaged together in a single vesicle and released all at once by painful stimuli, functioning in this fear circuit.this “This may be why some drugs that target only one neuropeptide have failed in clinical trials.”
“This new information provides insights that can aid in the development of new drugs that target multiple neuropeptide receptors simultaneously, potentially acting as better painkillers or helping to treat fear-related disorders such as PTSD.”
Armed with their new neuropeptide toolbox, the research team plans to soon begin investigating other brain circuits and processes. Future insights into neuropeptide signaling in other brain regions, as well as the emerging understanding that targeting multiple neuropeptides simultaneously, should lead to the development of more effective drugs to treat a variety of neurological disorders.
Other authors include Seahyung Park, Mao Ye, Sukjae Kang, Jinho Jhang, Joan Vaughan and Alan Saghatelian of the Salk Institute; Sekun Park, Jane Chen, Avery Hunker, Larry Zweifel and Richard Palmiter of the University of Washington; and Kathleen Caron of the University of North Carolina at Chapel Hill.
Funding: This research was supported by the National Institutes of Health (NIMH 5R01MH116203, NINDS 1RF1NS128680) and the Salk Institute for Innovation Grant.
About this fear and the news of neuroscience research
author: Salk Communications
sauce: Salk Institute
contact: Salk.com – The Salk Institute
image: Image courtesy of Neuroscience News
Original Research: The access is closed.
“Presynaptic sensors and silencers of peptide transmission reveal neuropeptides as key transmitters in pontine fear circuits” by Song Han et al. cell
Abstract
Presynaptic sensors and silencers of peptide transmission reveal neuropeptides as key transmitters in pontine fear circuits
highlight
- CybSEP2 is a genetically encoded LDCV sensor for presynaptic neuropeptide release
- NepLDCV Genetically encoded silencer for peptide transduction
- The primary transmitter of CGRP is a neuropeptide, not glutamate.PBel→CeA U.S. Circuit Court
- CGRP requires multiple neuropeptides, not just CGRP.PBel→CeA Pain transmission
summary
Neurons produce and release neuropeptides to communicate with each other. Despite their importance in brain function, the circuit-based mechanisms of peptide transmission remain poorly understood due to a lack of tools to monitor and manipulate neuropeptide release. In vivo.
Here, we report the development of two genetically encoded tools to investigate peptide transmission in behaving mice: a genetically encoded large dense core vesicle (LDCV) sensor that detects presynaptic neuropeptide release, and a genetically encoded silencer that specifically degrades neuropeptides within LDCVs.
Using these tools, we show that during Pavlovian threat learning, neuropeptides, and not glutamate, encode the unconditioned stimulus in the parabrachial-to-amygdala threat pathway.
We also show that neuropeptides play a key role in encoding positive valence and inhibiting conditioned threat responses in endogenous opioid circuits from the amygdala to the parabrachial nucleus.
These results demonstrate that our sensors and silencers for presynaptic peptide transmission are reliable tools to investigate neuropeptide systems in awake, behaving animals.
