Quanta Magazine

Quanta Magazine

While neuroscientists have learned about these aspects of PNNs over the past few decades, the influence of PNNs on chronic pain was an unexpected recent discovery. This work, which further extends the nets’ influence beyond critical periods, not only improves our understanding of the basic science of pain, but also gives us a better picture of PNNs themselves.

Chronic pain, which persists long after an injury, reflects a change in neuronal circuitry that can be difficult to overcome. When something hurts, our whole body gets involved. Specialized pain neurons throughout the body transmit neural impulses into the spinal cord, where they are relayed to the brain. This means the spinal cord plays a major role in our sense of pain; indeed, doctors often manage the pain of childbirth by administering an epidural, which involves injecting anesthetics into the space surrounding the lumbar spinal cord, blocking neural impulses from reaching the brain.

Now imagine if instead of suppressing neural transmission at this point, a nerve injury made those neurons hypersensitive. Even a gentle touch in the affected area would cause a barrage of neuronal impulses to travel up the spinal cord, registering as intense pain. Previous research identified several mechanisms that can cause such hypersensitization, but no one expected PNNs to be involved.

A few years ago, however, Khoutorsky saw a paper reporting that PNNs were coating certain small neurons in a brain region where pain information is transmitted. These “inhibitory interneurons” form synapses on the pain neurons, suppressing their ability to transmit pain signals. Khoutorsky wondered if PNNs might be doing something similar at the critical pain relay point inside the spinal cord, and he asked his graduate student Shannon Tansley to look into it. “At that time nothing was known,” Khoutorsky said.

Tansley did indeed find that PNNs were encasing certain neurons in the spinal cord where it relays pain signals to the brain. The neurons have long axons (the “tail” that sends signals to the next cell in line) that point up the spinal cord to the brain. They also have a set of inhibitory interneurons attached to them through small holes in the PNN, and the inhibitory neurons can squelch the firing of the long projecting neurons, shrinking the signal reaching the brain and blunting the sensation of pain. Tansley discovered, to her surprise, that only these inhibitory neurons in the spinal cord relay point were coated with PNNs.

This finding inspired Khoutorsky’s team to undertake experiments on laboratory mice to determine if these nets were somehow involved in chronic pain after a peripheral nerve injury. They cut branches of a mouse’s hind leg nerve, known as the sciatic, while it was under general anesthesia. This mimics sciatic injuries in people, which are known to cause persistent pain. Days later, Khoutorsky’s team measured the mouse’s pain threshold with non-harmful tests, such as timing how quickly it recoiled from a warmed surface. As expected, the team saw the mouse display sharply increased pain sensitivity — but they also noticed that the PNNs around the projecting neurons had dissolved. Just as the brain’s changes during critical periods affects PNNs, the abrupt changes after nerve injury in the mouse had modified the PNNs in its spinal cord’s pain circuit.

The team then figured out what was causing the nets’ destruction: microglia, the brain and spinal cord cells that initiate repairs after disease and injury. To test the connection between microglia and pain, the team turned to mice with virtually no microglia (made possible with genetic engineering) and performed the same operation. In these mice, the PNNs remained intact after the sciatic nerve surgery and, remarkably, the mice did not become hypersensitive to painful stimuli. To confirm the connection, the team used various means to dissolve the nets, which raised the mice’s sensitivity to pain.

This proved that the PNNs were directly suppressing pain sensitivity. By measuring synaptic transmission with electrodes, Khoutorsky’s team even found out how it works. Degrading the PNNs caused a chain reaction that resulted in increased signaling from the projecting neurons that send pain signals to the brain: When the microglia responding to the nerve injury dissolved the PNNs, this weakened the influence of the inhibitory neurons that normally dampen the firing of the brain-projection neurons. Losing their inhibitory brakes meant runaway neural firing and intense pain.

Microglia release many substances that cause pain neurons to become hypersensitive after nerve injury, but their unexpected action on PNNs has a major advantage: specificity. “Usually what perineuronal nets do is they lock plasticity, and they also protect cells,” Khoutorsky said. “So why are these nets only around these pain relay neurons, and not around other cell types [nearby]?” He suspects that it’s because this pain relay point in the spinal cord is so important that these neurons and their connections need extra protection so that their control of pain transmission is strong and reliable. Only something as dramatic as a neural injury can disrupt that stability.

“The beauty of this mechanism is that it is selective for specific cell types,” Khoutorsky said. The substances microglia release to increase neural firing and cause pain after neural injury affect all types of cells in the vicinity, but the PNNs encase only these neurons precisely at the critical relay point in the spinal cord.

Research is underway to better understand this new mechanism of chronic pain. If researchers can develop methods to rebuild PNNs on these neurons after injury, it could provide a new treatment for chronic pain — an urgent need, considering that opiates, the current solution, lose their potency over time and can become addictive or result in a fatal overdose.

What goes on inside neurons is fascinating and important to understand, but neural networks are formed by individual neurons linked together, and here it is the neglected cartilaginous cement in the space between them that is vital.

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