Scientists discover how our sixth sense really works

Your body constantly tracks where its muscles and limbs are, even with your eyes closed. That quiet sense, called proprioception, depends on nerve cells that must connect to exactly the right muscles, and scientists are beginning to uncover how that wiring is built.

Proprioception helps the nervous system monitor movement, posture and body position. Specialized sensory neurons carry information from structures in muscles and tendons to the spinal cord and brain, allowing motor circuits to adjust muscle activity.

A team led by Niccolò Zampieri at the Max Delbrück Center in Berlin examined how these proprioceptive sensory neurons develop distinct identities. The work focused on the molecular programs that help neurons connect with back, abdominal and hindlimb muscles.

“Its job is to collect information from the muscles and joints about our movements, posture, and position in space, and then pass that on to our central nervous system,” Zampieri said.

Proprioceptive neurons sit in clusters called dorsal root ganglia beside the spinal cord. Their nerve fibers connect to muscle spindles, which detect stretch, and Golgi tendon organs, which detect tension.

“These neurons form highly specific connections with different muscle groups,” said Dr. Stephan Dietrich, a researcher in Zampieri’s lab.

The team used single-cell RNA sequencing to examine gene activity in individual mouse neurons. At embryonic day 15.5, they isolated 960 cells from thoracic and lumbar dorsal root ganglia. Of those, 519 passed quality-control checks.

The researchers identified seven proprioceptor clusters after separating out other sensory cells. Several clusters came mainly from lumbar regions, where neurons serving hindlimb and some lower-back muscles are located. Others came mainly from thoracic regions, where neurons connected to back and abdominal muscles are concentrated.

One unexpected marker was Trpv1, a gene better known for pain and temperature sensing. About 5 percent of proprioceptors expressed it at this embryonic stage.

Follow-up experiments showed that embryonic Trpv1 expression marked a subset of proprioceptors that selectively innervated back muscles. Their central fibers targeted motor neurons associated with back and lower-back or tail muscles, while showing little, if any, input to limb-projecting motor neurons.

The group next compared neurons connected to back, abdominal and hindlimb muscles and identified distinct molecular signatures for each group.

Tox was strongly associated with back-innervating proprioceptors. C1ql2 marked a population linked to abdominal muscles, while Gabrg1 was associated with hindlimb-projecting neurons.

At thoracic levels, Tox appeared in about 60 percent of labeled proprioceptors and C1ql2 in about 28 percent. At lumbar levels 3 and 4, Gabrg1 appeared in about 46 percent, while Tox appeared in roughly 10 percent.

No single marker captured all hindlimb-projecting neurons. Gabrg1 and another gene, Efna5, together accounted for about 75 percent of labeled proprioceptive neurons in lumbar dorsal root ganglia. The authors note that this likely reflects the greater anatomical complexity of the limb. The mouse hindlimb contains 39 different muscles.

The researchers then traced neurons directly from individual muscles. Proprioceptors connected to the erector spinae back muscle largely expressed Tox, while those traced from the gastrocnemius and tibialis anterior hindlimb muscles expressed Gabrg1.

Crucially, these muscle-related genetic identities were already present during embryonic development. The patterns appeared by embryonic day 15.5, before the molecular identities of the three main proprioceptor receptor classes, Ia, Ib and II, had fully emerged.

That timing suggests muscle identity is established early, then combined with receptor-specific characteristics later.

Among the strongest molecular differences were genes from the ephrin-A and EphA families, which are involved in guiding growing nerve fibers.

Efna5, which encodes ephrin-A5, was associated with hindlimb-projecting proprioceptors. Epha3 showed the opposite pattern and appeared in proprioceptors connected to the erector spinae back muscle. Other EphA receptors also differed among the neuron groups.

To test whether ephrin-A5 actually affects wiring, the researchers studied mice lacking the protein. They injected a tracer into hindlimb muscles and counted labeled proprioceptors.

The most striking change occurred in the tibialis anterior. Mice without ephrin-A5 had a significant increase in proprioceptors labeled from that muscle compared with controls. The statistical result was p = 0.007308.

The gastrocnemius showed a similar trend, but the difference was not statistically significant, with p = 0.12. Motor neuron connectivity did not show a significant change.

The results indicate that removing ephrin-A5 reduces the precision of sensory connections to hindlimb muscles. The researchers suggest some axons may have been redirected from other muscle targets, although they could not determine where those axons were originally supposed to go.

That uncertainty is important. The study does not yet provide a complete molecular map for every proprioceptor, and the relatively small dataset makes some finer neuron clusters difficult to interpret.

The findings give scientists molecular handles for separating proprioceptors by the muscles they serve. That could support genetic or viral tools targeting distinct sensory channels.

Such tools could help researchers answer a basic unresolved question: how signals from different muscles combine with motor commands and other sensory information to produce coordinated movement and a stable sense of body position.

The work also provides a developmental framework. Muscle-specific identity appears before receptor identity fully matures, suggesting proprioceptor development happens in stages rather than through one final genetic program.

Zampieri has also linked faulty proprioceptive feedback to skeletal problems such as scoliosis, though this study does not establish a treatment. “We suspect that dysfunctional proprioception distorts muscle tension in the back, leading to spinal deformities,” he said.

“If we can better understand our sixth sense, we could develop therapies to counteract these and other types of skeletal damage,” Zampieri said.

For now, the clearest advance is a map of molecular differences that helps explain how the nervous system gives sensory neurons the right destination. The next challenge is resolving that map muscle by muscle and testing how each sensory channel shapes movement.

Research findings are available online in the journal Nature Communications.

The original story "Scientists discover how our sixth sense really works" is published in The Brighter Side of News.

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