Touch — the first sense to develop in the womb — is fundamental to our bodily experience and our everyday lives. Yet, as the least studied of the five senses, it remains somewhat mysterious at the molecular level. And the stakes are high: one in three people living in the United States will experience chronic pain due to somatosensory dysfunctions during their lives. Furthermore, the existing treatment options often fail to provide sufficient relief.

HHMI Hanna Gray Fellow Shan Meltzer's research is driven by this need. Her lab at Vanderbilt Universityexternal link, opens in a new tab is dedicated to increasing understanding of touch and pain circuits, which could bolster the development of new treatment options. Their latest project, a cell-by-cell map of the spinal cordexternal link, opens in a new tab, offers new insights into how the spine reflects — and sometimes is impacted in — neuropathic pain.

The Spine in the Spotlight

The spinal cord is the first processing hub for all somatosensory information, including pain, itch, touch, and proprioception (the body’s ability to sense its own movements). Because of its importance, other studies have already uncovered which cell types comprise the spine, as well as the genes that can define them. But how they connect and physically relate to one another was less clear.

The spinal cord has four different levels: cervical, thoracic, lumbar, and sacral. The lumbar segment contains a larger proportion of gray matter tissue — the densely packed region of neuron cell bodies and synaptic connections where most signal processing occurs — than other regions. Because gray matter is where sensory information is integrated and relayed, having more of it provides more cells to analyze, which is one reason that previous studies have focused exclusively on the lumbar level. But Meltzer wanted to analyze cells on the other levels, too.

Turning a List into a Map

Meltzer and her lab developed a custom, 500-gene panel tailored to the mouse spinal cord and applied MERFISH, an imaging-based transcriptomics technique that allows researchers to see which genes are active while preserving each cell’s exact location within tissue.

“A decade ago, these spatial transcriptomic technologies didn’t exist,” Meltzer explains. “Recent groundbreaking transcriptomics tools that can retain the spatial location of cells within tissues made this whole project possible.”

Using this approach, her lab — in collaboration with HHMI Investigator David Ginty — identified individual RNA molecules that helped distinguish different populations of spinal cells. Armed with this new spatial organization of the spinal cord, Meltzer and her lab compared the spinal cords of adult male and female mice. They also compared mice with neuropathic pain — pain stemming from the nervous system — and those without.

A Trio of Unexpected Findings

Three distinct threads emerged from the map, each leading to a new potential avenue of research.

First, they observed that the distribution of different types of cells is not homogenous: it changes across the length of the spine, and certain cells play region-specific roles in sensation and movement. For example, cervical segments process primarily input from the arms, whereas sacral segments regulate pelvic organs. With that in mind, treatments for neuropathic pain or spinal cord injury may need to be tailored to the affected spinal level.

Another surprise: male mice had many more motor neurons compared to females — but only on the lumbar level. This suggests that sex differences in processing pain might be region-specific within the spinal cord.

Finally, in mice with neuropathic pain, Meltzer found a reduction in the expression of molecules key to cell communication in multiple neuron subtypes in the dorsal horn, suggesting that cell-cell communication signals were broadly diminished. In short, neuropathic pain doesn’t seem to come from one or two affected cell types; it may be that the entire spinal circuit is rewired or rebalanced.

A New Platform for Neuropathic Discovery

Rather than keeping the dataset within her own lab, Meltzer is planning to make the spinal cord atlas openly available, along with an interactive website that allows researchers to explore it themselves. Scientists will be able to search for specific cell types, find where they sit within the cord, and investigate predicted signaling relationships between them.

“We really see this as a resource for the somatosensorial field,” Meltzer says. “Our goal was not only to define the organization of the spinal cord, but to give other researchers a framework they can use and explore to build new hypotheses.”

By opening the map to the scientific community, she hopes to support additional discoveries about how spinal circuits work — and how they break down in neuropathic pain.