In the split second when you accidentally touch the hot handle of a cast-iron skillet, pain and a sense of danger rush in. Sensory signals travel from the pain receptors in your finger, up through the spinal cord in your spine to your brain.
Once there, a special group of neurons relays these pain signals to a higher area of the brain called the amygdala, where it triggers your emotional fear response and helps you remember to avoid hot pans in the future.
The process of translating pain into a threat memory occurs so quickly that scientists thought it must be mediated by fast-acting molecules called neurotransmitters.
But a new study by researchers from the Salk Institute in the United States has found that larger, slower-acting molecules called neuropeptides are the key messages in this fear circuit.
Neuropeptides are known to play an important role in brain communication, but the details have been unclear because scientists haven’t had the right tools to study them.
Peptides
To determine the role of neuropeptides in this circuit, the Salk team has developed two new tools that finally allow scientists to monitor and manipulate the release of neuropeptides in the brains of living mice.
The new study, published in the journal Cell on July 22 and written about by EurekAlert, revealed that the danger circle relies on neuropeptides, not neurotransmitters, as its primary messengers, and more than one neuropeptide is involved in this process.
The researchers’ findings could lead to the development of more effective painkillers or new treatments for fear-related conditions such as anxiety and post-traumatic stress disorder.
“There is much more to discover about neuropeptides,” says co-author Professor Song Han.
To process and interact with things in our environment, information must travel through our body and brain. These signals are sent and received by neurons, which form organized circuits that direct information where it needs to go. Neurons communicate with each other by sending and receiving molecules such as neurotransmitters and neuropeptides.
To specifically target neuropeptides, Han’s team took advantage of one of their unique properties: While neurotransmitters are packed into small domains called synaptic vesicles, neuropeptides are packed into large, dense core vesicles.
By engineering biochemical tools to target these large vesicles, they created neuropeptide sensors. The sensor tags the large, dense core vesicles with proteins that glow when they are released from the nerve terminal, allowing the researchers to watch the neuropeptide release in real time.
“We have created a new way to track neuropeptide movement and function in the brains of living animals,” says researcher Dong-Il Kim. “Neuropeptide circuits enable neuroscientists to explore questions that were previously difficult to address.”
Better drug development
“These new tools and discoveries represent an important step toward better development of neurological drugs,” says Han.
“We found that multiple neuropeptides are bundled together in a single vesicle and released at once by a painful stimulus to act in this fear circuit, which made us think: This might be why some drugs that target just one neuropeptide fail in clinical trials,” he added.
With this new information, we can provide insights into developing new drugs that target multiple neuropeptide receptors simultaneously, which may serve as better pain relievers or help treat fear-related disorders such as PTSD.