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Understanding Neuronal Diversity in the Spinal Cord

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Cross-section image of spinal cord showing glowing green and magenta neurons.
Credit: Salk Institute, La Jolla, CA

The spinal cord, as a key part of our body’s central nervous system, contains millions of neurons that actively convey sensory and motor (movement) information to and from the brain. Scientists have long sorted these spinal neurons into what they call “cardinal” classes, a classification system based primarily on the developmental origin of each nerve cell. Now, by taking advantage of the power of single-cell genetic analysis, they’re finding that spinal neurons are more diverse than once thought.

This image helps to visualize the story. Each dot represents the nucleus of a spinal neuron in a mouse; humans have a very similar arrangement. Most of these neurons are involved in the regulation of motor control, but they also differ in important ways. Some are involved in local connections (green), such as those that signal outward to a limb and prompt us to pull away reflexively when we touch painful stimuli, such as a hot frying pan. Others are involved in long-range connections (magenta), relaying commands across spinal segments and even upward to the brain. These enable us, for example, to swing our arms while running to help maintain balance.

It turns out that these two types of spinal neurons also have distinctive genetic signatures. That’s why researchers could label them here in different colors and tell them apart. Being able to distinguish more precisely among spinal neurons will prove useful in identifying precisely which ones are affected by a spinal cord injury or neurodegenerative disease, key information in learning to engineer new tissue to heal the damage.

This image comes from a study, published recently in the journal Science, conducted by an NIH-supported team led by Samuel Pfaff, Salk Institute for Biological Studies, La Jolla, CA. Pfaff and his colleagues, including Peter Osseward and Marito Hayashi, realized that the various classes and subtypes of neurons in our spines arose over the course of evolutionary time. They reasoned that the most-primitive original neurons would have gradually evolved subtypes with more specialized and diverse capabilities. They thought they could infer this evolutionary history by looking for conserved and then distinct, specialized gene-expression signatures in the different neural subtypes.

The researchers turned to single-cell RNA sequencing technologies to look for important similarities and differences in the genes expressed in nearly 7,000 mouse spinal neurons. They then used this vast collection of genomic data to group the neurons into closely related clusters, in much the same way that scientists might group related organisms into an evolutionary family tree based on careful study of their DNA.

The first major gene expression pattern they saw divided the spinal neurons into two types: sensory-related and motor-related. This suggested to them that one of the first steps in spinal cord evolution may have been a division of labor of spinal neurons into those two fundamentally important roles.

Further analyses divided the sensory-related neurons into excitatory neurons, which make neurons more likely to fire; and inhibitory neurons, which dampen neural firing. Then, the researchers zoomed in on motor-related neurons and found something unexpected. They discovered the cells fell into two distinct molecular groups based on whether they had long-range or short-range connections in the body. Researches were even more surprised when further study showed that those distinct connectivity signatures were shared across cardinal classes.

All of this means that, while previously scientists had to use many different genetic tags to narrow in on a particular type of neuron, they can now do it with just two: a previously known tag for cardinal class and the newly discovered genetic tag for long-range vs. short-range connections.

Not only is this newfound ability a great boon to basic neuroscientists, it also could prove useful for translational and clinical researchers trying to determine which specific neurons are affected by a spinal injury or disease. Eventually, it may even point the way to strategies for regrowing just the right set of neurons to repair serious neurologic problems. It’s a vivid reminder that fundamental discoveries, such as this one, often can lead to unexpected and important breakthroughs with potential to make a real difference in people’s lives.


[1] Conserved genetic signatures parcellate cardinal spinal neuron classes into local and projection subsets. Osseward PJ 2nd, Amin ND, Moore JD, Temple BA, Barriga BK, Bachmann LC, Beltran F Jr, Gullo M, Clark RC, Driscoll SP, Pfaff SL, Hayashi M. Science. 2021 Apr 23;372(6540):385-393.


What Are the Parts of the Nervous System? (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)

Spinal Cord Injury (National Institute of Neurological Disorders and Stroke/NIH)

Samuel Pfaff (Salk Institute, La Jolla, CA)

NIH Support: National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Eunice Kennedy Shriver National Institute of Child Health and Human Development


  • MBA says:

    As a data science student, I am thinking that there are too much similerities with hidden layers. Which performs like a spinal cord. Very nice explanation. Thank you for sharing.

  • Judith T. says:

    What are the best therapies for cancer of the spinal nerves affecting digestion?

  • Andrew Goldstein says:

    “…fundamental discoveries…often can lead to unexpected and important breakthroughs with potential to make a real difference in people’s lives.”
    That statement is one of the most fundamental principles in science, serendipity.

  • Barend Slootweg says:

    “The researchers turned to single-cell RNA sequencing technologies to look for important similarities and differences in the genes expressed in nearly 7,000 MOUSE spinal neurons.”

    Please explain why mice instead of humans?

  • Leonard Friedand says:

    Your blogs are insightful, informative and fascinating. Thank you for sharing in this concise and thought-provoking way the inspiring transformative work of the NIH scientists, and for connecting the science to the patient.

  • Hilton T. Meadows says:

    I was entering a reasonably long commentary which was suddenly wiped out when it appeared that I might be challenging an interpretation of Your use of the terms “evolution” and “evolved”. I would like to know if You refer to naturally occurring mutations and aberrations or otherwise? I have a better than fair background in grad school genetics and realize the effects of mutations and aberrations. I am, however, an unshakeable believer in “Creation” of an anthropomorphic man and other living creatures.

  • Spinoza says:

    The aspect of mosaicism in human development is rather interesting. When SNPs can have huge differences in phenotype, one ponders about the aspects of post translational modifications and epigenetics. In fact the human body is quite a mosaic given the symbiosis of a variety of bacteria and virus that can effect the local micro-environment.
    How well protected is the central nervous system by the blood brain barrier?

  • Qian Wan says:

    I am so interested in the combination of biological knowledge and computer techniques. Now, I am still enduring the challenging and painful study of bioinformatics (particularly data processing of single cell dropseq sequencing). This commentary surely inspired me to stick with it and keep studying. Thanks very much.

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