Amazing stuff!
"... This process of translating pain into a threat memory occurs so quickly that scientists thought it must be mediated by fast-acting neurotransmitters. But when ... researchers investigated the role of larger, slower-acting molecules called neuropeptides, they discovered these were the primary messengers in this fear circuit. ...
The new study ... revealed that the danger circuit relies on neuropeptides as its primary messengers, not fast neurotransmitters, and 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 conditions like anxiety and PTSD (post-traumatic stress disorder). ...
Neuropeptides are generally accepted as neuromodulators that help and modulate the action of main neurotransmitters. However, early pioneers like Roger Guillemin proposed that neuropeptides can act as main transmitters themselves. This concept has not been rigorously tested due to the lack of tools for visualizing and manipulating their release in behaving 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, ... 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. ..."
From the highlights and abstract:
"Highlights
• CybSEP2 is a genetically encoded LDCV sensor for presynaptic neuropeptide release
• NEPLDCV is a genetically encoded silencer for peptidergic transmission
• Neuropeptides, not glutamate, are primary transmitters in the CGRPPBel→CeA US circuit
• Multiple neuropeptides, not CGRP alone, are required for CGRPPBel→CeA pain transmission
Summary
Neurons produce and release neuropeptides to communicate with one another. Despite their importance in brain function, circuit-based mechanisms of peptidergic transmission are poorly understood, primarily due to the lack of tools for monitoring and manipulating neuropeptide release in vivo. Here, we report the development of two genetically encoded tools for investigating peptidergic 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 inside LDCVs. Using these tools, we show that neuropeptides, not glutamate, encode the unconditioned stimulus in the parabrachial-to-amygdalar threat pathway during Pavlovian threat learning. We also show that neuropeptides play important roles in encoding positive valence and suppressing conditioned threat response in the amygdala-to-parabrachial endogenous opioidergic circuit. These results show that our sensor and silencer for presynaptic peptidergic transmission are reliable tools to investigate neuropeptidergic systems in awake, behaving animals."
Presynaptic sensor and silencer of peptidergic transmission reveal neuropeptides as primary transmitters in pontine fear circuit (no public access)
Graphical abstract
Two images of nerve endings in the amygdala (where fear signals are received and interpreted). On the left, there are no labels and two distinct vesicles in the nerve endings can be seen. On the right, neuropeptide sensors are labeled in dark color, and they can be seen inside large dense core vesicles.
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