Summary: Researchers have discovered that neuropeptides, not neurotransmitters, are the main messengers in the brain’s fear circuitry. The discovery could lead to better painkillers and treatments for fear-related disorders.
Using innovative tools, scientists observed the release of neuropeptides during fear responses in living mice. The study highlights the potential of targeting multiple neuropeptides for more effective therapies.
Highlights:
- Neuropeptides are the main messengers in the brain’s fear circuit.
- New tools allow real-time observation of neuropeptide release in living mice.
- Targeting multiple neuropeptides could improve treatments for PTSD and pain.
Source: Salk Institute
In a split second, when you accidentally touch the hot handle of a cast iron skillet, pain and a sense of danger flood through you. Sensory signals travel from the pain receptors in your finger, all the way to your spinal cord and brain stem. Once there, a special group of neurons relays these pain signals to a higher brain area called the amygdala, where they trigger your emotional fear response and help you remember to avoid hot pans in the future.
This process of translating pain into a threatening memory happens so quickly that scientists thought it must be mediated by fast-acting molecules called neurotransmitters. But when Salk researchers studied the role of larger, slower-acting molecules called neuropeptides, they discovered these were the main messengers of this fear circuit.
Neuropeptides are known to play an important role in brain communication, but the details were unclear because scientists lacked the proper tools to study them in working animals.
To determine the role of neuropeptides in this circuit, the Salk team created two new tools that finally allow scientists to observe and manipulate the release of neuropeptides in the brains of living mice.
The new study, published in Cell On July 22, 2024, it was revealed that the danger circuit relies on neuropeptides, not neurotransmitters, as its primary messengers, and that more than one neuropeptide is involved in the process.
Their findings could lead to the development of more effective painkillers or new treatments for fear-related disorders such as anxiety and post-traumatic stress disorder (PTSD).
“There is still so much we have to learn about neuropeptides, but fortunately at Salk we can look to the legacy of Nobel laureate Roger Guillemin’s work to highlight their importance and encourage our discovery,” says lead author Sung Han, associate professor and Pioneer Fund Development Chair at Salk.
“To do this, we created two genetically encoded tools to monitor and inhibit the release of neuropeptides from nerve endings. We believe these new tools will significantly advance the field of neuropeptide research, and our discovery of their role in fear processing is just the beginning.”
To process and react to things in our environment, information must flow through our bodies and brains. These signals are sent and received by neurons, which form organized circuits that guide the information where it needs to go. Neurons communicate with each other by sending and receiving molecules like neurotransmitters and neuropeptides.
Neuropeptides are generally considered neuromodulators that assist and modulate the action of major neurotransmitters. However, pioneers such as Roger Guillemin have suggested that neuropeptides may themselves act as major transmitters.
This concept has not been rigorously tested due to the lack of tools to visualize and manipulate their release in active animals. The Salk team set out to explore neuropeptides with the goal of developing new tools to better understand their role in brain circuits.
To specifically target neuropeptides, Han’s team took advantage of one of their unique characteristics: While neurotransmitters are packaged in small spheres called synaptic vesiclesNeuropeptides are packaged in large dense core vesiclesBy designing biochemical tools to target these large vesicles, they created a neuropeptide sensor And silent tools.
THE sensor Large dense-core vesicle markers contain proteins that glow when released from the nerve ending, allowing researchers to observe the release of neuropeptides in real time. silent specifically degrades neuropeptides in large, dense-core vesicles, revealing what happens in the brain when neuropeptides are absent.
“We have created a new method to track the movement and function of neuropeptides in the brains of living animals,” says Dong-Il Kim, first author of the study and a postdoctoral researcher in Han’s lab.
“These tools will help us better understand the brain’s neuropeptide circuits and allow neuroscientists to explore questions that were previously difficult to answer.”
Using their newly developed neuropeptide sensor and silencer, as well as existing sensor and silencer tools for glutamate (the most abundant neurotransmitter in the brain), the researchers studied how neuropeptides and glutamate behaved in living mice when they experienced a mild stimulus, just enough to stimulate the fear circuit.
They found that neuropeptides, but not glutamate, were released during the stimulus. Furthermore, suppressing neuropeptide release reduced fear behaviors in the mice, but suppressing glutamate had no effect.
To Han’s surprise and delight, this brainstem fear circuit relied on neuropeptides as the primary messenger molecules rather than glutamate. Moreover, their findings support their ongoing study of PACAP, a neuropeptide that modulates panic disorder.
“These new tools and findings are an important step toward better neurological drug development,” Han says. “We found that multiple neuropeptides are bundled into a single vesicle and released all at once by a painful stimulus to work in this fear circuit, which got us thinking, ‘This This may be why some drugs that target a single neuropeptide fail in clinical trials.
“With this new information, we can provide insights into developing new drugs that target multiple neuropeptide receptors at once, which could serve as more effective painkillers or help treat fear-related disorders such as post-traumatic stress disorder.”
Armed with their new neuropeptide toolkit, the team will soon begin exploring other brain circuits and processes. Future insights into neuropeptide signaling in other brain areas, as well as the new understanding that it is necessary to target multiple neuropeptides at once, should inspire 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 Salk; 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: The work was supported by the National Institutes of Health (NIMH 5R01MH116203, NINDS 1RF1NS128680) and a Salk Institute Innovation Grant.
About this news on fear and neuroscience research
Author: Salk Comm
Source: Salk Institute
Contact: Salk Comm – Salk Institute
Picture: Image credited to Neuroscience News
Original research: Access closed.
“Presynaptic sensor and silencing of peptidergic transmission reveal neuropeptides as the major transmitters in the pontine fear circuit” by Sung Han et al. Cell
Abstract
A presynaptic sensor and a silencer of peptidergic transmission reveal that neuropeptides are the main transmitters in the pontine fear circuit
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Summary
Neurons produce and release neuropeptides to communicate with each other. Despite their importance in brain function, circuit-based peptidergic transmission mechanisms are poorly understood, mainly due to the lack of tools to monitor and manipulate neuropeptide release in vivo.
Here we report the development of two genetically encoded tools to study peptidergic transmission in active mice: a genetically encoded large dense-core vesicle (LDCV) sensor that detects presynaptic neuropeptide release and a genetically encoded silencer that specifically degrades neuropeptides inside LDCVs.
Using these tools, we show that it is neuropeptides, not glutamate, that encode the unconditioned stimulus in the parabrachial-amygdalar threat pathway during Pavlovian threat learning.
We also show that neuropeptides play an important role in the coding of positive valence and suppression of the conditioned response to threat in the endogenous amygdala-parabrachial opioidergic circuit.
These results show that our sensor and silencer for presynaptic peptidergic transmission are reliable tools for studying neuropeptidergic systems in awake and active animals.
