Scientists finally figured out what drives our sixth sense

Sight, hearing, smell, taste, touch: we are all familiar with the five senses that allow us to perceive our surroundings. (CREDIT: Creative Commons)

We rely on specialized sensory neurons in our muscles and joints to perform coordinated movements. Without them, the brain would not know what the rest of our body is doing. A team led by Niccolò Zampieri studied their molecular markers to better understand how they work, and have described the results in Connection with nature.

Sight, hearing, smell, taste, touch: we are all familiar with the five senses that allow us to perceive our surroundings.

Equally important, but far less well-known, is the sixth sense: “Its job is to collect information from the muscles and joints about our movements, our posture and our position in space, and then transmit it to our central nervous system” – says the doctor. Niccolo Zampieri, head of the Neural Circuit Development and Functioning Laboratory at the Max Delbrück Center in Berlin.

“This sense, known as proprioception, allows the central nervous system to send the right signals through motor neurons to the muscles so that we can perform a specific movement.”

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This is the sixth sense, which, unlike the other five, completely unconsciously, keeps us from falling in the dark and allows us to bring a cup of coffee to our mouth in the morning with our eyes closed. But that’s not all: “People without proprioception can’t perform coordinated movements,” says Zampieri.

He and his team published a paper in the journal Nature Communications describing the molecular markers of the cells involved in this sixth sense. The findings should help researchers better understand how proprioceptive sensory neurons (pSNs) work.

Accurate connections are critical

The pSN cell bodies are located in the ganglia of the posterior roots of the spinal cord. They are connected by long nerve fibers to muscle spindles and Golgi tendon organs, which constantly register stretch and tension in every muscle of the body. The PSN sends this information to the central nervous system, where it is used to control the activity of motor neurons so that we can make movements.

Different populations of sensory neuron bodies in the dorsal root ganglia (right) and their axons in the spinal cord (left): cells highlighted in green detect proprioceptive information, while cells highlighted in red detect thermal and tactile information. (IMPLIED: Stefan Dietrich, Zampieri Lab, Max Delbrück Center)

“One of the prerequisites for this is the exact connection of pSN to the various muscles in our body,” says Dr. Stefan Dietrich, a member of the Zampieri laboratory. However, almost nothing was known about the molecular programs that provide these precise connections and give muscle-specific pSNs their unique identity. “That’s why we used our study to look for molecular markers that differentiate pSN for abdominal, back, and limb muscles in mice,” says Dietrich, lead author of the study, which was conducted at the Max Delbrück Center.

A Guide to Nascent Nerve Fibers

Using single cell sequencing, the team investigated which genes in the pSN of abdominal, back, and leg muscles are read and translated into RNA. “And we found characteristic genes for pSN associated with each muscle group,” says Dietrich. “We also showed that these genes are already active in the embryonic stage and remain active for at least some time after birth.” Dietrich explains that this means that there are fixed genetic programs that decide whether the proprioceptor will innervate the muscles of the abdomen, back, or limbs.

Scheme illustrating the central and peripheral connection of e15.5 proprioceptors at the thoracic (left) and lumbar (right) levels of the spine. (CREDIT: Nature Communications)

Among their findings, the Berlin researchers identified several genes for ephrins and their receptors. “We know that these proteins are involved in directing nascent nerve fibers to a target during the development of the nervous system,” says Dietrich. The team found that the connections between proprioreceptors and hindlimb muscles were disrupted in mice that cannot produce ephrin-A5.

One goal – the best neuroprostheses

“The markers we have identified should now help us further study the development and function of individual muscle-specific sensory networks,” says Dietrich. “For example, with the help of optogenetics, we can use light to turn proprioreceptors on and off individually or in groups. This will allow us to reveal their specific role in our sixth sense,” adds Zampieri.

Representative image of tdTomato+ afferents in the lumbar spinal cord from p7 Trpv1Cre; pvflip; Mice AI65. MMC, median motor column; LMC, side motor column. Scale bar: 100 µm. (CREDIT: Nature Communications)

This knowledge should ultimately benefit patients with spinal cord injuries, for example. “Once we better understand the details of proprioception, we can optimize the design of neuroprostheses that take over the motor or sensory abilities that are impaired by trauma,” says Zampieri.

Altered muscle tension causes spinal curvature

He adds that researchers in Israel recently discovered that properly functioning proprioception is also important for a healthy skeleton. For example, scoliosis is a condition that sometimes develops during adolescence in childhood and results in curvature and curvature of the spine.

The identity of the muscle type of proprioreceptors is manifested in the early stages of development. (CREDIT: Nature Communications)

“We suspect this is due to proprioceptive dysfunction, which alters the tension in the back muscles and deforms the spine,” says Zampieri.

Hip dysplasia, an abnormality of the hip joint, can also be caused by impaired proprioception. This led Zampieri to another result of the study: “If we can better understand our sixth sense, it will be possible to develop new treatments that effectively counteract these and other types of skeletal damage.”

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Note. Materials provided above Max Delbrück Center for Molecular Medicine. Content can be edited for style and length.

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